• 18 years of age or older.
• Plan to initiate treatment with either bi-specific antibody or CAR-T therapy either as standard of care or through clinical trial.
• Capacity to understand the protocol and its requirements, risks, and discomforts.
• Capacity and willingness to sign informed consent.

• Pregnancy or lactation (for females).
• Inability on the of the part of the patient to understand the informed consent or be compliant with the protocol.
• Any condition, which in the opinion of the patient's treating physician, or the provider performing the biopsy procedure, would make participation in this protocol unreasonably hazardous for the patient (including a history of a serious or life-threatening allergic reaction to such local ansesthetics as lidocaine or xylocaine).

1. Hypertension, defined as a mean supine blood pressure greater than 140/90 mmHg and taking at least one (1) standard of care therapies (including a diuretic, angiotensin converting enzyme inhibitor or angiotensin receptor blocker and a calcium channel blocker)
2. MDRD estimated GFR > 30 mL/min to be calculated at the screening visit by available serum creatinine
3. Male or female African Americans
4. Between the ages of 20 and 70 years
5. Have a body mass index (BMI) within the range of 18–40 kg/m2
6. Be able to communicate effectively with the study personnel
7. Be adequately informed of the nature and risks of the study and give written informed consent prior to receiving study medication

1. Known hypersensitivity or allergy to MANP or other natriuretic peptides
2. Women of child bearing age
3. Having received any investigational drug or device within 30 days prior to entry into the study; 4) A history (within the last 2 years) of alcohol abuse, illicit drug use, significant mental illness, physical dependence to any opioid, or any history of drug abuse or addiction
4. A history of difficulty with donating blood or donated blood or blood products within 45 days prior to enrollment
5. Clinically significant new illness in the 1 month before screening in the opinion of the investigator
6. History of severe allergies
7. History of coronary artery disease, cerebrovascular disease, or syncope
8. History of epilepsy or other seizure disorder
9. History of organ transplantation
10. Malignancy within 5 years
11. Clinically significant intrinsic renal disease, renal artery stenosis, or history of fibromuscular dysplasia of the renal arteries and
12. Consumption of a phosphodiesterase-5 inhibitor

• Participants in Parts A and C must have histologically or cytologically confirmed recurrent or persistent uterine serous carcinoma. For the purposes of this study, uterine carcinomas (with the exception of carcinosarcomas) that have any component that is considered serous will be considered a uterine serous carcinoma.
• Participants in Part B must have histologically or cytologically confirmed recurrent uterine carcinosarcoma. Additionally, the following features must also be present:
  • Presence of a p53 alteration (by either IHC or next generation sequencing);
  • Metastatic or extra-uterine component must be confirmed on pathology to be from the carcinoma component of the disease;
  • Patients without confirmation that the metastatic or extrauterine component of disease is of carcinoma histology may be considered after discussion with the PI;
  • Participants must have measurable disease, defined as at least one lesion that can be accurately measured per RECIST 1.1 criteria.
  • Participants must have had one prior platinum-based chemotherapy regimen for management of advanced or metastatic uterine serous carcinoma or uterine carcinosarcoma. Chemotherapy administered only in conjunction with primary RT as a radiosensitizer should not count as a systemic regimen. There is no restriction on the number of prior lines of therapy a participant may have previously received.
• Age 18 years or older.
• ECOG performance status 0 or 1.
• Participants must have normal organ and marrow function as defined below:
  • absolute neutrophil count ≥ 1,500/mcL;
  • hemoglobin ≥ 9 g/dL;
  • platelets ≥ 100,000/mcL;
  • total bilirubin ≤ upper limit of normal (ULN) or ≤ 1.5 x ULN in patients with liver metastases or well-documented Gilbert's Syndrome;
  • AST(SGOT)/ALT(SGPT) ≤ 3 × ULN or ≤ 5 × ULN in patients with liver metastases;
  • creatinine ≤ 1.5 × ULN; OR
  • creatinine clearance ≥ 45 mL/min/1.73 m^2 as calculated by the Cockroft-Gault method for participants with creatinine levels above institutional normal.
• Willingness to release archival tissue for research purposes.
• Participants in Part C must have biopsiable disease (in a lesion that is not being utilized as the target lesion for RECIST assessment) and be willing to undergo pre- and on-treatment biopsies.
• Participants in Part B with biopsiable disease must be willing to undergo pre- and on-treatment biopsies.
• The effects of AZD1775 on the developing human fetus are unknown. For this reason, women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control abstinence) from 2 weeks prior to study entry and for 1 month after study drug discontinuation.
• Patients of child-bearing potential should not be breastfeeding, and must have a negative serum or urine pregnancy test within 3 days prior to the start of study treatment. Should a woman become pregnant orsuspect she is pregnant while she is participating in this study, she should inform her treating physician immediately.
• Ability to understand and the willingness to sign a written informed consent document.

• Participants who have had chemotherapy, radiotherapy, or investigational therapy within 3 weeks (6 weeks for nitrosoureas or mitomycin C) prior to first dose of AZD1775, or those who have not recovered to Grade 1 from adverse events (excluding alopecia or anorexia) due to agents administered more than 3 weeks earlier. Participants may not have had hormonal therapy within 2 weeks of the first dose of AZD1775. Participants who are receiving any other investigational agents.
• Participants who have MSI-high or MMR-deficient tumors will not be eligible unless they have already received prior therapy with pembrolizumab or another PD1/PD-L1 immune checkpoint inhibitor or are deemed not to be a candidate for immune checkpoint therapy.
• Participants with known brain metastases or other CNS disease should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Participants with treated brain metastases that have no evidence of progression or hemorrhage for at least 2 weeks after treatment will be allowed on study.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to AZD1775.
• Participants may not have had prior receipt of a cell cycle checkpoint inhibitor (e.g., Chek1, Wee1, or ATR inhibition).
• Participants receiving any medications or substances that are sensitive CYP3A4 substrates or are CYP3A4 substrates with a narrow therapeutic index, or which are moderate to strong inhibitors/inducers of CYP3A4 which cannot be discontinued two weeks prior to Day 1 of dosing and withheld through the study until 2 weeks after the last dose of study drug. Co-administration of aprepitant or fosaprepitant during this study is prohibited.
• Transporter studies (in vitro) have shown that AZD1775 is an inhibitor of breast cancer resistance protein (BRCP). 
• Participants must not have undergone major surgical procedures within 28 days of beginning study treatment or minor surgical procedures within 7 days of beginning study treatment. Port-a-cath placement will be allowed within a 7 day window of starting study treatment.
• Participants must be able to swallow oral medication and may not have a percutaneous endoscopic gastrostomy (PEG) tube, be receiving total parenteral nutrition (TPN), or be dependent on IV fluid support. Participants with any of the following cardiac diseases currently or within the last 6 months as defined by the New York Heart Association (NYHA) ≥ Class 2 will not be eligible:
  • Unstable angina pectoris;
  • Congestive heart failure;
  • Acute myocardial infarction;
  • Conduction abnormality not controlled with pacemaker or medication;
  • Significant ventricular or supraventricular arrhythmias (patients with chronic rate-controlled atrial fibrillation in the absence of other cardiac abnormalities are eligible);
  • Participants with a mean resting corrected QT interval (QTc) ≥ 480msec at study entry, as calculated by the Frederica formula (QTcF) by institutional standards obtained from an electrocardiogram (ECG) or congenital long QT syndrome.
    • Note: if one ECG demonstrates a QTcF > 480 msec, then a mean QTcF of ≤ 480 msec obtained from 3 ECGs 2-5 minutes apart is required at study entry.
• Participants with any concomitant or prior invasive malignancies are ineligible with the following exceptions:
  • Treated limited-stage basal cell or squamous cell carcinoma of the skin;
  • Carcinoma in situ of the breast or cervix;
  • Prior cancer treated with curative intent with no evidence of recurrent disease 3 years following diagnosis and judged by the investigator to be at low risk of recurrence;
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
  • Pregnant women are excluded from this study because AZD1775 is an agent with an unknown potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with AZD1775, breastfeeding should be discontinued if the mother is treated with AZD1775.
  • Known HIV-positive participants are ineligible because of the potential for pharmacokinetic interactions of antiretroviral medications with AZD1775 and the potential for an increased risk of lethal infections for these participants when treated with marrow-suppressive therapy.
  • Because the composition, PK, and metabolism of many herbal supplements are unknown, the concurrent use of all herbal supplements is prohibited during the study (including, but not limited to, cannabis, St. John's wort, kava, ephedra [m huang], ginkgo biloba, dehydroepiandrosterone [DHEA], yohimbe, saw palmetto, and ginseng). Participants should stop herbal medications at least 7 days prior to first dose of AZD1775.

Subject must have a documented history of Lennox-Gastaut syndrome by:

• Evidence of more than one type of seizure, of which at least one should be an atonic or tonic seizure.
• History of an electroencephalogram (EEG) reporting diagnostic criteria for LGS (abnormal background activity accompanied by slow, spike and wave pattern <3.0 Hz).
• History of developmental delay.
• Male or female subjects.
• Subjects must be age 4-55 years at the time of consent/assent.
• Must have been < 11 years old at the onset of LGS.
• Subjects must have experienced at least 2 drop seizures with potential to fall (tonic, atonic, tonic-clonic) each week during the 4-week Baseline period preceding randomization. Drop seizures are defined as a seizure involving the entire body, trunk, or head that led or could have led to a fall, injury, slumping in a chair, or hitting the subject's head on a surface. For seizures that occur in clusters: if countable, an exact seizure count should be used; if uncountable, the caregiver should estimate the number of seizures.
• Subjects must have been receiving 1 to 4 concomitant anti-seizure medications (ASMs) at a stable dose for at least 4 weeks before Visit 1.
• If not taking Epidiolex, subjects may take other approved cannabidiol or over the counter cannabidiol products. If taking cannabidiol other than Epidiolex, consult Medical Monitor to determine if it counts as a concomitant ASM.
• Dietary therapy and any CNS stimulator settings must be stable for 4 weeks prior to baseline and maintain stable regimen throughout the study. The dietary therapy and CNS stimulators are not counted as an ASM.
• Parents or caregivers must be able to keep accurate seizure diaries.
• Subject is either not of childbearing potential, defined as premenarchal, postmenopausal for at least 1 year or surgically sterile (bilateral tubal ligation, bilateral oophorectomy, or hysterectomy), if of childbearing potential, must comply with an acceptable method of birth control during the study, for at least 4 weeks prior to study entry and for 4 weeks following completion of the study, if able.
• Subject and/or parent(s)/legal representative must be willing and able to give informed assent/consent for participation in the study.
• Subject and their caregiver must be willing and able (in the investigator's opinion) to comply with all study requirements.
• History of COVID-19 vaccination is permitted.

• Etiology of subject's seizures is a progressive neurologic disease. Subjects with tuberous sclerosis will not be excluded from study participation, unless there is a progressive brain tumor.
• Evidence of clinically significant disease (e.g., cardiac, respiratory, gastrointestinal, renal disease, hepatic disease) that in the opinion of the investigator(s) could affect the subject's safety or study conduct.
• Subjects who were on adrenocorticotropic hormone (ACTH) therapy in the 6 months prior to baseline.
• Subject on dietary therapy for less than 4 weeks prior to screening visit (Visit 1) or suffers from frequent stooling.
• Current use of felbamate with less than 18 months of continuous exposure.
• Concomitant use of vigabatrin: subjects who took vigabatrin in the past must be discontinued for at least 5 months before Visit 1 and must have documentation showing no evidence of a vigabatrin-associated clinically significant abnormality in an automated visual perimetry test, if able.
• Subject who had a history of hypoxia which needed emergency resuscitation within 12 months prior to baseline.
• Status epilepticus within 12 weeks of Visit 1.
• Any clinically significant illness (including COVID-19) in the 4 weeks prior to Visit 1, as determined by the Investigator.
• Subject has clinically significant abnormal laboratory values, in the investigator's opinion, at Visit 1 or time of randomization (Visit 2).
• Subject has a history of any serious drug-induced hypersensitivity; e.g., toxic epidermal necrolysis, or Drug Reaction with Eosinophilia and Systemic Symptoms [DRESS]) or any drug-related rash requiring hospitalization Vagus Nerve Stimulation (VNS), Deep Brain Stimulation (DBS), Responsive Neurostimulator System (RNS) or other neurostimulation for epilepsy device implanted or activated < 5 months year prior to enrollment. Stimulation parameters that have been stable for < 4 weeks, or battery life of unit not anticipated to extend for duration of trial.
• Subject is pregnant, may be pregnant, lactating or planning to be pregnant.
• Any suicidal ideation with intent, with or without a plan within 6 months before Visit 2 (i.e., answering "Yes" to questions 4 or 5 in the Suicidal Ideation section of the age- specific Columbia-Suicide Severity Rating Scale (C-SSRS) in subjects aged 6 and above who are able to be evaluated.
• Any suicidal behavior within 2 years before Visit 2 (i.e., answering YES to any question in the Suicidal behavior section of the age-specific Columbia-Suicide Severity Rating Scale (C-SSRS) in subjects aged 6 and above who are able to be evaluated.
• Evidence of significant active hepatic disease. Stable elevations of liver enzymes (alanine aminotransferase (ALT), and aspartate aminotransferase (AST)) due to concomitant medication(s) will be allowed if they are < 3 x ULN.
• Subject with total bilirubin [TBL] > 2 x ULN (except for Gilbert's syndrome).
• Active viral hepatitis (B or C) as demonstrated by positive serology at the Screening visit (Visit 1).
• History of positive antibody/antigen test for human immunodeficiency virus (HIV).
• If taking Epidiolex, subject may not use other approved cannabidiol or over the counter cannabidiol products.
• Scheduled for epilepsy-related surgery, VNS insertion, or any other stimulators/surgery during the projected course of the study.
• Subject who has taken or used any investigational drug or device in the 4 weeks prior to the screening visit (Visit 1).
• Concomitant use of medications known to be strong inducers of cytochrome P450 (CYP3A) including, but not limited to: phenobarbital, phenytoin, carbamazepine, primidone, rifampin, troglitazone, St. John's Wort, efavirenz, nevirapine, glucocorticoids (other than topical usage), modafinil, pioglitazone, and rifabutin.
• Evidence of cardiac disease, including unstable angina, myocardial infarction, within the past 2 years, uncontrolled heart failure, major arrhythmias, congenital short QT syndrome.
• Subject with a short QTc interval (<340 msec) or long QTc interval (>460 msec) as confirmed by a repeated electrocardiogram (ECG).
• Benzodiazepine rescue administered on average more than once a week in the month before Visit 1.
• Previous exposure to carisbamate or sensitivity/allergy to components of the oral suspension.

Eligibility last updated 6/7/23. Questions regarding updates should be directed to the study team contact.

Patients must have participated in a previous TAK-935 study and meet one of the following conditions:

• Successfully completed a TAK-935 clinical study. 
• In the opinion of the investigator, the patient has the potential to benefit from the administration of TAK-935 (not applicable for Spain).
• The patient provides written informed consent, or the patient’s legal representative (ie, parent or legal guardian) provides written informed consent and the patient provides assent, before any study procedures are performed.
• The patient and patient’s legal representative (i.e., parent or guardian [as applicable]) are willing to comply with all study requirements. 
• From signing of informed consent, throughout the duration of the study, and for 30 days after last dose of study drug, female patients of childbearing potential* who are sexually active with a non-sterilized male partner** must agree to use a highly effective method of contraception (from the list below). In addition, they must not donate ova during this period.  

* Females NOT of childbearing potential are defined as those who are prior to first menarche or who have been surgically sterilized (hysterectomy, bilateral oophorectomy, or tubal ligation) or who are postmenopausal (e.g., defined as ≥ 1 year since last regular menses with a follicle stimulating hormone level > 40 IU/L or ≥ 5 years since last regular menses, confirmed before any study drug is administered).

**Sterilized males should be ≥ 1 year post-vasectomy and have confirmed that they have obtained documentation of the absence of sperm in the ejaculate.

A highly effective method of contraception is defined as one that has no higher than a 1% failure rate per year when used consistently and correctly. In this study, the only acceptable methods of contraception are as follows:

• Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation:
  • Oral;
  • Intravaginal;
  • Transdermal.
• Progestogen-only hormonal contraception associated with inhibition of ovulation:
  • Oral;
  • Injectable;
  • Implantable.
• Double-barrier methods (each time the patient has intercourse):
  • Sponge (plus spermicidal cream or jelly) PLUS male condom with or without spermicidal cream or jelly;
  • Cap (plus spermicidal cream or jelly) PLUS male condom with or without spermicidal cream or jelly;
  • Diaphragm (plus spermicidal cream or jelly) PLUS male condom with or without spermicidal cream or jelly.
• Intrauterine device (Copper T PLUS condom).
• Intrauterine hormone-releasing system.
• Sterilization:
  • Bilateral tubal occlusion;
  • Vasectomized partner (provided that the partner is the sole sexual partner of the patient and the absence of sperm in the ejaculate has been confirmed).
• Sexual abstinence, if it is the preferred and usual lifestyle of the patient, will be considered an acceptable method of contraception on a case-by-case basis upon prior approval by the medical monitor. Patients practicing abstinence as a method of contraception must refrain from heterosexual intercourse throughout the duration of the study and for 30 days after last dose of study drug.

• Clinically significant disease, that, in the investigator’s opinion, precludes study participation.
• Enrollment in any other clinical trial involving an investigational drug, device, or treatment in the past 90 days (with the exception of an antecedent study involving TAK-935).
• Patient is currently pregnant or breastfeeding or is planning to become pregnant during the study or within 30 days of the last study drug administration.
• Suicide attempt within the last year, at significant risk of suicide (either in the opinion of the investigator or defined as ‘yes’ to suicidal ideation question 4 or 5 on the Columbia-Suicide Severity Rating Scale [C-SSRS] at Screening) or appearing suicidal per investigator judgment.

• Male and female.
• Aged 18
  •80 years old.
• Biopsy confirmed CD diagnosis (Pathology report confirmation by principal investigator).
• Self-reported adherence to a gluten-free diet for ≥ 12 months (documented by medical history).
• TG2 IgA antibody negative.
• Agree to maintain dosing of approved prescribed and OTC medications throughout the course of the study.
• Willing to take study treatment with each daily evening meal (e.g., dinner).
• Willing to take gluten foodstuff with each daily evening meal (e.g., dinner).
• If using a statin, willing to withhold statin therapy for 48 hours prior to in-clinic simvastatin ingestion and testing.
• Willing to maintain GFD for entire study duration.
• Willing to undergo multiple esophagogastroduodenoscopy procedures during the course of the trial.
• Access to a reliable telephone that would allow MSM dosing compliance telephone calls.
• Access to the internet via smartphone, tablet or computer device or equivalent to facilitate daily (end-of-day) symptom reporting.
• Willing to agree to minimal ingestion outside of three main daily meals.
• Willing to limit snacks outside the daily evening meal (e.g., dinner) to gluten-free snacks.
• Willing to not ingest grapefruit in any form (i.e., whole fruit, pulp, juice, etc.) during the 48 hour period prior to and during study visits 3 & 4.
• Willing and able to comply with all study procedures.
• Must read and understand English.
• Must sign informed consent.

• Active dermatitis herpetiformis lesions at the time of screening.
• History of any form of colitis.
• History of IgE-mediated reactions to wheat (i.e., “wheat allergy”).
• Any clinical contraindications to performing an endoscopy with intestinal biopsy.
• Received any systemic biologics (such as monoclonal antibodies or other protein therapeutics where the half-life overlaps with study start) within 6 months prior to study start.
• Taking any oral probiotic supplements (not including probiotics contained in commercially available food preparations) 6 months prior to entry.
• Use of any immunosuppressive medications (i.e., for chronic treatment of autoimmune disease or transplant-rejection prophylaxis) 6 months prior to entry.
• Use of systemic cortisone-like medications within 28-days prior to and during study treatment.
• History of alcohol abuse, illegal drug use (e.g. amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, and opiates) or medical and recreational cannabinoid use within the past 12 months.
• Laboratory values:
  • Elevated liver function tests (Alanine Aminotransferase [ALT], Aspartate Transaminase[AST],Alkaline Phosphatase [Alk Phos], or Gamma-Glutamyl Transferase [GGT]) > 2.5 times the upper limit of normal (ULN);
  • Total bilirubin > 1.5x ULN;
  • Serum creatinine > 1.5x ULN;
  • Hemoglobin < 10 g/dL or 100 g/L;
  • Calcium  < 8.0 mg/mL;
  • Platelet count< 75.0 x 109/L or 75,000/mm3;
  • Partial thromboplastin time (PTT) or prothrombin time (PT/INR) > 1.5 ULN;
  • Serum potassium < 3.0 mmol/L, > 5 mmol/L;
  • Total white blood cell count (WBC)  < 3.0 x 109/L or 3000/mm3;
  • Total lymphocyte < 1.0 x 109/L or 1000/mm3.
• Current untreated or active peptic ulcer disease, Grade B or greater esophagitis, motility disorders such as irritable bowel syndrome, functional dyspepsia, inflammatory bowel disease, and symptomatic GERD (gastroesophageal reflux disease) other than celiac disease.
• Women of Child Bearing Potential (WOCBP): positive urine pregnancy test.
• Unwilling to practice highly effective birth control (unless surgically sterilized or post-menopausal).
• Other than oral contraceptives, use of prescribed medications or over-the-counter medications that, in the opinion of the investigator might interfere with study results.
• Current use of anticoagulants (warfarin sodium, heparin, full-dose aspirin [325 – 650 mg/dose] or clopidogrel) during the 7-day period prior to randomization.
• Currently taking any medication(s) contraindicated for use with simvastatin that cannot be stopped 48 hours prior to visits 3 & 4 and restarted after visits 3 & 4, respectively.
• Received any experimental drug within 30 days of randomization, in the case of experimental biologics at least 6 months prior to randomization.
• The existence of any uncontrolled chronic disease or condition [for example HIV-AIDS, hepatitis, Type 1 or 2 diabetes, or cancer (other than skin cancer)], other than celiac disease.
• Uncontrolled complications of celiac disease, which, in the opinion of the investigator, could affect immune response or pose an increased risk to the patient (e.g. Type 1 diabetes or other autoimmune disease).
• Known allergy or hypersensitivity to any of the components of the placebo, IMGX003 (including sulfites), E. coli, or E. coli-derived proteins and simvastatin.
• Known adverse respiratory effects caused by sulfites.
• Inability to give informed consent.
• Any medical condition, other than celiac disease, which, in the opinion of the investigator, could adversely affect the patient’s participation in the trial.

• Able to provide written informed consent. Adult patients under guardianship may participate if permitted by local regulations with the consent of their legally authorized guardian. All local regulations concerning patients under guardianship must be followed.
• Age ≥ 18 years at the time of informed consent.
• Histologically confirmed diagnosis of cutaneous melanoma with metastases to the brain.
• Presence of BRAFV600 mutation in tumor tissue previously determined by a local PCR or NGS-based assay at any time prior to Screening or by a central laboratory during Screening.
• Patients are required to submit archival or fresh tumor tissue and a blood sample prior to enrollment. Tissue samples will be used to determine BRAFV600-mutation status by central laboratory.
• Must have at least 1 parenchymal brain lesion ≥ 0.5 cm and ≤ 4 cm, defined as an MRI contrast-enhancing lesion that may be accurately measured in at least 1 dimension. Note: Measurable intracranial lesions that have been previously irradiated and have not been shown to be progressing following irradiation should not be considered as target lesions.
• Patients may have received the following prior therapies.

Safety Lead-in, Phase 2 Randomized, Phase 2 Arm A Cohort 1:

• May have received prior local therapy for brain metastases including but not restricted to brain surgery, whole brain radiotherapy (WBRT), stereotactic radiotherapy or stereotactic radiosurgery (e.g., gamma knife, linear-accelerated-based radiosurgery, charged particles, and CyberKnife). Multiple local (brain) therapies or combinations of local therapies are allowed. For patients receiving local therapy to all brain lesions (including WBRT), progression of pre-existing lesions based on RECIST 1.1 (> 20% increase in longest diameter on baseline scan) or new measurable lesions are required. For patients receiving local therapy for some but not all lesions, disease progression based on RECIST 1.1 is not required as long as there are remaining brain lesions that are measurable and not previously treated.

Phase 2 Arm A Cohort 2:

• Received no prior local therapy (e.g., brain surgery, craniotomy, SRS or SRT) for brain metastases;
• All patients (Safety Lead-In and Phase 2): May have received prior immunotherapy;
• All patients (Safety Lead-In and Phase 2): If receiving concomitant corticosteroids must be on a stable or decreasing dose (up to a total daily dose of 4 mg of dexamethasone or equivalent) for at least 2 weeks prior to first dose of study treatment.
• An ECOG PS of 0 or 1 and Karnofsky score ≥ 80 (see Section 7.2.5).
• Adequate bone marrow, organ function and laboratory parameters:
  • ANC ≥ 1.5 × 10^9 /L;
  • Hemoglobin ≥ 9 g/dL with or without transfusions;
  • Platelets ≥ 100 × 10^9 /L;
  • AST and ALT ≤ 2.5 × ULN; in patients with liver metastases ≤ 5 × ULN;
  • Total bilirubin ≤ 1.5 × ULN.
    • Note: Patients with documented Gilbert syndrome or hyperbilirubinemia due to non-hepatic cause (e.g., hemolysis, hematoma) may be enrolled following discussion and agreement with the Sponsor Medical Monitor.
    • Serum creatinine ≤ 1.5 × ULN; OR calculated creatinine clearance > 50 mL/min by Cockcroft-Gault formula; OR estimated glomerular filtration rate > 50 mL/min/1.73m^2.
• Female patients of childbearing potential must have a negative serum β-HCG test result.
• Female patients of childbearing potential must agree to protocol-approved methods of contraception and to not donate ova from Screening until 30 days after the last dose of study drug.
• Male patients must agree to use methods of contraception that are highly effective or acceptable and to not donate sperm from Screening until 90 days after the last dose of study drug.
• The patient is deemed by the Investigator to have the initiative and means to comply with scheduled visits, treatment plan and study procedures.

• ​​​​​​​Patients with symptomatic brain metastasis (e.g., have neurologic symptoms related to brain metastases).
• Prophylactic or preventive anti-epileptic therapy.
  • Note: Anti-epileptic therapy indicated in order to prevent neurologic symptoms caused by a preexisting condition and not related to brain metastasis is allowed.
• Known hypersensitivity or contraindication to any component of study treatment or their excipients.
• Inability to swallow and retain study treatment.
• Uveal or mucosal melanoma.
• History of or current leptomeningeal metastases.
• Treatment with SRS or craniotomy within 14 days prior to start of study treatment, or treatment with whole-brain radiation within 28 days prior to study treatment. Patients who received local therapy should have complete recovery with no neurological sequelae.
• Either of the following:
  • Radiation therapy to non-brain visceral metastasis within 2 weeks prior to start of study treatment;
  • Continuous or intermittent small-molecule therapeutics or investigational agents within 5 half-lives of the agent (or within 4 weeks prior to start of study treatment, when half-life is unknown).
• Patients treated in the adjuvant setting with BRAF or MEK inhibitor(s) < 6 months prior to enrollment. Patients who received BRAF or MEK inhibitors in the metastatic setting are excluded.
• Is currently participating in a study and receiving an investigational agent; has received an investigational agent or used an investigational device within 14 days prior to start of study treatment.
• Patients who have undergone major surgery (e.g., inpatient procedure with regional or general anesthesia) ≤ 6 weeks prior to start of study treatment. For minor surgical procedures ≤ 6 weeks prior to start of study treatment, consult the Sponsor Medical Monitor.
• Patient has not recovered to ≤ Grade 1 from toxic effects of prior therapy before starting study treatment. Note: Stable chronic conditions (≤ Grade 2) that are not expected to resolve (such as neuropathy, myalgia, alopecia, prior therapy-related endocrinopathies) are exceptions and patients with these may enroll.
• Impaired cardiovascular function or clinically significant cardiovascular disease including, but not limited to, the following:
  • History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty or stenting) < 6 months prior to Screening;
  • Congestive heart failure requiring treatment (New York Heart Association Grade ≥ 2);
  • An LVEF < 50% as determined by MUGA or ECHO; d. Uncontrolled hypertension defined as persistent systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg despite current therapy;
  • History or presence of clinically significant cardiac arrhythmias (including resting bradycardia, uncontrolled atrial fibrillation or uncontrolled paroxysmal supraventricular tachycardia); f. Triplicate average baseline QTcF interval ≥ 480 msec.
• Continuous or intermittent small-molecule therapeutics or investigational agents within 5 half-lives of the agent (or within 4 weeks prior to start of study treatment, when half-life is unknown). 9. Patients treated in the adjuvant setting with BRAF or MEK inhibitor(s) < 6 months prior to enrollment. Patients who received BRAF or MEK inhibitors in the metastatic setting are excluded.
• Is currently participating in a study and receiving an investigational agent; has received an investigational agent or used an investigational device within 14 days prior to start of study treatment.
• Patients who have undergone major surgery (e.g., inpatient procedure with regional or general anesthesia) ≤ 6 weeks prior to start of study treatment. For minor surgical procedures ≤ 6 weeks prior to start of study treatment, consult the Sponsor Medical Monitor.
• Patient has not recovered to ≤ Grade 1 from toxic effects of prior therapy before starting study treatment. Note: Stable chronic conditions (≤ Grade 2) that are not expected to resolve (such as neuropathy, myalgia, alopecia, prior therapy-related endocrinopathies) are exceptions and patients with these may enroll.
• Impaired cardiovascular function or clinically significant cardiovascular disease including, but not limited to, the following:
  • History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty or stenting) < 6 months prior to Screening;
  • Congestive heart failure requiring treatment (New York Heart Association Grade ≥ 2);
  • An LVEF < 50% as determined by MUGA or ECHO;
  • Uncontrolled hypertension defined as persistent systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg despite current therapy;
  • History or presence of clinically significant cardiac arrhythmias (including resting bradycardia, uncontrolled atrial fibrillation or uncontrolled paroxysmal supraventricular tachycardia);
  • Triplicate average baseline QTcF interval ≥ 480 msec.
• Other severe, acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study treatment administration or that may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient an inappropriate candidate for the study.

• Any adult  > 18 years of age.
• Patient must have received a concussion within ten (10) weeks from planned procedure under anesthesial.

• Patients with neurologic history including history of severe cognitive disease, disorder, or delay, attention disorder, moderate-to-severe TBI history, neurovascular order or trauma.

Newly-Diagnosed

• Age ≥ 18 years.
• Histologically confirmed Grade IV GBM, inclusive of gliosarcoma (WHO criteria; IDH wild-type by immunohistochemistry [IHC] or sequencing for IDH) established following either a surgical resection or biopsy. An MRI scan with the required imaging sequences performed within 21 days prior to randomization preferably. The post-operative MRI scan performed within 96 hours of surgery or the MRI scan performed for radiation therapy planning may serve as the MRI scan performed during screening if all required imaging sequences were obtained.
• Karnofsky performance status ≥ 60%. performed within a 14-day window prior to randomization.
• Availability of tumor tissue representative of GBM from definitive surgery or biopsy.

Recurrent

• Age ≥ 18 years.
• Histologically confirmed Grade IV GBM, inclusive of gliosarcoma (WHO criteria; IDH wild-type by immunohistochemistry [IHC] or sequencing for IDH) at first or second recurrence after initial standard, control or experimental therapy that includes at a minimum radiation therapy (RT).
• Evidence of recurrent disease demonstrated by disease progression using slightly modified Response Assessment in Neuro-Oncology (RANO) criteria.
• Two scans to confirm progression are required: at least 1 scan at the time of progression and 1 scan prior to the time of progression.
• Karnofsky performance status ≥ 70% performed within a 14-day window prior to randomization.
• Availability of tumor tissue representative of GBM from initial definitive surgery and/or, recurrent surgery, if performed.

Newly-Diagnosed

• Received any prior treatment for glioma including:
  • Prior prolifeprospan 20 with carmustine wafer;
  • Prior intracerebral, intratumoral, or cerebral spinal fluid (CSF) agent;
  • Prior radiation treatment for GBM or lower-grade glioma;
  • Prior chemotherapy or immunotherapy for GBM or lower-grade glioma. Receiving additional, concurrent, active therapy for GBM outside of the trial.
• Extensive leptomeningeal disease.
• QTc > 450 msec if male and QTc > 470 msec if female.
• History of another malignancy in the previous 2 years, with a disease-free interval of < 2 years. Patients with prior history of in situ cancer or basal or squamous cell skin cancer are eligible.

Recurrent

• Early disease progression prior to 3 months (12 weeks) from the completion of RT.
• More than 2 prior lines for chemotherapy administration. (NOTE: In the 1st line adjuvant setting, combination of temozolomide (TMZ) with an experimental agent, is considered one line of chemotherapy).
• Received any prior treatment with lomustine, agents part of any of the experimental arms, and bevacizumab or other vascular endothelial growth factor (VEGF) or VEGF receptor-mediated targeted agent.
• Any prior treatment with prolifeprospan 20 with carmustine wafer.
• Any prior treatment with an intracerebral agent.
• Receiving additional, concurrent, active therapy for GBM outside of the trial.
• Extensive leptomeningeal disease.
• QTc > 450 msec if male and QTc > 470 msec if female.
• History of another malignancy in the previous 2 years, with a disease-free interval of < 2 years. Patients with prior history of in situ cancer or basal or squamous cell skin cancer are eligible.

Eligibility last updated 2/16/22. Questions regarding updates should be directed to the study team contact.

• Have active, relapsed or refractory AML. Active, relapsed or refractory AML is defined as any one of the following:
  • primary induction failure (PIF) after 2 or more cycles of therapy; or
  • first early relapse after a remission duration of fewer than 6 months; or
  • relapse refractory to salvage combination therapy; or
  • second or subsequent relapse (Schmid, 2006).
• Have documented CD45 expression by leukemic cells via flow cytometry (a “blast gate” on CD45 vs. side scatter analysis consist.nt with AML);
• Be ≥ 55 years of age.
• Have a circulating blast count of less than 10,000/mm^3 (control with hydroxyurea is allowed).
• Have a calculated creatinine clearance (Cockroft-Gault equation) > 50 mL/min.
• Have adequate hepatic function (direct bilirubin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT), defined as ≤ 2 times the upper limit of normal [ULN]).
• Have a Karnofsky score ≥ 70.
• Have an expected survival of > 60 days.
• Have a central venous catheter line in place prior to study treatment administration.
• Have 8/8 allele-level, related or unrelated, HSC donor matching at human leukocyte antigen (HLA)-A, HLA-B, HLA-C, and DRB1 with a donor who is medically cleared.
• Syngeneic donors that meet these criteria are allowed.
• Women of childbearing potential, be surgically sterile or agree to practice abstinence or utilize acceptable contraception (intrauterine, injectable, transdermal, or combination oral contraceptive) through 1-year post transplant; Males who are sexually active with women of childbearing potential must be surgically sterile or using an acceptable method of contraception (defined as barrier methods in conjunction with spermicides) from time of screening through 12 weeks after last dose of study drug.
• Be able to understand the study procedures, agree to participate in the study program, and voluntarily provide written Informed Consent.

Exclusion Criteria: 

• Have circulating HAMA noted on initial screening.
• Have received prior radiation to maximally tolerated levels to any critical normal organ.
• Have active leukemic central nervous system (CNS) involvement, as defined by any leukemic blasts detected in the cerebrospinal fluid (CSF) by morphology or flow cytometry and/or any chloromas detected by CNS imaging.
• Have previously received a HCT (includes both allogeneic and autologous HCT).
• Clinically significant cardiac disease (NYHA Class III or IV); clinically significant arrhythmia; i.e., ventricular tachycardia, ventricular fibrillation, or “Torsade de Pointes”. Myocardial infarction with uncontrolled angina within 6 months, congestive heart failure, or clinically significant cardiomyopathy.
• Have abnormal QTcF (> 450 milliseconds) after electrolytes have been corrected (at least two different ECG readings and at least 15 minutes between readings). Subjects with paced rhythm or prolonged QTcF may be exempt from this exclusion if considered eligible for transplant per treating physician clinical judgment, with optional cardiology consultation.
• Have current or prior positive test results for human immunodeficiency virus (HIV) or hepatitis B (HBV) or C. Subjects who have positive HBV test results due to having been previously vaccinated against hepatitis B, as evidenced by negative hepatitis B surface antigen (HBsAg), negative anti- hepatitis B core protein (HBc) and positive antibody to the HBsAg (anti-HBs) are not excluded; Subjects who have positive hepatitis test results with adequate organ function as defined in the protocol are not excluded.
• Have active serious infection uncontrolled by antibiotics or antifungals.
• Have acute promyelocytic leukemia and the associated cytogenetic translocation t(15;17).
• Have active malignancy within 2 years of entry. Active malignancy is defined as those malignancies requiring treatment with anti-cancer therapy or in the event of indolent malignancies, having measurable disease.  Exceptions to this exclusion include:
  • myelodysplastic syndrome;
  • treated non-melanoma skin cancer;
  • completely resected Stage 0 or 1 melanoma no less than 1 year from resection;
  • carcinoma in situ or cervical intraepithelial neoplasia;
  • successfully treated organ-confined prostate cancer with no evidence of progressive disease based on prostate specific antigen (PSA) levels and are not on active therapy;
• Have a perceived inability to tolerate diagnostic or therapeutic procedures, particularly treatment in radiation isolation.
• Currently receiving any other active investigational agents.

• Patient or legal representative voluntarily agreed to participate by signing and dating the written informed consent form after trial has been fully explained.
• Patient 18 years of age or older.
• History of recurrent CDI.
• Current active qualifying CDI episode.
• Females (assigned at birth) must fulfill at least 1 of the following criteria: 
• Postmenopausal, defined as amenorrhea ≥ 1 year; or 
  • Surgically sterile: hysterectomy, bilateral oophorectomy, or tubal ligation; or 
  • Abstinent or willing to use adequate contraception from Screening through the week 24 visit.
• Males (as assigned at birth) must fulfill the following criteria:
  • Abstinent or willing to use adequate contraception from Screening through the Week 24 visit.

• Known stool samples testing positive for enteric pathogens (e.g., Salmonella, Shigella, diarrhoeagenic E. coli, Campylobacter, Giardia) within 28 days prior to Screening.
• Inability to ingest capsules (e.g., severe nausea, vomiting, gastroparesis, gastric outlet obstruction, dysphagia and/or history of chronic aspiration).
• Active or suspected ileus, toxic megacolon, or bowel obstruction.
• Historical or current diagnosis of inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis, indeterminate colitis, or microscopic colitis).
• Recent diagnosis (< 6 months prior to Screening) of diarrhea-predominant irritable bowel syndrome (post-infection or not related to an enteric infection). Patients with diarrhea-predominant irritable bowel syndrome ≥ 6 months prior to Screening may be randomized following confirmation of eligibility.
• Current diagnosis of chronic diarrheal illness with pre-CDI baseline diarrhea. This includes but is not limited to celiac disease, bile salt diarrhea, chronic pancreatitis, and short gut syndrome.
• Past administration of bezlotoxumab (Zinplava™), or past enrollment in a C. difficile vaccine trial within 12 months prior to Randomization.
• Participation in PRISM3 (CDI-001) or PRISM-EXT (CP101-CDI-E02) or received CP101 at any time in the past.
• Fecal transplant or other live microbiome therapeutics for any condition, regardless of route of administration within 12 months prior to Randomization.
• Initiation of any systemic cancer treatment (e.g., chemotherapy, radiotherapy, biologic, immunotherapy, others) for active malignancy that is planned 8 weeks prior to Randomization or during the 8 weeks following Randomization. Patients on maintenance treatment for malignancy may be randomized following confirmation of eligibility.
  • NOTE: Patients on hormone therapy alone are eligible.
• Known primary or secondary immunodeficiency, including but not limited to, IgA deficiency, common variable immunodeficiency, severe combined immunodeficiency, or human immunodeficiency virus/acquired immune deficiency syndrome.
• History of solid organ transplantation or stem cell transplant.
• Initiation or dose escalation of systemic immunosuppressive agents, at the discretion of the Investigator, for any condition during the 8 weeks prior to Randomization or planned during the 8 weeks following Randomization. Examples may include but are not limited to corticosteroid agents given orally or intravenously, cyclosporine, tacrolimus, or tumor necrosis factor inhibitors. Patients on stable low dose of systemic immunosuppressive agents or short courses (< 2 weeks) may be randomized following confirmation of eligibility.
• Major intra-abdominal surgery (e.g., bowel resection) within the past 60 days prior to Screening (excluding appendectomy or cholecystectomy)and/or planned invasive surgery/hospitalization during the trial.
• History of total colectomy or ileostomy.
• Use of a systemic antibiotic for any condition (other than CDI) during the Screening period, or any anticipated use of a systemic antibiotic for any condition other than CDI during the trial for 8 weeks after Randomization. This includes patients who have a known medical procedure that requires antibiotic prophylaxis (e.g., elective surgical procedure or dental procedure requiring prophylactic antibiotics) scheduled during the trial.
• Active drug, chemical, or alcohol dependency as determined by the Investigator through history or optional toxicology screen.
• Enrollment in any other investigational drug, device, or observational trial within 30 days or 5 half-lives of the last dose, prior to Randomization (Day 1) or at any time during this trial.
• Pregnant, breast-feeding, or planning to become pregnant during the trial.
• Clinically significant abnormal laboratory values including, but not limited to, white blood cell count ≥ 15 × 10^9/L, absolute neutrophil count of < 1 × 10^9 neutrophils/L, or laboratory evidence of acute kidney injury at Investigators discretion, at Screening.
• Screening nasopharyngeal PCR test is positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
• Any acute, chronic, or unstable medical comorbidity, psychiatric, social, or other circumstances that, in the opinion of the Investigator, may interfere with trial compliance, completion, or accurate assessment of trial outcomes/safety. Examples include but not limited to acute myocardial infarction, acute stroke, uncompensated congestive heart failure, or decompensated liver disease.
  • NOTE: Trial patients may be screened while an inpatient in an acute care facility/hospital but must be discharged from inpatient medical admission prior to Randomization.
• Life expectancy < 24 weeks.
• Known hypersensitivity to CP101 or any component of its formulation or history of severe adverse reactions or other common drug class effects during prior exposure to similar compounds per the judgment of the investigator.

Eligibility last updated 2/1/22. Questions regarding updates should be directed to the study team contact.

• Age ≥ 18 years.
• Ability to provide informed consent.
• Clinical suspicion of UGIB based on initial physical evaluation and intake history; e.g., prior episodes of UGI, presence of comorbid illnesses or medications associated with UGIB, laboratory data and symptom assessment, and patient is a candidate for endoscopy.

Exclusion  Criteria:

• Based on investigator’s assessment there is a clear need for urgent endoscopy or surgery at the time of consent.
• Known GI tract stricture.
• History of Zenker’s diverticulum and fistulas.
• Using a pacemaker or other implantable electrical device.
• Dysphagia or difficulties in swallowing pills the size of the capsule.
• History of achalasia or known esophageal dysmotility.
• History of gastroparesis.
• History of severe constipation (1 bowel movement per week or less).
• Currently taking medications intended for stimulation of GI motility.
• Patients that have had Upper GI barium study within the previous 24 hours.
• Currently pregnant or breastfeeding, or intend to become pregnant during the investigation.
• Presence of psychological issues preventing participation.
• Presence of known gastric bezoar.
• History of Crohn’s disease.
• History of small or large bowel obstruction.
• Suspected or previously diagnosed obstructing gastrointestinal tumor.
• Currently participating in another clinical trial that in the opinion of the investigator would interfere with the outcomes of this study or increase risk to the subject.
• Planned MRI investigation (MRI needed before the capsule is excreted).
• Presence of known hiatal hernia 5 cm or greater.
• Presence of known gastrointestinal abnormalities that could impact capsule performance.
• Presence of other concurrent conditions or known history that in the opinion of the Investigator would compromise patient safety or study objectives

Eligibility last updated 3/4/22. Questions regarding updates should be directed to the study team contact.

• Able to understand and voluntarily sign an informed consent form (ICF).
• Male and female adults ≥ 18 years of age at the time of informed consent 
• Advanced solid malignancies for which no standard therapy is available. Subjects in whom available standard therapy is contraindicated may be eligible. 
• For Dose Expansion Phase
  •Expansion Group A:
  • Histologically confirmed unresectable locally advanced or metastatic (AJCC stage IIIB, IIIC, or IV) cutaneous malignant melanoma for which no standard therapy is suitable. 
• At least 1 measurable site of disease as defined per RECIST v1.1 criteria (Dose Expansion Phase) or evaluable disease (Dose Escalation Phase only).
• Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1.
• Life expectancy of > 12 weeks.
• Adequate hematologic status within 28 days prior to dosing as demonstrated by not requiring transfusion support or granulocyte-colony stimulating factor (G-CSF) to maintain: 
  • Absolute neutrophil count (ANC) ≥1.5 × 109/L
  • Platelet count ≥ 100 × 10^9/L 
  • Hemoglobin ≥ 90 g/L.
• Adequate liver function as demonstrated by:
  • Serum bilirubin < 2 × the upper limit of normal (ULN);
  • Aspartate transaminase (AST) and alanine aminotransferase (ALT) ≤ 3 × ULN or ≤ 5 × ULN in subjects with liver metastases;
  • Gamma-glutamyl transferase ≤ 5 × ULN ;
  • Alkaline phosphatase ≤ 3 × ULN or ≤ 5 × ULN if bone or liver metastasis is present,
• Serum creatinine ≤ 1.5 × ULN or estimated creatinine clearance ≥ 50 mL/min according to the Cockcroft-Gault formula.
• Prothrombin time (PT) (or International Normalized Ratio [INR]) and activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN or within the intended therapeutic range within 72 hours before the first dose of study drug in subjects receiving anticoagulant therapy.
• Willing and able to comply with scheduled visits, treatment plan, and laboratory tests.
• Absence of any other malignancy which has been active or treated within the past 3 years, except for cervical intraepithelial neoplasia, and nonmelanoma skin cancers (basal cell and squamous cell carcinomas).
• Men who are sterile (including vasectomy confirmed by post vasectomy semen analysis) OR agree to use a condom with spermicide and to not donate sperm during the study and for at least 90 days following last dose of PT01.
• Female subjects must be postmenopausal (>12 months without menses) or surgically sterile (ie,by hysterectomy and/or bilateral oophorectomy) or must be using highly effective contraception (ie, oral contraceptives, intrauterine device, double barrier method of condom and spermicide) and agree to continue use of contraception for 90 days after their last dose of PT01.
• Subjects who are of childbearing potential must have a negative serum pregnancy test at Screening and within 72 hours prior to the first dose.
• Peripheral forearm veins suitable for venous access including cannulation for infusion of PT01 and multiple blood sampling

• Received prior arginase or arginine deiminase therapy.
• Received recent anticancer therapy defined by: 
  • Chemotherapy, immunotherapy, hormonal therapy, and monoclonal antibodies (but excluding nitrosourea, mitomycin-C, targeted therapy) ≤ 28 days prior to starting study drug or who have not recovered from side effects of such therapy to Grade≤1 (National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v4.03) except for subjects with alopecia; subjects receiving luteinizing hormone-releasing hormone agonists may be considered for enrollment after discussion with the Sponsor;
  • Last administration of nitrosourea or mitomycin-C ≤ 42 days prior to starting study drug or who have not recovered from the side effects of such therapy to Grade ≤ 1;
  • Targeted therapy (e.g., sunitinib, sorafenib, pazopanib) ≤ 14 days prior to starting study drug, or who have not recovered from the side effects of such therapy to Grade ≤ 1; 
  • Radiotherapy ≤ 28 days prior to starting study drug or ≤ 14 days prior to starting study drug in the case of localized radiotherapy (e.g., for analgesic purpose or for lytic lesions at risk of fracture) or who have not recovered from radiotherapy toxicities to Grade ≤ 1.
• Undergone major surgery (e.g., intrathoracic, intraabdominal, or intrapelvic), open biopsy, or significant traumatic injury ≤ 28 days prior to starting study treatment; subjects who have had minor procedures, percutaneous biopsies, or placement of vascular access device ≤ 7 days prior to starting study drug; or subjects who have not recovered from side effects of such procedure or injury.
• Uncontrolled concurrent illness including, but not limited to, ongoing or active serious infection requiring systemic antimicrobials (within 14 days prior to first dose), uncontrolled arterial hypertension (>160/100 mm Hg on antihypertensive medications), chronic pulmonary disease requiring oxygen, known bleeding disorders, uncontrolled endocrine diseases, altered mental status, or psychiatric illness/social situations that would limit compliance with protocol requirements.
• Significant cardiac or pulmonary disease defined by New York Heart Association Class III or IV, history of myocardial infarction within 6 months prior starting study drug, significant unstable arrhythmia, or evidence of ischemia on ECG.
• Symptomatic or uncontrolled brain metastases requiring current treatment (fewer than 28 days from last cranial radiation or from last steroids use).
• Healing or open wound(s).
• Lack of recovery of prior AEs to Grade ≤ 1 severity (except alopecia or lymphopenia) due to medications administered prior to the first dose of study drug.
• Any other condition or finding (including social situation) that, in the opinion of the Investigator, may render the subject to be either at excessive risk for treatment complications or not able to provide evaluable outcome information.
• Pregnant or breast-feeding women.
• Known allergy to any of the formulation components of PT01.

• Male or female patients age 18 to 80 years of age, inclusive, at Baseline.
• Biopsy-confirmed diagnosis of ulcerated NL. Biopsies of continually active lesions performed outside of this clinical study will need to be reviewed and the diagnosis confirmed by a study pathologist. For patients with no previous history of biopsy, no biopsy within the previous 5 years, or a biopsy that is not confirmed to be NL, a biopsy to confirm a diagnosis of NL will be performed on the reference leg at the Screening visit.
• Ulcers on a single leg (“reference leg”) at Baseline should consist of at least one (1) ulcer with a minimum ulcer surface area of 1 cm2 , total ulcer area of a minimum of 2 cm2 , and no more than 6 ulcers. If ulcers are present on both legs, the Investigator will select the “reference leg”. The ulcer(s) on the reference leg (“reference ulcers”) and all other ulcers associated with the patient’s NL (“other ulcers”) present at the Baseline visit will be followed in the study.
• Women of childbearing potential must have a negative serum pregnancy test at the Screening Visit and a negative urine pregnancy test at Baseline before dosing.
• Women of childbearing potential must use one of the following acceptable methods of contraception throughout the study: oral contraceptive medication, intrauterine device (IUD), hormonal implants, injectable contraceptive medications, doublebarrier methods, or tubal ligation.
• Females who are postmenopausal (age-related amenorrhea ≥ 12 consecutive months and increased follicle-stimulating hormone [FSH] > 40 mIU/mL. If necessary, to confirm postmenopausal status, an FSH will be drawn at Screening) or who have undergone hysterectomy or bilateral oophorectomy are exempt from pregnancy testing.
• Male patients must be willing to use appropriate contraceptive measures and refrain from sexual activity with any female who is pregnant or lactating.
• Patient must be willing and able to swallow whole tablets.
• Patient must be willing and able to comply with study procedures.
• Patient must be willing and able to provide signed, informed consent.and able to provide signed, informed consent.

• Current or previous (within 6 weeks of Baseline) treatment with:
  • Oral corticosteroids;
  • Topical drugs (including prescription and over-the counter) on the reference leg (topical non-medicated moisturizer treatment products can be administered);
  • Systemic pentoxifylline, theophylline, or cilostazol;
  • Oral retinoid;
  • Other systemic immunosuppressant or immunomodulatory drugs, including but not limited to calcineurin inhibitors (e.g., tacrolimus), thalidomide, apremilast, anti-malarials (e.g., hydroxychloroquine, chloroquine), cyclosporine, mycophenolate mofetil, azathioprine, methotrexate, etc.
• Current or previous (within 12 weeks of Baseline) treatment with any biologic therapy (e.g., adalimumab, etanercept, infliximab, anakinra, etc.).
• Phototherapy/photochemotherapy (NBUVB, UVB, PUVA) within 6 weeks prior to Baseline.
• Skin grafting or other surgical procedure (other than debridement) within 6 weeks prior to Baseline.
• History of drug allergy, including but not limited to pentoxifylline or other xanthine derivatives, or other allergy, which in the opinion of the Investigator, contraindicates participation.
• Anticipated concurrent use of a strong CYP1A2 inhibiting drug, including but not limited to cimetidine and/or fluvoxamine, during the course of the study (after Screening).
• Fever (> 38°C), or chronic, persistent, or recurring infection(s) at Screening or Baseline.
• Any infection requiring oral antimicrobial therapy within 2 weeks prior to Baseline and/or any infection requiring parenteral antibiotics or hospitalization within 12 weeks prior to Baseline. Any treatment for such infections must have been completed and the infection cured for at least 2 weeks prior to Baseline.
• History of sarcoidosis, pyoderma gangrenosum, or any other disorder (in the judgment of the Investigator) that would interfere with the evaluation of NL or require protocol prohibited medication.
• History of any life-threatening infection or sepsis within 12 months of Baseline.
• Clinically significant cardiac disease including but not limited to unstable angina, acute myocardial infarction within 6 months of Baseline, and arrhythmia requiring therapy.
• Patient has QTc interval ≥ 480 milliseconds on Screening ECG; a second Screening ECG may be done at investigator’s discretion but the average of the two QTc screening intervals must not be ≥ 480 milliseconds.
• History of cerebral hemorrhage, cerebrovascular accident, transient ischemic attack, gastrointestinal bleeding, or retinal hemorrhage within 6 months of Baseline.
• Patient has active or history of neoplastic disease (except for adequately treated noninvasive basal cell and/or squamous cell carcinoma or carcinoma in situ of the cervix) within the past 5 years prior to Baseline.
• Presence of clinically significant medical condition(s) including but not limited to: renal, hepatic, cardiovascular, hematological, gastrointestinal, endocrine, pulmonary, neurological, psychiatric, substance abuse, and/or any other clinically significant disease or disorder, which in the opinion of the Investigator (by its nature or by being inadequately controlled), may put the patient at risk due to participation in the study, influence the results of the study, and/or affect the patient’s ability to complete the study.
• History of or current diagnosis of active tuberculosis (TB); undergoing treatment for latent TB infection (LTBI); untreated LTBI (as determined by documented results within 3 months of the Screening Visit of a positive TB skin test with purified protein derivative with induration >= 5 millimeter (mm), a positive QuantiFERON-TB test or positive or borderline T-SPOT [Elispot] test); or positive TB test at Screening. Patients with documented completion of appropriate LTBI treatment would not be excluded and are not required to be tested.
• Vaccination with live or live-attenuated virus vaccine within 1 month prior to Baseline.
• The results of the following laboratory tests performed at the central laboratory at Screening meet any of the criteria below:
  • Hemoglobin < 8.0 g/dL (International System of Units (SI): < 80 g/L);
  • White blood cells < 3.0 x 10^3 cells/mm^3 (SI: < 3.0 x 10^9 cells/L);
  • Neutrophils < 1.0 x 10^3 cells/mm^3 (SI: < 1.0 x 10^9 cells/L);
  • Lymphocytes < 0.5 x 10^3 cells/mm^3 (SI: < 0.5 x 10^9 cells/L);
  • Platelets < 100 x 10^3 cells/mm^3 (SI: < 100 x 10^9 cells/L).
  • Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and/or alkaline phosphatase (ALP) ≥ 2 x upper limit of normal (ULN).
  • Total bilirubin level ≥ 2 x ULN unless the individual has been diagnosed with Gilbert's disease and this is clearly documented.
  • Estimated glomerular filtration rate < 40 mL/min/1.73 m^2 based on the Modification of Diet in Renal Disease (MDRD) formula.
  • Positive HIV serology.
  • Evidence of active Hepatitis B Virus (HBV) infection.
  • Evidence of active Hepatitis C Virus (HCV) infection.
• Women who are pregnant or breastfeeding.
• Patient unwilling or unable to swallow tablets whole.
• Any other medical condition, serious intercurrent illness, or extenuating circumstance that, in the opinion of the Investigator, would preclude participation in the study.
• Use of any investigational product within 30 days prior to Baseline or currently enrolled in another study that involves clinical investigations.

Screening

• Have a diagnosis of hepatocellular carcinoma (HCC) and high risk for HCC recurrence
• Able to provide written informed consent
• Male and female patients of any race, 18 years or older
• De novo recipients of a primary orthotopic liver transplant from a deceased or living donor
• Patients willing to comply with study requirements
• Women of child-bearing potential (WOCBP) must agree to use an effective method(s) of contraception during treatment and during the post treatment follow-up period

Screening

• Past or present malignancy within the last 5 years.
• Severe infection considered by the local site investigator to be unsafe for study participation.
• Use of other investigational drugs at the time of screening or within the last 30 days.
• Patients scheduled for a combined transplant (such as liver-kidney), or having a previous solid organ, bone marrow, or autologous islet cell transplant.
• Recipients of donor/recipient ABO incompatible grafts.
• Recipients of organs from human immunodeficiency virus (HIV) or HBsAg positive donors.
• Macrovascular tumor invasion.
• Proteinuria greater than 2 grams.
• Conditions which can result in impaired absorption, distribution, metabolism or excretion of the study treatment.
• Patients with non-infectious pneumonitis.
• Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test.
• Women of child-bearing potential (WOCBP) not practicing an effective method(s) of contraception.
• Patients who receive sirolimus (Rapamune®) as part of their transplant immunosuppression regimen

Randomization Screening Inclusion Criteria :

- For patients with a history of any hepatic vessel thrombosis, occlusion, stent placement, or major revision of liver vessels, must have a Doppler ultrasound prior to randomization to rule out any hepatic vessel complication, including hepatic arterial thrombosis (HAT).

Randomization

• Patients who receive sirolimus (Rapamune) any time prior to randomization will be withdrawn from the study.
• Patients who develop clinically significant systemic infections requiring active use of IV antibiotics any time prior to randomization.
• Wound healing problem, per Investigator's assessment, that would make the patient ineligible for study randomization
• Confirmed presence of a thrombosis in a major hepatic artery(s), major hepatic vein(s), portal vein or inferior vena cava via Doppler ultrasound or other imaging obtained prior to randomization.
• Proteinuria greater than 2 grams
• Consideration by the investigator, for any reason, that the subject is an unsuitable candidate to receive everolimus or be randomized into the study.

- Karnofsky performance status ≥ 60% (Eastern Cooperative Oncology Group [ECOG] ≤ 2).

- Absolute neutrophil count ≥ 1,500/mcL.

- Platelets ≥ 100,000/mcL.

- Hemoglobin ≥ 10 g/dL.

- Total bilirubin ≤ 2 x institutional upper limit of normal (ULN).

- Aspartate aminotransferase (AST) serum glutamic oxaloacetic transaminase (SGOT)/alanine transaminase (ALT) serum glutamic-pyruvic transaminase (SGPT) ≤ 3 x
institutional ULN.

- Glomerular filtration rate (GFR) ≥ 30 mL/min/1.73 m^2.

- Human immunodeficiency virus (HIV)-infected patients on effective anti-retro-viral therapy with undetectable viral load within 6 months are eligible for this trial.

- For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.

- Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.

- Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the
investigational regimen are eligible for this trial.

- Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better.

- The effects of selinexor (KPT-330) and temozolomide on the developing human fetus are unknown. For this reason and because selective nuclear export inhibitors as well as
deoxyribonucleic acid (DNA) alkylating agents are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or
barrier method of birth control; abstinence) prior to study entry and for the duration of study participation, and for 180 days after the last dose of temozolomide. Should a
woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 90 days after completion of study treatment administration.

- Ability to understand and the willingness to sign a written informed consent document.  Participants with impaired decision-making capacity who have a legally-authorized representative (LAR) and/or family member available will also be eligible.

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Eligibility last updated 9/7/22. Questions regarding updates should be directed to the study team contact.

Enrollment criteria (n = 40):

Adult subjects undergoing MR imaging for radiation therapy planning will be recruited. No more than 40 subjects will be recruited to this study.

• All tissue collected will be from sun-exposed sites.
• Adult patients, 18 years and older.

• Children, below 18 years of age.

• Signed and dated written informed consent form and any required privacy authorization prior to the initiation of any trial procedure, after the nature of the trial has been explained according to local regulatory requirements.
• Females ≥ 40 up to ≤ 65 years of age at randomization.
• For hysterectomized subjects: documented hysterectomy must have occurred at least 6 weeks prior to the start of screening. Hysterectomy can be total or subtotal (i.e., cervix was not removed).
• For non-hysterectomized subjects: uterus with bi-layer endometrial thickness ≤ 4 mm on TVUS (Amendment 3, 08 October 2019 and Amendment 4, 03 February 2020).
• For non-hysterectomized subjects: endometrial biopsy taken during screening that reveals no abnormal results; i.e., presence of hyperplasia (simple or complex, with or without atypia), presence of carcinoma, and presence of disordered proliferative findings. The screening biopsy should have sufficient endometrial tissue for diagnosis. Biopsies without tissue or with insufficient tissue may be repeated once.
• Seeking treatment for relief of VMS associated with menopause:
  • For the Efficacy Study part: at least 7 moderate to severe bothersome VMS per day or at least 50 moderate to severe bothersome VMS per week in the last 7 consecutive days during the Screening period;
  • For the Safety Study part: at least 1 moderate to severe VMS per week.
• Body mass index ≥ 18.0 kg/m² to ≤ 38.0 kg/m².
• A mammogram that shows no sign of significant disease performed during screening or within 9 months prior to the start of screening.*
• Post-menopausal status defined as any of the following:
• For non-hysterectomized subjects:
  • or at least 6 weeks postsurgical bilateral oophorectomy;
  • or at least 6 months of spontaneous amenorrhea with serum FSH > 40 mIU /mL and E2 < 20 pg/mL (value obtained after washout of estrogen/progestin containing drugs;
  • or at least 6 weeks postsurgical bilateral oophorectomy.
• For hysterectomized subjects:
  • serum FSH > 40 mIU/mL and E2 < 20 pg/mL (values obtained after washout of estrogen/progestin containing drug;
  • or at least 6 weeks post-surgical bilateral oophorectomy.
• Good physical and mental health, in the judgement of the Investigator as based on medical history, physical and gynecological examination, and clinical assessments performed prior to Visit 1.
• Able to understand and comply with the protocol requirements, instructions, and protocol-stated restrictions.
• Able and willing to complete trial daily diaries and questionnaires.

* Subjects must have a Breast Imaging-Reporting And Data System (BI-RADS) score of 1 or 2 to enroll in the study. An incomplete mammogram result, i.e., BI-RADS 0, is not acceptable. and requires further assessment (Amendment 5, 23 September, 2020). The site must obtain a copy of the official report for the subject's study file. A digitalized imaging should be obtained if mammography is done as part of this study.

• History of malignancy with the exception of basal cell or squamous cell carcinoma of the skin if diagnosed more than 1 year prior to the Screening visit.
• Any clinically significant findings found by the Investigator at the breast examination and/or on mammography suspicious of breast malignancy that would require additional clinical testing to rule out breast cancer (however, simple cysts confirmed by ultrasound are allowed).
• Papanicolaou (PAP) test with atypical squamous cells undetermined significance (ASC-US) or higher (low-grade intraepithelial lesion [LSIL], atypical squamous cells- cannot exclude high-grade squamous intraepithelial lesion [HSIL] [ASC-H], HSIL dysplastic or malignant cells) in sub-totally hysterectomized and non-hysterectomized subjects.
  • Note: ASC-US is allowed if a reflex human papilloma virus (HPV) testing is performed and is negative for high risk oncogene HPV.
• For non-hysterectomized subjects:
  • History or presence of uterine cancer, endometrial hyperplasia, disordered proliferative findings;
  • Presence of endometrial polyp;
  • Undiagnosed vaginal bleeding;
  • Endometrial ablation;
  • Enlarged uterus with myoma.
• Systolic blood pressure (BP) higher than 130 mmHg, diastolic BP higher than 80 mmHg during screening.
• History of venous or arterial thromboembolic disease (e.g., superficial or deep vein thrombosis, pulmonary embolism, stroke, myocardial infarction, angina pectoris, etc.), or first degree family history of venous thromboembolism (VTE).
• History of known acquired of congenital coagulopathy or abnormal coagulation factors, including known thrombophilias.
• Diabetes mellitus with poor glycemic control in the last 6 months assessed by laboratory values of fasting glucose outside the normal ranges and glycated hemoglobin above 7%.
• Dyslipoproteinaemia (LDL > 190 mg/dL and triglycerides > 300 mg/dL).
• Smoking:
  • Efficacy Study part: subjects smoking > 5 cigarettes per day or > 2 packs per week;
  • Safety Study part: subjects smoking > 15 cigarettes per day or > 6 packs per week.
• Presence or history of gallbladder disease, unless cholecystectomy has been performed.
• Systemic lupus erythematosus.
• Any malabsorption disorders including gastric by-pass surgery.
• History of acute liver disease in the preceding 12 months before the start of screening or presence of chronic liver disease [alanine transaminase (ALT) or aspartate transaminase (AST) >2 x upper limit of normal (ULN), bilirubin >1.5 ULN].
• Chronic or current acute renal impairment (estimated glomerular filtration rate <60 ml/min).
• Porphyria.
• Diagnosis or treatment of major psychiatric disorder (e.g., schizophrenia, bipolar disorder, etc.) in the judgement of the Investigator.
• Use of estrogen/progestin containing drug(s) up to:
  • 1 week before screening start for vaginal non systemic hormonal products (rings, creams, gels).
  • 4 weeks before screening start for vaginal or transdermal estrogen or estrogen/progestin products.
  • 8 weeks before screening start for oral estrogen and/or progestin products and/or selective estrogen receptor modulator therapy.
  • 8 weeks before screening start for intrauterine progestin therapy.
  • 3 months before screening start for progestin implants or estrogen alone injectable drug therapy.
  • 6 months before screening start for estrogen pellet therapy or progestin injectable drug therapy.
  • Use of androgen/ dehydroepiandrosterone (DHEA) containing drugs:
    • 8 weeks before screening start for oral, topical, vaginal or transdermal androgen;
    • 6 months before screening start for implantable or injectable androgen therapy.
• Use of phytoestrogens or black cohosh for treatment of VMS up to 2 weeks before the start of screening.
• For the women participating in the Efficacy Study part: use of prescription or over-the-counter products used for the treatment of VMS; e.g., anti-depressants: paroxetine, escitalopram, methyldopa, opioid and clonidine up to 4 weeks before the start of screening, and venlafaxine and desvenlafaxine up to 3 months before the start of screening , and not willing to stop these during their participation in the trial.
• Inadequately treated hyperthyroidism at screening.
• History or presence of allergy/intolerance to the investigational product or drugs of this class or any component of it, or history of drug or other allergy that, in the opinion of the Investigator contraindicates subject participation.
• For non-hysterectomized subjects: history or presence of allergy to peanuts.
• History of alcohol or substance abuse (including marijuana, even if legally allowed) or dependence in the previous 12 months before the start of screening as determined by the Investigator, based on reported observations.
• Sponsor or contract research organization (CRO) employees or employees under the direct supervision of the Investigator and/or involved directly in the trial.
• Subjects with known or suspected history of a clinically significant systemic disease, unstable medical disorders, life-threatening disease or current malignancies that would pose a risk to the subject in the opinion of the Investigator.
• Participation in another investigational drug clinical trial within 1 month (30 days) or having received an investigational drug within the last 1 month (30 days) before the start of screening.
• Is judged by the Investigator to be unsuitable for any reason.

• Histologically or cytologically confirmed diagnosis of metastatic or unresectable colorectal cancer (mCRC), based on documentation from local or outside review of pathology according to each site’s established institutional procedure.
• Documentation of an activating genomic alteration(s) in FGF/FGFR1-3 (gain of function mutations, translocations, and amplifications allowed) in tumor tissue or blood tested at a Clinical Laboratory Improvement Amendments (CLIA) – certified laboratory.
• Provide informed written consent.
• Age ≥ 18 years. Age = ________.
• Patient must have received and progressed on, or be intolerant to, each of the following treatments for mCRC (or have contraindication to these treatments):
  • Fluoropyrimidine;
  • Oxaliplatin;
  • Irinotecan;
  • Pembrolizumab;
  • Nivolumab;
  • Anti-VEGF (vascular endothelial growth factor) monoclonal antibody, if eligible for this therapy;
• Anti-EGFR (epidermal growth factor receptor) monoclonal antibody, if eligible for this therapy.
• Measurable disease as defined:
  • A non-nodal lesion is considered measurable if its longest diameter can be accurately measured as ≥ 2.0 cm with chest x-ray, or as ≥ 1.0 cm with CT scan, or MRI;
  • A superficial non-nodal lesion is measurable if its longest diameter is ≥ 1.0 cm in diameter as assessed using calipers (e.g., skin nodules) or imaging. In the case of skin lesions, documentation by color photography, including a ruler to estimate the size of the lesion, is recommended;
  • A malignant lymph node is considered measurable if its short axis is > 1.5 cm when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm).
  • NOTE: Tumor lesions in a previously irradiated area are not considered measurable disease.
• ECOG Performance Status (PS) of 0, 1, or 2. Form is available on the ACCRU web site.
• ECOG Performance Status = ________.
• The following laboratory values obtained ≤ 28 days prior to registration:
• Earliest laboratory test date __ __/__ __/__ __ __ __; latest laboratory test date __ __/__ __/__ __ __ __. 
  • NOTE: These dates pertain to the following labs only:
    • Absolute neutrophil count (ANC) ≥ 1500/mm^3. ANC = _______;
    • Platelet count ≥ 100,000/mm^3. Platelet count = ________;
    • Hemoglobin ≥ 9.0 g/dL. Hemoglobin = ________;
    • Total bilirubin < 1.5 x upper limit of normal (ULN), or < 2.5 x ULN if patient has Gilbert syndrome or disease involving the liver.
• Does subject have Gilbert syndrome or disease involving the liver? (this question may be answered 1=Yes or 2=No).
  • ____ Yes. Total bilirubin (≤ 2.5 x ULN) = _______; ULN = _______.
  • ____ No. Total bilirubin (≤ 1.5 x ULN) = _______; ULN = _______.
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 x ULN (or <5 x ULN in presence of suspected liver metastases).
• Does subject have suspected liver metastases? (this question may be answered 1=Yes or 2=No).
  • ____ Yes. AST (≤ 5 x ULN) = _______; ULN = _______.
  •                 ALT (≤ 5 x ULN) = _______; ULN = _______.
  • ____ No. AST (≤ 2.5 x ULN) = _______; ULN = _______.
  •                 ALT (≤ 2.5 x ULN) = _______; ULN = _______.
• Serum phosphate < institutional ULN. Serum phosphate = _______; ULN = _______.
• Serum calcium within institutional normal range, or serum albumin-corrected calcium within institutional normal range (if serum albumin is outside of the institutional normal range).
  Which test was done to satisfy eligibility?
  ____ Serum calcium. Serum calcium = _______; LLN = _______; ULN = _______.
  ____ Serum albumin-corrected calcium = _______; LLN = _______; ULN = _______.
• Potassium levels > institutional lower limit of normal (supplementation can be used to correct potassium level during screening). Potassium = _______; LLN = _______.
• Serum creatinine < 1.5 x ULN, or calculated creatinine clearance >30 mL/min using the Cockcroft-Gault formula or 24-hours urine collection analysis.
  Which test was done to satisfy eligibility?
  ____ Serum creatinine. Serum creatinine = _______; ULN = _______.
  ____ Calculated creatinine clearance = _______.
• Corrected QT interval (QTc) by Fridericia’s method (QTcF) assessed by electrocardiogram (ECG) completed ≤ 28 days prior to registration, and resulted as:
  • QTcF < 450 msec in men;or
  • QTcF < 470 msec in women.
• Negative serum pregnancy test completed ≤  7 days prior to registration, for women of childbearing potential only.
  See Appendix I for definition of WOCBP.
  If not a woman of childbearing potential or male (check NA)
  If a woman of childbearing potential – Negative serum pregnancy test date __ __/__ __/__ __ __ __.
• Willing to provide tissue and blood samples for correlative research purposes.
• Willing to allow transfer of tissue and blood samples, clinical information, and outcome data collected from this trial for future research.

All responses in above section must be “Yes” unless specified as “NA.”

• Prior treatment with Pemigatinib.
• Prior treatment with a selective FGFR inhibitor <180 days (6 months ) prior to registration.
• Known hypersensitivity or severe reaction to an FGFR inhibitor, or to the excipients of Pemigatinib (i.e. microcrystalline cellulose, sodium starch glycolate, and magnesium stearate).
• Current evidence of clinically significant corneal or retinal disorder confirmed by ophthalmologic examination.
• Treatment with other investigational study drug for any indication for any reason, or receipt of anticancer medications <14 days prior to registration.
• Major surgery < 28 days prior to registration.
• External beam radiation therapy < 28 days prior to registration, or palliative radiation for non-CNS disease <14 days prior to registration.
• External beam radiation therapy < 28 days prior to registration.
  If no prior external beam radiation therapy (check NA).
  If prior external beam radiation therapy
  •Last day of external beam radiation therapy.
  __ __/__ __/__ __ __ __
• Palliative radiation for non-CNS disease <14 days prior to registration.
  If no prior palliative radiation for non-CNS disease (check NA).
  If prior palliative radiation for non-CNS disease
  •Last day of palliative radiation for non-CNS disease.
  __ __/__ __/__ __ __ __
• Brain metastases, central nervous system (CNS) metastases, leptomeningeal disease, or spinal cord compression.
  • NOTE: Patients who are asymptomatic or previously treated and stable, without evidence of progression for > 28 days prior to registration are eligible.
  • NOTE: Patients taking concomitant corticosteroids and/or anticonvulsants are allowed if patient is on a stable or decreasing dose of such treatment for > 28 days prior to registration.
• History or presence of significant cardiovascular disease or condition including:
  • Uncontrolled angina pectoris (Canadian Cardiovascular Society Grade II-IV despite medical therapy);
  • Congestive heart failure (New York Heart Association Class III or IV);
  • Uncontrolled arrhythmia requiring therapy.
    • NOTE: Patients with a pacemaker and well-controlled rhythm for > 28 days prior to registration are not excluded;
  • Any of the following occurring < 6 months prior to registration: Myocardial infarction, angioplasty, cardiac stenting, coronary/peripheral artery bypass graft, cerebrovascular accident or transient ischemic attack.
• Failure to adequately recover (i.e., to < Grade 1 (according to CTCAE v.5) or to pre-treatment baseline) from adverse events (AEs) deemed by the investigator as clinically significant and attributed to prior therapy. Exception: alopecia.
• Current use of prohibited medication:
  • Concomitant administration of potent CYP3A4 inhibitors and inducers and moderate CYP3A4 inducers. Based on the low overall bioavailability of topical ketoconazole, there are no restrictions on topical ketoconazole;
  • Any concomitant use of a selective FGFR inhibitor (other than Pemigatinib);
  • Investigational study drug for any indication;
  • Use of any anticancer medications (other than Pemigatinib).
• Use of any potent CYP3A4 inhibitors or inducers or moderate CYP3A4 inducers < 14 days or 5 half-lives (whichever is shorter) prior to registration.
  • NOTE: Topical ketoconazole will be allowed.
• History of hypovitaminosis D requiring supraphysiologic doses to replenish the deficiency.
  • NOTE: Patients receiving Vitamin D food supplements are allowed.
• History and/or current evidence of ectopic mineralization/calcification, including but not limited to soft tissue, kidneys, intestine, myocardia, or lung; with the exception of calcified lymph nodes and asymptomatic arterial or cartilage/tendon calcification.
• Unable or unwilling to swallow Pemigatinib and keep a medication diary, or significant gastrointestinal disorder(s) that could interfere with absorption, metabolism or excretion of Pemigatinib per the discretion of the investigator.
• Any of the following because this study involves an agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:
  • Pregnant women;
  • Nursing women;
  • Women of childbearing potential or men able to father children who have a female partner of childbearing potential, who are unwilling to employ acceptable contraception.
• Known history of human immunodeficiency (HIV) infection or positivity on immunoassay confirmed per local standards.
  • NOTE: HIV test is not required for screening, but patients with a known history of HIV infection will be excluded.
• Evidence of active hepatitis B (HBV) or hepatitis C (HCV) infection.
• Other known active malignancy < 5 years prior to registration.
  • EXCEPTIONS: Non-melanotic skin cancer or carcinoma in situ of the cervix, provided there is no known active disease and no additional therapy for the condition is ongoing or required during the trial period.
  • NOTE: Anti-estrogen/androgen therapy or bisphosphonates allowed.
• Co-morbid systemic illness, other severe concurrent disease, or psychiatric illness/social situation which, in the judgment of the investigator, would make the patient inappropriate for entry into this study, limit compliance with study requirements, or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimen.

All responses in above section must be “No” unless specified as “NA”.

• Voluntarily signed consent.
• Age of ≥ 18 and ≤ 80 years.
• Received sufficient prior lines of myeloma therapy.
• Received treatment with at least one proteasome inhibitor, one IMiD and daratumumab.
• The patients should have measurable disease per IMWG definition.
• Estimated life expectancy > 12 weeks.
• ECOG performance score 0-1.
• Patients should have reasonable CBC counts, renal and hepatic functions.
• Sufficient venous access for leukapheresis collection, and no other contraindications to leukapheresis.
• Women of childbearing age must undergo a serum pregnancy test with negative results before screening, and are willing to use effective and reliable method of contraception for at least 6 months after T cell infusion.
• Men must be willing to use effective and reliable method of contraception for at least 6 months after T cell infusion.

• Pregnant or lactating women.
• HIV, active hepatitis C virus (HCV), or active hepatitis B virus (HBV) infection.
• Any uncontrolled active infection.
• AEs from previous treatment that have not recovered.
• Patients who have had anti-BCMA therapy.
• Patients who have graft versus host disease (GvHD).
• Patients have received stem cell transplantation less than 12 weeks before leukapheresis.
• Patients have received any anti-cancer treatment before leukapheresis.
• Patients have received steroids before leukapheresis or lymphodepletion.
• Patients have plasma cell leukemia, Waldenström macroglobulinemia, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome or clinically significant symptomatic immunoglobulin light chain (AL) amyloidosis with evidence of end-organ damage.
• Patients have been administered live attenuated vaccine before leukapheresis or lymphodepletion.
• Patients allergic to Flu, Cy, tocilizumab, dimethyl sulfoxide (DMSO) or CT053 CAR BCMA T cell.
• Patients have clinical significant cardiac conditions that researchers believe that participating in this clinical trial may endanger the health of the patients.
• Patients have clinical significant pulmonary conditions.
• Patients are known to have active autoimmune diseases including but not limited to psoriasis, rheumatoid arthritis and other needs of long-term immunosuppressive therapy.
• Patients with second malignancies in addition to MM are not eligible.
• Patients have central nervous system (CNS) metastases or CNS involvement.
• Patients have significant neurologic disorders.
• Patients are unable or unwilling to comply with the requirements of clinical trial.

Eligibility last updated 11/24/21. Questions regarding updates should be directed to the study team contact.

• Patients must be greater than or equal to 3 years and less than 22 years of age at the time of enrollment.
• Patients must be newly diagnosed and have:
  • Eligibility confirmed by rapid central pathology and molecular screening review on APEC14B1:
    • classical histologic type (non LC/A) WNT medulloblastoma;
    • positive nuclear β-catenin by IHC;
    • positive for CTNNB1 mutation;
    • negative for MYC and MYCN by FISH.
• Patient must have negative lumbar CSF cytology.
  • Note: CSF cytology for staging should be performed no sooner than 14 days post operatively to avoid false positive CSF. Ideally, CSF should be obtained between Day 14 and Day 21 to allow for final staging status before enrollment onto the study. Patients with positive CSF cytology obtained 0 to 14 days after surgery should have cytology repeated to determine eligibility and final CSF status.  Patients with negative CSF cytology from lumbar puncture obtained 0 to 14 days after surgery do not need cytology repeated. Patients with negative CSF cytology from lumbar puncture obtained prior to surgery do not need cytology repeated post-operatively.
• Patients must have eligibility confirmed by Rapid Central Imaging Review on APEC14B1. Patients must have ≤ 1.5 cm2 maximal cross-sectional area of residual tumor (see Section 3.1.4). Whole brain MRI with and without gadolinium and spine MRI with gadolinium must be performed.
• Patients must be enrolled, and protocol therapy must be projected to begin, no later than 36 days after definitive diagnostic surgery (Day 0). 
• Adequate Bone Marrow Function Defined As:
  • Peripheral absolute neutrophil count (ANC) ≥ 1000/μL;
  • Platelet count ≥ 100,000/μL (transfusion independent);
  • Hemoglobin ≥ 8.0 g/dL (may receive RBC transfusions).
• Adequate Renal Function Defined As:
  • Creatinine clearance or radioisotope GFR ≥ 70 mL/min/1.73 m^2; or
  • A serum creatinine based on age/gender as follows:
    • Age | Maximum Serum Creatinine (mg/dL) | Male | Female
    • 3 to < 6 years | 0.8 | 0.8
    • 6 to < 10 years | 1.0 | 1.0
    • 10 to < 13 years | 1.2 | 1.2
    • 13 to < 16 years | 1.5 | 1.4
    • ≥ 16 years | 1.7 | 1.4
  • The threshold creatinine values in this Table were derived from the Schwartz formula for estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing child length and stature data published by the CDC.
• Adequate Liver Function Defined As:
  • Total or direct bilirubin ≤ 1.5 x upper limit of normal (ULN) for age; and
  • SGPT (ALT) ≤ 135 U/L (3x ULN). For the purpose of this study, the ULN for SGPT is 45 U/L.
• Central Nervous System Function Defined As:
  • Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled.
  • Patients must not be in status epilepticus, a coma or on assisted ventilation at the time of study enrollment.
• Patients must have receptive and expressive language skills in English, French, or Spanish to complete the QoL and Neurocognitive assessments. If a patient meets these criteria but the parent/guardian speaks a language other than English, French, or Spanish, the patient may still be enrolled and tested, and the parent-report measures should be omitted.

• Patients with metastatic disease by either MRI evaluation (brain and spine) or lumbar CSF cytology are not eligible. Patients who are unable to undergo a lumbar puncture for assessment of CSF cytology are ineligible.
• Patients must not have received any prior radiation therapy or chemotherapy (tumor-directed therapy) other than surgical intervention and/or corticosteroids.
• Female patients who are pregnant are ineligible due to risks of fetal and teratogenic adverse events as seen in animal/human studies.
• Lactating females are not eligible unless they have agreed not to breastfeed their infants.
• Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained.
• Sexually active patients of reproductive potential are not eligible unless they have agreed to use an effective contraceptive method for the duration of their study participation.
• Patients with a history of moderate to profound intellectual disability (i.e., IQ < 55) are not eligible for enrollment.
  • PLEASE NOTE: Children with a prior history of attention deficit hyperactivity disorder (ADHD) or a specific learning disability (e.g., dyslexia) are eligible for this study.
• All patients and/or their parents or legal guardians must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines.
• All institutional, FDA, and NCI requirements for human studies must be met.

• Scheduled and indicated for standard-of-care liver tissue ablation for either hepatocellular carcinoma (HCC) or metastatic liver tumor(s) using either radiofrequency (RF) or microwave (MW) energy.
• At least 21 years of age.
• Single tumor, or multiple tumors only if the distance between the ablated tumor and all other tumors allows for distinct separation between the necrotic zones (minimum of 1cm), based on the physician’s discretion.
• Distance between the tumor and the edge of any previous necrotic zones allows for distinct separation between the necrotic zones (minimum of 1cm), based on the physician’s discretion.
• Single ablation, using a single ablation needle, per tumor.
• Able and willing to give informed consent.

• Liver tumor that cannot be ablated with a single ablation needle, according to the investigator’s clinical discretion.
• Subject cannot tolerate/undergo contrast-enhanced CT.
• Planned ablation includes adjunctive means other than RF or MW energy (e.g., ethanol, hepatic artery embolization, etc.) or overlapping ablations using a single ablation needle.
• Ablation area cannot be visualized continuously using ultrasound throughout the entire ablation procedure.
• Pregnant or lactating.
• Currently participating in another clinical trial of an unapproved investigational device or drug that has not concluded the follow-up period.
• Unable or unwilling to give informed consent.

Eligibility last updated 5/24/22. Questions regarding updates should be directed to the study team contact.

• Patients must have histologically confirmed World Health Organization (WHO) grade II-III meningioma which has relapsed after prior radiation therapy with radiologically progressive or recurrent disease.
• Patients must have measurable disease, defined as at least 1 lesion that can be accurately measured in at least one dimension as >= 1 cm on brain MRI but with the maximum dimension =< 5 cm OR gross tumor volume < 20 cm^3. All relapsed disease would need to be eligible to be treated with reirradiation.
• Patients must have at least one prior surgery with available archival formalin-fixed paraffin-embedded (FFPE) tumor blocks of the initial or recurrent meningioma. If there are multiple tumor blocks from multiple surgeries, the most recent tumor block (and ideally of the relapsed tumor after initial radiation therapy) should be submitted. Annotation regarding whether the tumor block is before or after initial radiation therapy should be provided.
• Prior initial radiation therapy may include external beam radiation or radiosurgery, or combination of both. However, the total dose of prior radiation exposure to the site of recurrent tumor (for consideration of re-irradiation) cannot be more than 70 Gy. The duration since the previous radiation exposure to the site of reirradiation need to be at least 6 months.
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
  •Leukocytes >= 3,000/mcL.
• Absolute neutrophil count >= 1,500/mcL.
• Platelets >= 100,000/mcL.
• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN).
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN.
• Creatinine =< 1.5 x institutional ULN OR glomerular filtration rate (GFR) >= 30 mL/min/1.73 m^2 for patients with creatinine levels above 1.5 x institutional normal.
• The effects of nivolumab and/or ipilimumab on the developing human fetus are unknown. For this reason and because radiation therapy is known to be teratogenic, women of childbearing potential (WOCBP) and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. WOCBP should use an adequate method to avoid pregnancy for 5 months after the last dose of investigational drug. Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 24 hours prior to the start of nivolumab. Women must not be breastfeeding. Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. Men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 7 months after the last dose of investigational product. Women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile as well as azoospermic men) do not require contraception.
• Women of childbearing potential (WOCBP) is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal. Menopause is defined clinically as 12 months of amenorrhea in a woman over 45 in the absence of other biological or physiological causes. In addition, women under the age of 55 must have a documented serum follicle stimulating hormone (FSH) level less than 40 mIU/mL.
• WOCBP receiving nivolumab will be instructed to adhere to contraception for a period of 5 months after the last dose of investigational product. Men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 7 months after the last dose of investigational product. These durations have been calculated using the upper limit of the half-life for nivolumab (25 days) and are based on the protocol requirement that WOCBP use contraception for 5 half-lives plus 30 days and men who are sexually active with WOCBP use contraception for 5 half-lives plus 100 days
  •Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
• Ability to understand and the willingness to sign a written informed consent document.

• Patients who have had chemotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study.
• Patients who have had radiation therapy (to the site of reirradiation) within 6 months prior to entering the study.
• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1); however, alopecia, sensory neuropathy =< grade 2, or other =< grade 2 not constituting a safety risk based on the investigator's judgment are acceptable.
• Patients who are receiving any other investigational agents.
• Patients who have previous treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to nivolumab and/or ipilimumab.
• History of severe hypersensitivity reaction to any monoclonal antibody.
• Current use of immunosuppressive medication (EXCEPT for the following: Intranasal, inhaled, topical steroids, or local steroid injection [e.g. intra-articular injection]; systemic corticosteroids at doses =< 4 mg/day of dexamethasone or equivalent; steroids as premedication for hypersensitivity reactions [e.g., computed tomography (CT) scan premedication]).
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. However, patients with human immunodeficiency virus (HIV) on stable therapy with minimal viral loads and patients with hepatitis B and hepatitis C who have received treatment with minimal viral loads will be eligible.
• Pregnant women are excluded from this study because radiation therapy is teratogenic and that the effects of nivolumab and/or ipilimumab on the developing human fetus are unknown. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with nivolumab and/or ipilimumab, breastfeeding should be discontinued if the mother is treated with nivolumab and/or ipilimumab.
• Patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids, should be excluded. These include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded because of the risk of recurrence or exacerbation of disease. Patients with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible. Patients with rheumatoid arthritis and other arthropathies, Sjogren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible
  •Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger (precipitating event).
• Prior organ transplantation including allogeneic stem cell transplantation. 
• Other severe acute or chronic medical conditions including immune colitis, inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis, or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior, or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
• Live vaccination within 4 weeks of the first dose of nivolumab and while on trial is prohibited except for administration of inactivated vaccines.

• Male and female.
• Provision of signed and dated written informed consent form (ICF) and any locally required authorization (e.g., Health Insurance Portability and Accountability Act in the US, EU Data Privacy Directive in the EU) obtained from the patient (or legal representative / impartial witness where mandated & allowed by local regulations) prior to any mandatory study-specific procedures, sampling, and analyses, including screening evaluations.
• Age ≥ 18 years at the time of screening. For patients aged < 20 years and enrolled in Japan, a written informed consent should be obtained from the patient and his or her legally acceptable representative. Patients aged < 21 years must not be enrolled in Egypt or Singapore.
• Histologically or cytologically (or radiologically for patients undergoing curative ablation) confirmed HCC, newly diagnosed, and successfully completed curative therapy (resection or ablation). (a) Hepatic resection and have the following pathologic and/or radiologic findings from surgery: (i) Any size with microvascular invasion (clear pathologic assessment on microvascular invasion: Yes or No) and/or satellite tumor (ii) 3 or less tumors, with at least one > 5 cm (iii) 4 or more tumors, ≤ 5 cm each (b) Ablation (radiofrequency or microwave, cryoablation, or PEI per institutional standard. Embolisation (e.g., TACE/TAE) is acceptable so long as it is part of the local planned ablative process) where all curative procedures are completed within a 12 week window, and have the following radiologic findings prior to ablation: (i) Solitary tumor, 3 to 5 cm (ii) 2 to 4 tumors, ≤ 5 cm each (iii) Exclude patients with 5 or more tumors.
• Patients must be randomized within 12 weeks of completion of curative hepatic resection, or final curative ablation procedure.
• Imaging to confirm disease-free status within 28 days prior to randomization.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 or 1 at enrollment.
• Child-Pugh score of 5 or 6. 8 Patients with active HBV infection (as characterized by positive hepatitis B virus surface antigen [HBsAg] and/or anti-hepatitis B core antibodies (HBcAbs) with detectable HBV deoxyribonucleic acid (DNA) [≥10 IU/mL or above the limit of detection per local laboratory]) must receive antiviral therapy at least after enrollment (sign of ICF) per institutional practice. Patients must remain on antiviral therapy for the study duration and for 6 months after the last dose of study treatment. Patients must show evidence of HBV stabilization or signs of viral response (e.g., reduction HBV DNA levels) prior to randomization. Patients who test positive for anti-HBcAb with undetectable HBV DNA (< 10 IU/mL or under the limit of detection per local laboratory) do not require antiviral therapy. These patients will be tested at every cycle to monitor HBV DNA levels and initiate antiviral therapy if HBV DNA is detected (≥ 10 IU/mL or above the limit of detection per local laboratory). Patients with detectable HBV DNA during the study must initiate and remain on antiviral therapy for the study duration and for 6 months after the last dose of study treatment.
• Patients with active HCV infection (as characterized by the presence of detectable HCV ribonucleic acid (RNA)) must be managed per local institutional practice for the study duration.
• Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. A definition of post-menopausal.
• Adequate organ and marrow function, as defined below. Criteria “a,” “b,” “c,” and “f” cannot be met with transfusions, infusions, or growth factor support administered within 14 days of starting the first dose:
  • Hemoglobin ≥ 9 g/dL;
  •  Absolute neutrophil count ≥ 1000/µL;
  • Platelet count ≥ 65000/µL;
  • Total bilirubin (TBL) ≤ 2.0 × upper limit of normal (ULN);
  • Aspartate aminotransferase (AST) and ALT ≤ 5 × ULN;
  •  Albumin ≥ 2.8 g/dL;
  • International normalized ratio ≤ 1.6 (for patients receiving Warfarin, please consult with the study physician);
  • Urine protein 2+ or less;
  • Tested blood urea nitrogen or creatinine ≤ 1.5 × ULN or calculated creatinine clearance (CL) ≥ 51 mL/min as determined by the Cockcroft-Gault formula (using actual WT) or 24-hour urine creatinine CL;
  • Males: Creatinine CL (mL/min)=WT (kg) × (140
    •Age) 72 × serum creatinine (mg/dL); Females:  Creatinine CL (mL/min) = WT (kg) × (140
    •Age) × 0.85 72 × serum creatinine (mg/dL).

• History of deep vein thrombosis, pulmonary embolism, or any other significant thromboembolism (venous port or catheter thrombosis or superficial venous thrombosis are not considered “significant”) during the 3 months prior to randomization.
• History of significant bleeding disorders, vasculitis, or a significant bleeding episode from the GI tract within 3 months prior to study randomization.
• History of GI perforation and/or fistulae within 6 months prior to randomization.
• Any history of nephrotic or nephritic syndrome.
• Evidence of symptomatic congestive heart failure (New York Heart Association II to IV) or symptomatic or poorly controlled cardiac arrhythmia.
• History of arterial thrombotic event, including myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack, within 6 months prior to randomization.
• Uncontrolled arterial hypertension defined by a systolic pressure ≥ 150 mm Hg or diastolic pressure ≥ 90 mm Hg despite standard medical management.
• Serious or non-healing wound, peptic ulcer, or bone fracture within 28 days prior to randomization.
• Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.
• Evidence, by Investigator assessment, of varices at risk of bleeding on upper endoscopy or contrast-enhanced cross-sectional imaging undertaken at the screening visit, or within 6 months (24 weeks) of randomization.
• Evidence of distant metastasis (except regional lymph node metastases related to the disease under study, per Appendix F), co-existing malignant disease or macrovascular invasion on baseline imaging.
• History of hepatic encephalopathy within 12 months prior to randomization or requirement for medications to prevent or control encephalopathy (no lactulose, rifaximin, etc, if used for purposes of hepatic encephalopathy).
• Evidence of portal vein thrombosis, visible on baseline/eligibility imaging, and patients with Vp1, Vp2, Vp3 and Vp4 (benign portal vein thrombosis is allowed, where not related to tumor thrombus, and anti-thrombotics may be used as needed).
• Clinically meaningful ascites, defined as ascites requiring non-pharmacologic intervention (e.g., paracentesis) to maintain symptomatic control, within 6 months prior to the first dose of study treatment. (a) Patients with ascites who have required pharmacologic intervention (e.g., diuretics) and who have been on stable doses of diuretics for ascites for ≥ 2 months before randomization are eligible.
• Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis or Crohn's disease], diverticulitis [except for diverticulosis], systemic lupus erythematosus, sarcoidosis syndrome, or Wegener syndrome [e.g., granulomatosis with polyangiitis, Graves’ disease, rheumatoid arthritis, hypophysitis, and uveitis]). The following are exceptions to this criterion:
  • Patients with vitiligo or alopecia;
  • Patients with hypothyroidism (e.g., following Hashimoto syndrome), stable on hormone replacement;
  • Any chronic skin condition that does not require systemic therapy;
  • Patients without active disease in the last 5 years may be included but only after consultation with the Study Physician;
  • Patients with celiac disease controlled by diet alone.
  • Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, active interstitial lung disease (ILD), serious chronic GI conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirements, substantially increase the risk of incurring AEs or compromise the ability of the patient to give written informed consent.
  • History of another primary malignancy except for the following:
    • Prostate cancer of pathologic stage less than or equal to T2cN0M0 determined from a prior prostatectomy without biochemical recurrence and who, in the opinion of the Investigator, are not deemed to require active intervention, or patients with incidental histologic findings of prostate cancer that has not been treated prior to the study and who do not require specific therapy for prostate cancer beyond the surgery described in the Clinical Study Protocol and also are considered to be at low risk for recurrence per the Investigator;
    • Malignancy treated with curative intent and with no known active disease ≥ 5 years before the first dose of study treatment and of low potential risk for recurrence;
    • Adequately treated non-melanoma skin cancer or lentigo malignant without evidence of disease;
    • Adequately treated carcinoma in situ without evidence of disease;
    • Patients with another primary malignancy that is not active or expected to be clinically relevant in the next 5 years may be considered further to discussion with the Study Physician.
• Active infection, including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice) or human immunodeficiency virus (HIV; positive for HIV 1/2 antibodies).
• Active co-infection with both HBV and hepatitis D virus.
• Known allergy or hypersensitivity to any of the study treatments or any of the study treatment excipients.
• History of aneurysm (Patients with a capped aneurysm may be included but only after consultation with the Study Physician).
• Major surgery (as defined by the Investigator) within 28 days prior to randomization, or central venous access device placement within 7 days prior to randomization (biopsy from any type of surgery within 28 days is not an exclusion criteria, nor are procedures to treat varices).
• Receipt of routine treatment for chronic condition with nonsteroidal anti-inflammatory agents (e.g., indomethacin, ibuprofen, naproxen, or similar agents) or other anti-platelet agents (e.g., clopidogrel, ticlopidine, dipyridamole, or anagrelide). Require minimum washout period of 5 days prior to randomization. Low dose aspirin (≤ 325 mg/day) is permitted. Prohibited concomitant medications with exceptions.
• Receipt of prior systemic anticancer therapy for HCC.
• History of allogeneic organ transplantation or those who are on a waiting list for liver transplantation.
• Receipt of live attenuated vaccine within 30 days prior to the first dose of study treatment.
  • Note: Patients, if enrolled, should not receive live vaccine while receiving study treatment and up to 90 days after the last dose of study treatment.
• Current or prior use of immunosuppressive medication within 14 days before the first dose of study treatment. The following are exceptions to this criterion:
  • Intranasal, inhalational, topical steroids, or local steroid injections (e.g., intra-articular injection);
  • Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent;
  • Steroids as pre-medication for hypersensitivity reactions (e.g., CT-scan premedication).
• Receipt of treatment with herbal medications labelled for the treatment of HCC (e.g., Huaier) within 14 days prior to first dose of study treatment.
• Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ highly effective birth control from screening to 6 months after the last dose of study treatment. Not engaging in sexual activity, per the patient’s preferred and usual lifestyle, for the total duration of the treatment and 6 months after the last dose of study treatment is an acceptable practice.
• Judgment by the Investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions, and requirements.
• Involvement in the planning and/or conduct of the study for both AstraZeneca staff and/or staff at the study site.

Eligibility last updated 10/7/21. Questions regarding updates should be directed to the study team contact.

For Phase 1

• MSS-CRC who are currently receiving systemic treatment with a fluoropyrimidine and oxaliplatin and/or irinotecan that may include a VEGF or EGFR targeting therapy as their 1L or 2L therapy for metastatic disease OR who have experienced disease progression following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan that may include a VEGF or EGFR targeting therapy, but have not initiated a new line of therapy;
• NSCLC who are currently receiving systemic treatment with an anti-PD-(L)1 antibody in combination with cytotoxic, platinum-based chemotherapy OR who have experienced disease progression following treatment an anti-PD-(L)1 antibody in combination with cytotoxic, platinum-based chemotherapy (or antiPD-(L)1 alone if patient refuses platinum-based chemotherapy), but have not initiated a new line of therapy;
• PDA who are currently receiving systemic cytotoxic chemotherapy as their 1L therapy for metastatic disease OR who have experienced disease progression on 1L systemic cytotoxic chemotherapy, but have not initiated a new line of therapy;
• Any solid tumor histology where the patient has experienced disease progression with all available therapies known to confer clinical benefit.

For Phase 2

• MSS-CRC who are currently receiving systemic treatment with a fluoropyrimidine and oxaliplatin and/or irinotecan that may include a VEGF or EGFR targeting therapy as their 1L therapy for metastatic disease OR who have experienced disease progression following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan that may include a VEGF or EGFR targeting therapy and have not received additional lines of systemic therapy in the metastatic setting;
• NSCLC who are currently receiving systemic treatment with an anti-PD-(L)1 antibody in combination with cytotoxic, platinum-based chemotherapy OR who have experienced disease progression following treatment an anti-PD-(L)1 antibody followed by cytotoxic, platinum-based chemotherapy (or anti-PD-(L)1 alone if patient refuses platinum-based chemotherapy) and have not received additional lines of systemic therapy in the metastatic setting (Patients whose tumor harbors KRAS G12C may also receive a targeted therapy that inhibits KRAS G12C as prior therapy in addition to pembrolizumab and platinum-based chemotherapy);
• PDA who are currently receiving systemic cytotoxic chemotherapy as their 1L therapy for metastatic disease OR who have experienced disease progression on 1L systemic cytotoxic chemotherapy and have received no more than 1 prior line of therapy in the metastatic setting;
• Any solid tumor histology where the patient has experienced disease progression with all available therapies known to confer clinical benefit.
• Patient’s tumor possesses one of the mutations as determined per local institutional standard.
• ≥ 18 years of age.

• Tumors with genetic characteristics as follows:
  • For NSCLC, patients with a known genetic driver alteration in EGFR, ALK, ROS1, RET, or TRK;
  • Patients with known MSI-high disease based on institutional standard.
• Known exposure to chimpanzee adenovirus within the prior 5 months or any history of anaphylaxis in reaction to a vaccination or hypersensitivity to study drug components.
• Bleeding disorder (e.g., factor deficiency, coagulopathy) or history of significant bruising or bleeding following IM injections or blood draws.
• Patient has received prior therapy consisting of anti-CTLA-4, anti-PD-1, anti-PD-L1, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways, with the exception of patients with NSCLC or a mutation-positive solid tumor.
• History of allogenic/solid organ transplant .
• Active, known, or suspected autoimmune disease.
• Active tuberculosis or recent (<2 week) clinically significant infection, or evidence of active hepatitis B or hepatitis C.
• Known history of positive test for human immunodeficiency (HIV) or known acquired immunodeficiency syndrome (AIDS) Complete inclusion and exclusion criteria are listed in the clinical study protocol.

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Eligibility last updated 2/1/23. Questions regarding updates should be directed to the study team contact.