• 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).

• Males or females age ≥ 18 years
• Patient has non-metastatic, histologically confirmed primary or locoregionally recurrent estrogen receptor (ER) ≤ 10%, progesterone receptor (PR) ≤ 10%, and HER2-negative breast cancer (triple negative breast cancer [TNBC]) either using the baseline biopsy specimen or the post-neoadjuvant chemotherapy (NAC) residual surgical specimen and residual cancer burden (RCB)2 or RCB3, as defined by Symmans et al., 2007, and received neoadjuvant anthracycline and/or taxane-based chemotherapy OR patient has non-metastatic, histologically confirmed primary ER > 10% and/or PR > 10%, HER2-negative breast cancer with RCB3 and received neoadjuvant anthracycline and/or taxane-based chemotherapy OR patient has locoregionally recurrent TNBC or ER > 10% and/or PR > 10%, HER2-negative breast cancer.
  • Note: The RCB can be calculated at http://www3.mdanderson.org/ap/medcalc/index.cfm?pagename=jsconvert2
  • Note: Results from any CLIA-certified lab are acceptable for the purpose of determining study eligibility.
  • Note: For patients with primary breast cancer, there is no minimum number of neoadjuvant cycles required provided the patient received an anthracycline or taxane preoperatively. Patients with locoregionally recurrent breast cancer are not required to have received preoperative chemotherapy.
• Patient has undergone total mastectomy or wide local excision with axillary staging, and the margins of the resected wide local excision or mastectomy specimens are free of invasive tumor and ductal carcinoma in situ (DCIS) or patient has undergone axillary surgery for regionally recurrent breast cancer. Unresected axillary level III, internal mammary, and supraclavicular nodal disease is permitted.
  • Note: For patients who have undergone mastectomy, immediate reconstruction is allowed.
• Patients must have completed their final breast surgery including re-excision of margins for invasive cancer and DCIS, or received their last adjuvant chemotherapy infusion,  within 90 but not fewer than 21 days prior to registration unless patient received postoperative chemotherapy in which case patients must have completed their adjuvant chemotherapy within 90 days but not fewer than 28 days prior to registration. but no sooner than 21 days prior to the initiation of RT for surgery or 28 days for chemotherapy. Post-radiotherapy adjuvant systemic therapy (e.g. adjuvant capecitabine) may not be completed less than 21 days prior to the first fraction of RT or begin less than 28 days from the last fraction of RT.
• Patient must have recovered from surgery with the incision completely healed and no signs of infection prior to registration.
• Patients must be proceeding with breast/chest wall and regional nodal irradiation including internal mammary node treatment. BFor patients with bilateral breast cancer is permitted provided that , RT ismust be indicated and administered only to one side.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
• Willing to provide tissue and blood samples for correlative research:
  • 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]) ≤ 3 x institutional ULN;
  • Creatinine ≤ institutional ULN; OR
  • Glomerular filtration rate (GFR) ≥ 60 mL/min/1.73 m^2 for patients with creatinine levels above ULN.
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral 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.
• Negative urine or serum pregnancy test for individuals of childbearing potential.
  • Note: The effects of berzosertib on the developing human fetus are unknown. For this reason and because DNA-damage repair inhibitors as well as radiation used in this trial 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 6 months after completion of M6620 administration. 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 6 months after completion of berzosertib administration.
• Ability to understand and the willingness to sign a written informed consent document.

• Patients who have had chemotherapy within 4 weeks prior to entering the study.
• Prior RT to the ipsilateral chest wall or ipsilateral breast or thorax. Individuals with prior RT to the contralateral breast or chest wall are eligible.
• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia and grade 1-2 taxane-induced neuropathy which will be permitted.
• Patients who are receiving any other investigational agents or concomitant anti-neoplastic treatment, except endocrine therapies and bisphosphonates which are permitted without restriction even during protocol treatment. Postoperative chemotherapy is allowed but must be discontinued >28 days prior to registration.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to berzosertib.
• Berzosertib is primarily metabolized by CYP3A4; therefore, concomitant administration with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir, indinavir, nelfinavir, and saquinavir) or inducers of CYP3A4 (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, St. John's wort) should be avoided. Patients requiring any medications or substances that are strong inhibitors or inducers of CYP3A during the course of the study and for 14 days prior to enrollment are ineligible. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product.
• Patients with uncontrolled intercurrent illness. This includes but is not limited to, ongoing uncontrolled serious infection requiring IV antibiotics at the time of registration, symptomatic congestive heart failure, unstable angina pectoris, symptomatic/uncontrolled cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Active systemic lupus, scleroderma, or dermatomyositis with a CPK level above normal.
• Pregnant women are excluded from this study because berzosertib as a DNA damage repair inhibitor may have the potential for teratogenic or abortifacient. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with berzosertib, breastfeeding should be discontinued if the mother is treated with berzosertib.
• Patients with known hereditary syndromes predisposing to radiosensitivity such as Li Fraumeni syndrome and ataxia telangiectasia are excluded from the study. Patients with mutations in breast cancer predisposition genes such as BRCA1, BRCA2, PALB2, CHEK2, and ATM are eligible.
• Patients with a prior or concurrent malignancy, excluding non-melanoma skin cancers and non-invasive cancers whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen.

• 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.

In the study eye since randomization,
new retinal detachment, or retinal tear
that, in the opinion of the investigator,
may preclude successful subretinal
injection of ABBV-RGX-314.

New subfoveal fibrosis or subfoveal atrophy since randomization, as defined in subbullets below, or any condition preventing VA improvement in the study eye.
•Central subfield fibrosis (central 1mm) in the study eye, as determined by the CRC.
•Any central subfield atrophy (central 1mm) in the study eye (eg, incomplete RPE and outer retinal atrophy, or complete RPE and outer retinal atrophy), as determined by the CRC.

3. Ocular or periocular infection or intraocular inflammation in the study eye that may interfere with the surgical procedure.

4. Myocardial infarction, cerebrovascular accident, or transient ischemic attacks since randomization.

5. Uncontrolled hypertension (systolic BP >180 mmHg, diastolic BP > 100 mmHg) despite maximal medical treatment.

History of malignancy or hematologic malignancy that may compromise the immune system requiring chemotherapy and/or radiation since randomization. Localized basal cell carcinoma will be permitted, as will any cancer not being treated with chemotherapy or other therapy that may compromise the immune system.

Polypoidal choroidal vasculopathy in the study eye, as determined by the investigator or the CRC.

7. Any subretinal hemorrhage in the study eye > 50% of the total lesion area or within the parafovea (3-mm center of the macula), as determined by the CRC.

8. Presence of any retinal pigment epithelial tear involving the central subfield (central 1 mm) in the study eye, as determined by the CRC.

9. Any prior nAMD treatment with photodynamic therapy or retinal laser in the study eye.

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

Eligibility last updated 10/25/23. Questions regarding updates should be directed to the study team contact.

• Age 3 to < 13 years at the time of randomization.
• Amblyopia associated with anisometropia, strabismus, or both.
• Criteria for strabismic amblyopia: At least one of the following must be met: 
  • Presence of a heterotropia on examination at distance or near fixation (with or without optical correction);
  • Documented history of strabismus which is no longer present (which in the judgment of the investigator could have caused amblyopia).
• Criteria for anisometropia: At least one of the following criteria must be met: 
  • ≥ 1.00 D difference between eyes in spherical equivalent (SE); 
  • ≥ 1.50 D difference in astigmatism between corresponding meridians in the two eyes.
• Criteria for combined-mechanism amblyopia: Both of the following criteria must be met: 
  • Criteria for strabismus are met (see above);
  • ≥ 1.00 D difference between eyes in spherical equivalent OR ≥ 1.50 D difference in astigmatism between corresponding meridians in the two eyes. 
• No previous treatment for amblyopia, including no more than 24 hours of spectacle wear.
• Investigator planning to initiate spectacle correction of refractive error meeting the following criteria based on a cycloplegic refraction that has been performed within 30 days: 
  • Full correction of spherical and cylindrical anisometropia;
  • Full correction of astigmatism with the same axis found by the cycloplegic refraction;
  • Allow symmetric reduction of sphere up to 1.50, prescribing such that the most hyperopic meridian is not rendered myopic, in the non-amblyopic eye at baseline;
  • Allow symmetric addition of only -0.25 sphere for participants with plano sphere, spherical myopia, simple or compound myopic astigmatism in the non-amblyopic eye at baseline.
• At enrollment, single VA measured in each eye assessed in trial frames with the spectacle correction the investigator plans to prescribe, using the investigator’s routine method as follows:
  • VA in the amblyopic eye 20/40 to 20/200 inclusive;
  • Age-normal VA in the fellow eye:40,41;
  • 3 years: 0.4 logMAR (20/50) or better; 
  • 4 years: 0.3 logMAR (20/40) or better;
  • 5-6 years: 0.2 logMAR (20/32) or better;
  • 7-12 years: 0.12 logMAR (78 letters) or better; 
  • Interocular difference ≥ 3 logMAR lines (0.3 logMAR) or ≥ 15 letters;
  • When participants return for the Spectacle Baseline / Randomization Visit with their new spectacles, they will need to meet the same criteria as above using the ATS HOTV or E-ETDRS protocol after wearing the new spectacles for at least 10 minutes (based upon the mean of a test and retest of VA in those new spectacles).
• Investigator is willing to prescribe spectacle wear followed sequentially by patching or simultaneous spectacles and patching treatment per protocol.
• Parent and participant willing to forego option of contact lens wear for the duration of the study. 
• Parent understands the protocol and is willing to accept randomization. 
• Parent has phone (or access to phone) and is willing to be contacted by Jaeb Center staff or other study staff. 
• Relocation outside of area of an active PEDIG site for this study within the next 56 weeks is not anticipated.

• Previous spectacle wear.
• Previous treatment for amblyopia.

• Patients must have biopsy-proven conventional CS which is:
  • Either metastatic or locally advanced and unresectable; and
  • Measurable at study entry according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria; and
  • Amenable to biopsy with imaging guidance at no or acceptable risk to the patient as defined by institutional guidelines for research-related biopsies or the treating investigator's assessment. 
• Pathology review and confirmation of diagnosis will occur at the site enrolling the patient on this study.
• Patients may have been treated with any number of prior systemic therapies. Because there are no Food and Drug Administration (FDA)-approved treatments for this disease, patients who have received no prior systemic therapy are also eligible. However, disease must be deemed surgically unresectable.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%).
• Patients must have adequate organ and marrow function as defined below:
  • Absolute neutrophil count ≥ 1,000/mm^3;
  • Hemoglobin 8 g/dL;
  • Platelet count ≥ 75,000/mm^3;
  • 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 x institutional ULN;
  • Creatinine ≤ 1.5 x institutional ULN; OR
  • Glomerular filtration rate (GFR) ≥ 45 mL/min/1.73 m^2.
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral 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 treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression, if patients have been clinically asymptomatic, and if patients have not received systemic corticosteroids for at least 28 days. Patients with brain metastases not meeting these criteria are not eligible -Patients must be disease-free of prior invasive malignancies for > 5 years, with the exception of curatively-treated basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix.
  • NOTE: If there is a history of prior malignancy, patients must not be receiving other specific treatment for that cancer.
• 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 belinostat and SGI-110 (guadecitabine) on the developing human fetus are unknown. For this reason, and because the DNA methyltransferase inhibitor decitabine, the active metabolite of SGI-110 (guadecitabine), is known to be teratogenic, and because belinostat may cause teratogenicity and/or embryo-fetal lethality by virtue of targeting actively dividing cells, 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. 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 3 months after completion of belinostat and SGI-110 (guadecitabine) administration.
• Patients must be able to understand and willing to sign a written informed consent document. Participants with impaired decision-making capacity (IDMC) who have a legally-authorized representative (LAR) and/or family member available will also be eligible.

• Patients with dedifferentiated, mesenchymal, or clear cell chondrosarcoma are not eligible.
• Patients who have not recovered from adverse events (AEs) (i.e., have residual toxicities > grade 1) due to prior anti-cancer therapy are not allowed, with the exceptions of alopecia and endocrinopathies from prior immunotherapy-based treatments that are well-controlled with hormone replacement.
• Patients who are receiving any other investigational agents.
• Patients with known history of allergic reactions or sensitivity attributed to compounds of similar chemical or biologic composition to SGI-110 (guadecitabine), its active metabolite decitabine, or belinostat.
• Chronic use of any medications or substances that are strong inhibitors of UGT1A1 is not allowed. Patients must switch to alternative medications 7-14 days before treatment with belinostat. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product.
• Patients with any known UGT1A1 polymorphism, heterozygous or homozygous, associated with reduced function (UGT1A1*6, UGT1A1*28, or UGT1A1*60).
• Patients with uncontrolled intercurrent illness.
• Patients with psychiatric illness/social situations that would limit compliance with study requirements.
• Pregnant women are excluded from this study because SGI-110 (guadecitabine) is a derivative of decitabine, which has the potential for teratogenic or abortifacient effects, and because belinostat may cause teratogenicity and/or embryo-fetal lethality by virtue of targeting actively dividing cells. Because there is an unknown but potential risk for AEs in nursing infants secondary to treatment of the mother with SGI-110 (guadecitabine) and belinostat, breastfeeding should be discontinued.
• Patients with a history of prior therapy with histone deacetylase (HDAC) or DNA methyltransferase (DNMT) inhibitors.
• Prolongation of the heart-rate corrected QT (QTc) interval ≥ 450 ms (i.e., grade 1 or higher) on the screening electrocardiogram (ECG) prior to initiation of study treatment. If baseline QTc on screening ECG is ≥ 450 ms (i.e., grade 1 or higher):
  • Check potassium and magnesium serum levels; and
  • Correct any identified hypokalemia and/or hypomagnesemia and repeat ECG to confirm a QTc interval < 450 ms.

Pre-Registration – Inclusion Criteria

• Age ≥ 18 years.
• Radiologically or pathologically confirmed hepatocellular carcinoma (HCC).
• Willingness to provide mandatory tissue specimens for correlative research.

Pre-Registration
•Exclusion Criteria

• Prior organ transplantation.

Registration –

• Tumor tissue must be FGF19 positive by mRNA or IHC.
• Disease characteristics:
  • Radiologically confirmed hepatocellular carcinoma (HCC) that is not eligible for curative resection, transplantation, or ablative therapies
  • Received at least one prior systemic treatment for HCC;
  • NOTE: Prior radiation, chemoembolization, radioembolization, or other local ablative therapies or hepatic resection are permitted.
  • Measurable disease by any imaging modality as defined by RECIST 1.1 criteria in at least one site not previously treated with radiation or liver directed therapy (including bland, chemo- or radio-embolization, or ablation).
  • NOTE: Tumor lesions in a previously irradiated area are not considered measurable disease; disease that is measurable by physical examination only is not eligible.
• ECOG Performance Status (PS) 0, 1 or 2.
• The following laboratory values obtained ≤ 15 days prior to registration:
  • Absolute neutrophil count (ANC) ≥ 1500/mm^3;
  • Hemoglobin ≥ 9.0 g/dL;
  • Platelet count ≥ 75,000/mm^3;
  • Albumin ≥ 2.5 g/dL;
  • Alanine aminotransferase (ALT) and aspartate transaminase (AST) ≤ 2.5 × ULN (or ≤ 5 × ULN for patients with liver metastasis);
  • Total bilirubin ≤ 1.5 × ULN;
  • Phosphorus ≤ 1.5 × ULN;
  • Calcium ≤ 1.5 × ULN;
  • PT/INR/aPTT ≤ 1.5 × ULN OR if patient is receiving anticoagulant therapy then INR or aPTT is within target range of therapy;
  • Serum creatinine ≤ 1.5 × ULN;
  • Calculated creatinine clearance ≥ 40 ml/min using the Cockcroft-Gault formula
• Child-Pugh scores of ≤ 7 (Child-Pugh A or B7).
• BCLC stage A, B, or C.
• Negative pregnancy test done ≤ 7 days prior to registration, for persons of childbearing potential only.
• Willing to use an adequate method of contraception from Registration through 120 days after the last dose of study medication
  • NOTE: Only for
  • persons of childbearing potential; or
  • persons able to father a child with partners of childbearing potential).
• Able to swallow oral medication.
• Provide written informed consent.
• Willingness to provide mandatory blood specimens for correlative research .
• Willingness to provide mandatory tissue specimens for correlative researchsee 
• Willingness and the ability to comply with scheduled visits (including geographical proximity), treatment plans, laboratory tests, and other study procedures.
• Ability to complete questionnaires by themselves or with assistance.

Registration
•

• Known standard therapy for the patient’s disease that is potentially curative or definitely capable of extending life expectancy.
• Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:
  • Pregnant persons;
  • Nursing persons;
  • Persons of childbearing potential who are unwilling to employ adequate contraception.
• Any of the following prior therapies:
  • Surgery ≤ 4 weeks prior to registration;
  • Radiotherapy for extended field ≤4 weeks prior to registration or limited field radiotherapy ≤ 2 weeks prior to registration;
  • Systemic anticancer therapy ≤ 2 weeks prior to registration;
  • NOTE: Prior immunotherapy is allowed unless patient discontinued due to Grade 4 AE.
  • Live vaccine ≤30 days prior to registration;
  • Prior treatment with FGFR inhibitor;
  • Received strong inhibitors and inducers and sensitive substrates of CYP3A4 ≤ 2 weeks prior to registration
  • Received a drug that has not received regulatory approval for any indication as follows:
  • ≤ 2 weeks prior to registration for nonmyelosuppressive agents; or
  • ≤ 4 weeks prior to registration for myelosuppressive agents.
• History and/or current evidence of any of the following disorders:
  • Retinal or corneal disorder confirmed by retinal/corneal examination and considered clinically significant in the opinion of the Investigator.
  • History of pneumonitis or interstitial lung disease within ≤ 3 years prior to pre-registration.
• Active CNS metastasis and/or carcinomatous meningitis.
  • NOTE: Patients with previously treated brain metastases that are clinically and radiologically stable (for at least 4 weeks prior to enrollment) are eligible.
• History of hepatitis B (HBV) and viral load ≥ 100 IU/ml.
  • NOTE: Patients who have received antiviral therapy and have viral load <100 IU/ml are eligible..
• Corrected QT interval using Fridericia’s formula (QTcF) > 480 msec.
  • NOTE: Patients with an atrioventricular pacemaker or other condition (for example, right bundle branch block) that renders the QT measurement invalid are an exception and the criterion does not apply.
• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
• Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm.
• History or risk of autoimmune disease, including, but not limited to, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis.
  • Notes:  Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone are eligible;
  • Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen are eligible;
  • Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis would be excluded) are permitted provided that they meet the following conditions:
  • Must not have ocular manifestations;
  • Rash must cover less than 10% of body surface area (BSA);
  • Disease is well controlled at baseline and only requiring low potency topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, flucinolone 0.01%, desonide 0.05%, aclometasone dipropionate 0.05%);
  • No acute exacerbations of underlying condition within the last 6 months (not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate, retinoids, biologic agents, oral calcineurin inhibitors; high potency or oral steroids).
• Known active human immunodeficiency virus (HIV) infection (defined as patients who are not on anti-retroviral treatment and have detectable viral load and CD4+ < 500/ml).
• NOTE: HIV-positive patients who are well controlled on anti-retroviral therapy are allowed to enroll.
• Currently taking strong CYP3A inhibitors/inducers and unable to discontinue ≤ 7 days prior to registration.
• History and/or current evidence of any of the following disorders:
  • Non-tumor related alteration of the calcium-phosphorus homeostasis that is considered clinically significant in the opinion of the Investigator;
  • Ectopic mineralization/ calcification, including but not limited to soft tissue, kidneys, intestine, or myocardia and lung, considered clinically significant in the opinion of the Investigator;
  • Retinal or corneal disorder confirmed by retinal/corneal examination and considered clinically significant in the opinion of the Investigator.
• Uncontrolled intercurrent illness including, but not limited to:
  • Ongoing or active severe infection;
  • NOTE: Must be afebrile >7 days to be eligible. Patient may be eligible if fever is present and infection has been ruled out or fever is related to tumor.
  • Psychiatric illness/social situations that would limit compliance with study requirements.
• Clinically significant or uncontrolled cardiac disease, including unstable angina, acute myocardial infarction within 6 months from Day 1 of study treatment administration, New York Heart Association Class III and IV congestive heart failure, and uncontrolled arrhythmia
  • NOTE: Participants with pacemaker or with atrial fibrillation and well controlled heart rate are allowed.
• Other active malignancy < 6 months prior to pre-registration.

Eligibility last updated 1/19/22 for Amendment 3. Questions regarding updates should be directed to the study team contact.

• Adult (age 18 or greater) patients who consent for enrollment in the study.
• Have undergone allogeneic HSCT within 100 days or autologous HSCT within 30 days.

Exclusin Criteria: 

• Subject transferred from another institution having already been admitted there for > 24h. This proposal seeks to create a biorepository whose purpose will be to determine mechanism of ARF/ARDS development based on initial hospital course. If a substantial part of a patient’s hospital course preceeds enrollment (and is affected by care received at another institution), we may not get meaningful insights into the ARDS mechanism by enrolling them well into the disease processes that are involved in the pathogenesis of ARDS.
• ARDS at the time of hospital admission. Since this study is looking at the mechanisms of ARDS development, we would seek to enroll patients before ARDS develops. 
• Patient’s goals of care are such that ICU transfer (and specifically use of noninvasive or mechanical ventilation) would not be considered. As such, these patients would not be able to develop the outcome of interest (ARDS).
• Admitted for:
  1. Admission only for chemotherapy administration.
  2. Control of symptoms related to diarrhea, vomiting, dehydration due to inability to swallow, dysphagia, pain or mucositis. 

Eligibility last updated 12/7/22. Questions regarding updates should be directed to the study team contact.

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 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.

• Documented diagnosis of UC at least 12 weeks prior to screening.
• Active UC with an an adapted Mayo score of 5 to 9 points, endoscopic subscore of ≥ 2. 
• Demonstrated an inadequate response, loss of response, or intolerance to at lease one of the following treatments including, 5-aminosalicylic acids (ASAs), corticosteroids, immunosuppressants, anti-tumor necrosis factor (TNF)-α agents, integrin inhibitor.

• Participant with current diagnosis of Crohn's disease (CD) or diagnosis of indeterminate colitis (IC), ischemic colitis, pseudomembranous colitis.
• Current evidence of fulminant colitis, abdominal abscess, toxic megacolon, or bowel perforation. 
• History or evidence of any extensive colonic resection, subtotal or total colectomy, with or without presence of a stoma or ileoanal pouch.

Key

• Diagnosed with 1 of the following diagnoses according to the 2016 World Health Organization (WHO) classification for systemic mastocytosis (SM):
  • Indolent systemic mastocytosis (ISM);
  • Smoldering systemic  mastocytosis (SSM).
• Moderate-to-severe symptoms based on a disease-specific PRO and after establishing a stable regimen of at least 2 antimediator therapies over a 14-day eligibility period.
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 2.
• For patients receiving corticosteroids, the dose must be ≤ 10 mg/day of prednisone or
• equivalent.

Key

• Diagnosed with any of the following WHO SM classifications: bone marrow mastocytosis, advanced systemic  mastocytosis including SM with associated hematologic neoplasm, aggressive SM, mast cell leukemia; or mast cell sarcoma.
• Diagnosed with mastocytosis of the skin without systemic involvement.
• Received prior treatment with any targeted KIT inhibitor.
• Received prior cytoreductive therapy or investigational agent for < 14 days or 5 half-lives of the drug and for cladribine, interferon alpha, pegylated interferon, or antibody therapy < 28 days or 5 half-lives of the drug (whichever is longer), before starting screening assessments.
• Received radiotherapy or psoralen and ultraviolet A therapy <14 days before starting screening assessments
• Received any hematopoietic growth factor support  < 14 days before starting screening assessments.
• History of clinically significant bleeding event within 30 days before the first dose of study drug or need for therapeutic anticoagulation on study.
• Need for treatment of corticosteroids at > 10 mg/day of prednisone or equivalent.

Eligibility last updated 3/2/23. Questions regarding updates should be directed to the study team contact.

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

Eligibility last updated 9/15/22. Questions regarding updates should be directed to the study team contact.

Eligibility last updated 6/20/22. 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.

• Willing and able to provide written informed consent. If the subject is unable to consent for himself/herself, a legally acceptable representative must provide informed consent on his/her behalf.
• Males or females ≥ 18 years of age.
• Established mycological diagnosis of candidemia and/or invasive candidiasis from a sample taken ≤ 4 days (96 hours) before randomization defined as:
  • ≥ 1 blood culture positive for yeast or Candida; OR
  • Positive test for Candida from a Sponsor-approved rapid IVD; OR
  • Positive gram stain (or other method of direct microscopy) for yeast or positive culture for Candida spp. from a specimen obtained from a normally sterile site.
• Presence of one or more systemic signs attributable to candidemia or invasive candidiasis appearing from ≤ 12 hours prior to the qualifying positive culture through time of randomization.
• Willing to initiate or continue medical treatment to cure infections, including receipt of antibiotics and surgical procedures, if required.
• Female subjects of childbearing potential (all female subjects between 18 years < 2 years post-menopausal unless surgically sterile) must agree to and comply with using one barrier method (e.g., female condom with spermicide) plus one other highly effective method of birth control, or sexual abstinence while participating in this study. Male subjects must be vasectomized, abstain from sexual intercourse, or agree to use barrier contraception, and also agree not to donate sperm while participating in the study and for 90 days thereafter (and at least 120 days from the last dose of study drug).
• For Candidemia only subjects, drawing of a set of blood cultures within 12 hours prior to randomization in the study. The result of these blood cultures is not required for inclusion in the study.

• Any of the following forms of invasive candidiasis at baseline:
  • Septic arthritis in a prosthetic joint (septic arthritis in a native joint is allowed;
  • Osteomyelitis;
  • Endocarditis or myocarditis;
  • Meningitis, endophthalmitis, chorioretinitis, or any central nervous system infection;
  • Chronic disseminated candidiasis;
  • Urinary tract candidiasis due to ascending Candida infection secondary to obstruction or surgical instrumentation of the urinary tract. 
• Received systemic treatment with an antifungal agent at approved doses for treatment of candidemia for > 48 hours (e.g., > 2 doses of a once daily antifungal agent or > 4 doses of a twice daily antifungal agent) ≤ 4 days (96 hours) before randomization.
  • Exception: Receipt of antifungal therapy to which any Candida spp. isolated in culture is not susceptible.
• Alanine aminotransferase or aspartate aminotransferase levels > 10-fold the upper limit of norma.
• Severe hepatic impairment in subjects with a history of chronic cirrhosis (Child-Pugh score > 9).
• Presence of an indwelling vascular catheter or device that cannot be removed or an abscess that cannot be drained and is likely to be the source of candidemia or invasive candidiasis.
• Known hypersensitivity to Rezafungin for Injection, caspofungin, any echinocandin, or to any of their excipients.
• Meets National Cancer Institute Common Terminology Criteria for Adverse Events, version 5, criteria for ataxia, tremor, motor neuropathy, or sensory neuropathy of Grade 2 or higher.
• History of severe ataxia, tremor, or neuropathy or a diagnosis of multiple sclerosis or a movement disorder (including Parkinson's Disease or Huntington's Disease).
• Planned or ongoing therapy at Screening with a known neurotoxic medication.
• Previous participation in this or any previous rezafungin study.
• Current participation in another interventional treatment trial with an investigational agent.
• Recent use of an investigational medicinal product within 28 days of the first dose of study drug or presence of an investigational device at the time of screening.
• Pregnant or lactating females.
• The Principal Investigator (PI) is of the opinion the subject should not participate in the study

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.

• 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.

• Participants diagnosed with Atopic Dermatitis (AD) as defined by the Hanifin and Rajka criteria.
• Participants with AD duration of at least 3 months (participant/parent/guardian may verbally report signs and symptoms of AD with onset at least 3 months prior).
• Participants with IGA score of 2 to 3 at the screening and baseline visits.
• Participants with % BSA (excluding scalp) of AD involvement of 3% to 20% at screening and baseline visits.
• For children aged 6 years to < 12 years, baseline itch NRS score ≥ 4.
• Participants/guardians who agree to discontinue all agents used by the participant to treat AD from the screening visit through the final safety follow-up visit.
• Participants with at least 1 target lesion that measures at least 5 cm^2 at the screening and baseline visits. The target lesion must be representative of the participant's disease state but not located on the hands, feet, or genitalia.
• Willingness to avoid pregnancy or fathering a child for the duration of study participation.

• An unstable course of AD (spontaneously improving or rapidly deteriorating) as determined by the investigator over the previous 4 weeks before the baseline visit. -Concurrent conditions and history of other diseases as follows:
  • Immunocompromised;
  • Chronic or acute infection requiring treatment with systemic antibiotics, antivirals, antiparasitics, antiprotozoals, or antifungals within 2 weeks before the baseline visit;
  • Active acute bacterial, fungal, or viral skin infection within 1 week before the baseline visit;
  • Any other concomitant skin disorder, pigmentation, or extensive scarring that in the opinion of the investigator may interfere with the evaluation of AD lesions or compromise participant safety;
  • Presence of AD lesions only on the hands or feet without prior history of involvement of other classic areas of involvement such as the face or the flexural folds;
  • Other types of eczema;
  • Chronic asthma requiring more than 880 µg of inhaled budesonide or equivalent high dose of other inhaled corticosteroids.
• Any serious illness or medical, physical, or psychiatric condition(s) that, in the investigator's opinion, would interfere with full participation in the study, including administration of study drug and attending required study visits; pose a significant risk to the participant; or interfere with interpretation of study data.
• Use of any of the following treatments within the indicated washout period before the baseline visit:
  • 5 half-lives or 12 weeks, whichever is longer – biologic agents (e.g., dupilumab);
  • 4 weeks – systemic corticosteroids or adrenocorticotropic hormone analogues, cyclosporin, methotrexate, azathioprine, or other systemic immuno-suppressive or immunomodulating agents (e.g., mycophenolate or tacrolimus);
  • 2 weeks – immunizations with live-attenuated vaccines; sedating antihistamines unless on a long-term stable regimen (nonsedating antihistamines are permitted).
  • Note: Live-attenuated vaccines are not recommended during the VC period. Note: COVID-19 vaccination is allowed;
  • 1 week – use of topical treatments for AD (other than bland emollients; e.g., Aveeno® creams, ointments, sprays, soap substitutes), such as topical antipruritics (e.g., doxepin cream), corticosteroids, calcineurin inhibitors, PDE4 inhibitors, coal tar (shampoo), topical antibiotics, or antibacterial cleansing body wash/soap.
  • Note: Diluted sodium hypochlorite "bleach" baths are allowed as long as they do not exceed 2 baths per week and their frequency remains the same throughout the study.
• Participants who have previously received JAK inhibitors, systemic or topical.
• Ultraviolet light therapy or prolonged exposure to natural or artificial sources of UV radiation (e.g., sunlight or tanning booth) within 2 weeks prior to the baseline visit and/or intention to have such exposure during the study, which is thought by the investigator to potentially impact the participant's AD.
• Positive serology test results at screening for HIV antibody.
• Current treatment or treatment within 30 days or 5 half-lives (whichever is longer) before the baseline visit with another investigational medication or current enrollment in another investigational drug protocol.
• In the opinion of the investigator, unable or unlikely to comply with the administration schedule and study evaluations.
• Employees of the sponsor or investigator or otherwise dependents of them.

Eligibility last updated 5/9/22. Questions regarding updates should be directed to the study team contact.

• Pathologically proven diagnosis of extensive stage small cell lung cancer.
• Partial response (PR) or stable disease (SD) after 4-6 cycles of etoposide/platinum (E/P) doublet plus atezolizumab by re-staging scans (positron emission tomography [PET]/computed tomography [CT] scan, diagnostic CT scan, magnetic resonance imaging [MRI] optional per treating physician); atezolizumab should continue through randomization. Patients must be randomized within 9 weeks of last dose of etoposide/platinum or 6 weeks from completion of prophylactic cranial irradiation (PCI).
• At the time of enrollment, patients must have had measurable disease (per Response Evaluation Criteria in Solid Tumors [RECIST]) and 3 or fewer observable liver metastases and no evidence of progressive disease (per RECIST) at time of enrollment.
• Patients presenting with a pleural effusion will be eligible if thoracentesis is cytologically negative and non-bloody or if pleural fluid is too small a volume to effectively sample by thoracentesis and does not show increased metabolic activity on CT/PET imaging.
• Appropriate stage for study entry based on the following diagnostic workup:
  • History/physical examination within 14 days prior to registration;
  • Imaging within 42 days prior to registration to include:
    • MRI brain with contrast or CT brain with contrast;
    • CT chest, abdomen and pelvis or whole body PET/CT scan after the fourth cycle of chemotherapy.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 at the time of registration.
• Absolute neutrophil count (ANC) ≥ 1,000/cells/mm^3 (within 14 days prior to registration).
• Platelets ≥ 75,000 cells/mm^3 (within 14 days prior to registration).
• Hemoglobin ≥ 8 g/dL (within 14 days prior to registration).
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (within 14 days prior to registration).
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 3.0 x ULN (AST and/or ALT ≤ 5 ULN for patients with liver involvement) (within 14 days prior to registration).
• Alkaline phosphatase ≤ 2.5 x ULN (≤ 5 ULN for patients with documented liver involvement or bone metastases) (within 14 days prior to registration).
• Adequate renal function ≤ 2.0 x ULN.
• Adequate renal function within 30 days prior to registration defined as follows: glomerular filtration rate (GFR) ≥ 40 mL/min/1.73 m^2.
• Upfront central nervous system (CNS) radiotherapy for treatment of brain metastases is permitted provided there is no evidence of CNS progression at the time of randomization and patients are clinically stable on a dose of steroids < 10 mg prednisone a day or equivalent. Upfront radiation therapy of symptomatic metastatic site is permissible if causing patient pain or impending fracture.
• Patients with bone metastases are eligible. However, to assess response after radiation for bone metastases, must order at least diagnostic CT scan to measure response.
• For women of childbearing potential, a negative serum or urine pregnancy test within 14 days prior to registration.
  • Note: Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:
    • Women < 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy);
    • Women ≥ 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses > 1 year ago, had chemotherapy-induced menopause with last menses > 1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry.

• Metastatic disease invading the liver (> 3 metastases), heart or > 10 metastatic sites detectable after induction systemic therapy. Each visible bone metastasis on radiographic scan count as one site. For site of bony metastases, must order diagnostic CT scan for assessment of response.
• Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for 5 years prior to randomization. Cancers with a negligible risk of metastasis or death (e.g., expected 5-year OS > 90%) treated with expected curative outcome are eligible (such as adequately treated carcinoma in situ of the cervix or oral cavity; localized prostate cancer treated surgically with curative intent, or ductal carcinoma in situ treated surgically with curative intent).
• Prior radiotherapy except in the thorax, where there may be some overlap in the mediastinum and spine, as long as overlap fields meet dose constraints.
• History of autoimmune disease, including, but not limited to: systemic lupus erythematosus; rheumatoid arthritis; inflammatory bowel disease (e.g., Crohn's, ulcerative colitis); vascular thrombosis associated with antiphospholipid syndrome; Wegener's granulomatosis; Sjogren's syndrome; Guillain-Barre syndrome; multiple sclerosis; vasculitis; or glomerulonephritis.
  • Note: the following are eligible:
    • Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone are eligible;
    • Patients with controlled type 1 diabetes mellitus on a stable insulin regimen are eligible;
• Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis would be excluded) are permitted provided that they meet the following conditions:
  • Patients with psoriasis must not have ocular manifestations within the past year;
  • Rash must cover less than 10% of body surface area (BSA);
  • Disease is well controlled on topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, fluocinolone 0.01%, desonide 0.05%, alclometasone dipropionate 0.05%).
• No acute exacerbations of underlying condition within the last 12 months (not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate, retinoids, biologic agents, oral calcineurin inhibitors or oral steroids).
• Severe, active co-morbidity defined as follows:
  • Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications;
  • Active tuberculosis;
  • Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis; cirrhosis; fatty liver; and inherited liver disease.
• Patients with past or resolved hepatitis B infection (defined as having a negative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc [antibody to hepatitis B core antigen] antibody test) are eligible.
• Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA). (The HCV RNA test must be performed for patients who have a positive HCV antibody test).
• Known immunosuppressive disease, for example history of bone marrow transplant or chronic lymphocytic leukemia (CLL).
• Patients positive for human immunodeficiency virus (HIV) are allowed on study, but HIV-positive patients must have:
  • A stable regimen of highly active anti-retroviral therapy (HAART);
  • No requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infections;
  • A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard PCR-based tests.
• Chronic obstructive pulmonary disease (COPD) requiring chronic oral steroid therapy of > 10 mg prednisone daily or equivalent at the time of registration. Inhaled corticosteroids are not exclusionary.
• Unstable angina and/or congestive heart failure requiring hospitalization within the last 3 months.
• History of recent myocardial infarction within 6 months prior to registration.
• Clinically significant interstitial lung disease.
• Pregnancy:
  • Administration of atezolizumab may have an adverse effect on pregnancy and poses a risk to the human fetus, including embryo-lethality. 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, for the duration of study treatment, and for 5 months (150 days) after the last dose of study agent. 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;
  • Women who are breastfeeding and unwilling to discontinue.
• History of allogeneic organ transplant.
• Patients who have had immunotherapy-induced pneumonitis.

• Pathologically proven diagnosis of extensive stage small cell lung cancer.
• Partial response (PR) or stable disease (SD) after 4-6 cycles of etoposide/platinum (E/P) doublet plus atezolizumab by re-staging scans (positron emission tomography [PET]/computed tomography [CT] scan, diagnostic CT scan, magnetic resonance imaging [MRI] optional per treating physician); atezolizumab should continue through randomization. Patients must be randomized within 9 weeks of last dose of etoposide/platinum or 6 weeks from completion of prophylactic cranial irradiation (PCI).
• At the time of enrollment, patients must have had measurable disease (per Response Evaluation Criteria in Solid Tumors [RECIST]) and 3 or fewer observable liver metastases and no evidence of progressive disease (per RECIST) at time of enrollment.
• Patients presenting with a pleural effusion will be eligible if thoracentesis is cytologically negative and non-bloody or if pleural fluid is too small a volume to effectively sample by thoracentesis and does not show increased metabolic activity on CT/PET imaging.
• Appropriate stage for study entry based on the following diagnostic workup:
  • History/physical examination within 14 days prior to registration;
  • Imaging within 42 days prior to registration to include:
    • MRI brain with contrast or CT brain with contrast;
    • CT chest, abdomen and pelvis or whole body PET/CT scan after the fourth cycle of chemotherapy.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 at the time of registration.
• Absolute neutrophil count (ANC) ≥ 1,000/cells/mm^3 (within 14 days prior to registration).
• Platelets ≥ 75,000 cells/mm^3 (within 14 days prior to registration).
• Hemoglobin ≥ 8 g/dL (within 14 days prior to registration).
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (within 14 days prior to registration).
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 3.0 x ULN (AST and/or ALT ≤ 5 ULN for patients with liver involvement) (within 14 days prior to registration).
• Alkaline phosphatase ≤ 2.5 x ULN (≤ 5 ULN for patients with documented liver involvement or bone metastases) (within 14 days prior to registration).
• Adequate renal function ≤ 2.0 x ULN.
• Adequate renal function within 30 days prior to registration defined as follows: glomerular filtration rate (GFR) ≥ 40 mL/min/1.73 m^2.
• Upfront central nervous system (CNS) radiotherapy for treatment of brain metastases is permitted provided there is no evidence of CNS progression at the time of randomization and patients are clinically stable on a dose of steroids < 10 mg prednisone a day or equivalent. Upfront radiation therapy of symptomatic metastatic site is permissible if causing patient pain or impending fracture.
• Patients with bone metastases are eligible. However, to assess response after radiation for bone metastases, must order at least diagnostic CT scan to measure response.
• For women of childbearing potential, a negative serum or urine pregnancy test within 14 days prior to registration.
  • Note: Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:
    • Women < 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy);
    • Women ≥ 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses > 1 year ago, had chemotherapy-induced menopause with last menses > 1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry.

• Metastatic disease invading the liver (> 3 metastases), heart or > 10 metastatic sites detectable after induction systemic therapy. Each visible bone metastasis on radiographic scan count as one site. For site of bony metastases, must order diagnostic CT scan for assessment of response.
• Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for 5 years prior to randomization. Cancers with a negligible risk of metastasis or death (e.g., expected 5-year OS > 90%) treated with expected curative outcome are eligible (such as adequately treated carcinoma in situ of the cervix or oral cavity; localized prostate cancer treated surgically with curative intent, or ductal carcinoma in situ treated surgically with curative intent).
• Prior radiotherapy except in the thorax, where there may be some overlap in the mediastinum and spine, as long as overlap fields meet dose constraints.
• History of autoimmune disease, including, but not limited to: systemic lupus erythematosus; rheumatoid arthritis; inflammatory bowel disease (e.g., Crohn's, ulcerative colitis); vascular thrombosis associated with antiphospholipid syndrome; Wegener's granulomatosis; Sjogren's syndrome; Guillain-Barre syndrome; multiple sclerosis; vasculitis; or glomerulonephritis.
  • Note: the following are eligible:
    • Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone are eligible;
    • Patients with controlled type 1 diabetes mellitus on a stable insulin regimen are eligible;
• Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis would be excluded) are permitted provided that they meet the following conditions:
  • Patients with psoriasis must not have ocular manifestations within the past year;
  • Rash must cover less than 10% of body surface area (BSA);
  • Disease is well controlled on topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, fluocinolone 0.01%, desonide 0.05%, alclometasone dipropionate 0.05%).
• No acute exacerbations of underlying condition within the last 12 months (not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate, retinoids, biologic agents, oral calcineurin inhibitors or oral steroids).
• Severe, active co-morbidity defined as follows:
  • Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications;
  • Active tuberculosis;
  • Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis; cirrhosis; fatty liver; and inherited liver disease.
• Patients with past or resolved hepatitis B infection (defined as having a negative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc [antibody to hepatitis B core antigen] antibody test) are eligible.
• Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA). (The HCV RNA test must be performed for patients who have a positive HCV antibody test).
• Known immunosuppressive disease, for example history of bone marrow transplant or chronic lymphocytic leukemia (CLL).
• Patients positive for human immunodeficiency virus (HIV) are allowed on study, but HIV-positive patients must have:
  • A stable regimen of highly active anti-retroviral therapy (HAART);
  • No requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infections;
  • A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard PCR-based tests.
• Chronic obstructive pulmonary disease (COPD) requiring chronic oral steroid therapy of > 10 mg prednisone daily or equivalent at the time of registration. Inhaled corticosteroids are not exclusionary.
• Unstable angina and/or congestive heart failure requiring hospitalization within the last 3 months.
• History of recent myocardial infarction within 6 months prior to registration.
• Clinically significant interstitial lung disease.
• Pregnancy:
  • Administration of atezolizumab may have an adverse effect on pregnancy and poses a risk to the human fetus, including embryo-lethality. 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, for the duration of study treatment, and for 5 months (150 days) after the last dose of study agent. 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;
  • Women who are breastfeeding and unwilling to discontinue.
• History of allogeneic organ transplant.
• Patients who have had immunotherapy-induced pneumonitis.

Key

• Are able and willing to comply with the Protocol and provide signed informed consent prior to any study-specific procedures.
• Are male or female ≥ 18 years old.
• Have a body mass index of ≥ 16.5 kg/m^2.
• Have findings consistent with bronchiectasis per computerized tomography (CT) (or high-resolution CT [HRCT]).
  • Note: A CT or HRCT that demonstrates the above criterion is required during Screening or the Screening Period unless such an examination has been performed within the last 5 years and meets the above criterion.
• Have microbiological evidence of pulmonary P. aeruginosa infection from a sputum sample within the last 24 months. Sputum cultures may be repeated on up to 3 occasions during the Screening Period to document P. aeruginosa presence if the initial sputum culture is negative.
• Are willing and able to provide an induced sputum sample at Screening or during the Screening Period and at designated time points during the study and are willing and able to provide a spontaneously expectorated or induced sputum at all other time points.
• Have ≥ 104 colony-forming units of P. aeruginosa per gram of induced sputum obtained at Screening or during the Screening Period. Up to 3 specimens may be collected to meet this criterion.
• Have forced expiratory volume (FEV1) ≥ 35% of predicted normal for age, gender, race, and height (using Global Lung Function Initiative standards) at Screening (regardless of the timing of the most recent prior administration of short-acting bronchodilator) or during the Screening Period.
• Have, at the Baseline Visit, stable lung function, as determined by the Investigator, provided that the FEV1 at the Baseline Visit has not decreased by more than 10% compared to the FEV1 measured at Screening or during the Screening Period.
• Have no acute infection or exacerbation of primary disease, as determined by the Investigator, prior to randomization and first dose of study drug.
• Are able to reproducibly perform spirometry per American Thoracic Society/European Respiratory Society Standards.
• Have past experience administering inhaled antibiotics and/or feel comfortable administering inhaled antibiotics and/or have a caregiver that is comfortable administering inhaled antibiotics to the subject.
• For Cohort A, have not received chronic inhaled antipseudomonal antibiotic regimen for at least 3 months prior to Visit 1. For Cohort B, have received chronic inhaled antipseudomonal antibiotic regimen for at least 3 months prior to Visit 1.
• Are able to comply with study visits and study procedures as judged by the Investigator.
• Have a negative serum pregnancy test at Screening and a negative urine pregnancy test at the Baseline Visit, with results known prior to randomization and first dose of study drug, if a woman of childbearing potential.
• Must agree to use a highly effective method of birth control (defined as those, alone or in combination, that result in a low failure rate [ie, less than 1% per year]) from Screening through 60 days following the last dose of study drug if female or female partner of male subjects, of childbearing potential; and
• Must agree to use barrier contraception (ie, condoms) from Day 1 through 60 days following the last dose of study drug if male. Male subjects must refrain from donating sperm throughout the study and until 60 days after the last dose of study drug.

• Have previously received 1 or more doses of AP-PA02 in any context, including, but not limited to, prior participation in study AP-PA02-101, prior enrollment in this study, or emergency use (with or without prior authorization).
• Have a history of lung transplantation.
• Have a history of primary or acquired immunodeficiency syndromes, including, but not limited to, hypogammaglobulinemia and common variable immunodeficiency.
• Have a history of cystic fibrosis.
• Have a history of α1-antitrypsin deficiency.
• Have a history of pulmonary malignancy (primary or metastatic) or any other malignancy requiring treatment (including, but not limited to, chemotherapy, radiation therapy, or immunotherapy) within 1 year prior to Screening or anticipated during the study period (Exceptions: Basal cell carcinoma of the skin and carcinoma in situ of the cervix surgically excised and assessed as definitely removed).
• Have, at Screening or during the Screening Period, either of the following findings:
  • A personal history or subject-reported family history of prolonged QT syndrome; or
  • Severe cardiovascular disease such as severe uncontrolled hypertension, unstable ischemic heart disease or cardiac arrhythmia and any other cardiac conditions that would confound the evaluation of safety in the opinion of the Investigator.
• Have a history of hemoptysis meeting either of the following criteria:
  • Within the 6 months prior to Screening, was hospitalized for management or evaluation of hemoptysis; or
  • Within the 3 months prior to Screening, had hemoptysis totaling greater than 30 mL in a single day.
• Have, within the 3 months prior to Screening, used supplemental oxygen during the day while at rest.
• Have, within the 3 months prior to Screening, lost more than 10% of their body weight.
• Have, within the 2 months prior to Screening, participated in any clinical study involving an investigational drug, an investigational device, or any systemic antibiotic.
• Note: For systemic drugs or antibiotics with a half-life > 12 days, the exclusion period is 5 half-lives.
• Have, within the 30 days prior to Screening, received any intravenous, intramuscular, or oral antipseudomonal antibiotic (Exception: Chronic oral macrolide treatment with a stable dose is permitted).
  • Note: Inhaled antibiotic use for chronic suppression of P. aeruginosa is acceptable for subjects enrolling in Cohort B.
• Have, within 30 days prior to Screening, had changes in either the treatment regimen or initiation of treatment with any of the following medications: oral macrolides (e.g., azithromycin, erythromycin, or clarithromycin), hypertonic saline, mucolytics, bronchodilator medications, or oral corticosteroids.
• Have, within the 30 days prior to Screening, received a course of any systemic antibiotics (by any route) for a new active infection at any site, unless assessed as fully resolved and not clinically significant by the Investigator with concurrence of the Medical Monitor.
• Are, at Screening or during the Screening Period, receiving treatment for active pulmonary infection due to any of the following pathogens: nontuberculous mycobacteria, Staphylococcus aureus, Burkholderia cepacia complex, Aspergillus species, or endemic mycoses.
• Are receiving treatment for allergic bronchopulmonary aspergillosis.
• Have, within 30 days prior to Screening, received either a systemic corticosteroid at a dose equivalent to > 20 mg/day of prednisone (including every other day dosing of > 40 mg equivalent) or any immunosuppressive medication or biologic for the treatment of inflammatory or autoimmune disease.
• Have history of AIDS (human immunodeficiency virus positive with AIDS-defining condition and/or CD4 count 3 × ULN or total bilirubin ≥ 2 × ULN at Screening.
  • Note: Abnormal laboratory results may be repeated once and only once at the discretion of the Investigator. Subjects with values outside the normal range may be permitted if the value is not clinically significant in the opinion of the Investigator with concurrence from the study Medical Monitor and/or Sponsor designee.
• Have, in the opinion of the Investigator, any acute or chronic medical, psychiatric, or behavioral condition or laboratory abnormality such that any of the following apply: the subject is considered not medically stable or in any other way not suitable for the study; participation in the study is not in the subject’s best interest, including, but not limited to, concern that participation in the study has the potential to put the subject at undue risk or to interfere with the results of the study or the outcome measures.

Eligibility last updated 12/20/23. Questions regarding updates should be directed to the study team contact.

Inclusion Criteria
•Pre-Registration:

• Age ≥ 18 years.
• Measurable disease as defined by RECIST criteria that is:
  • A non-nodal lesion is considered measurable if its longest diameter can be accurately measured as ≥ 1.0 cm with CT scan;
  • CT component of a PET/CT; or
  • MRI and/or 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; Disease that is measurable by physical examination only is not eligible.
• Received  ≤ four (4) prior chemotherapy regimens in the metastatic setting.
• Cohort A One of the following must be true:
  • Distant disease progression during administration of combination therapy with taxane based chemotherapy and anti-HER2 therapy (trastuzumab or pertuzumab) for metastatic disease.
    • Note: patients who began treatment with this combination and discontinued taxane-based chemotherapy due to intolerability before distant disease progression are eligible;
  • Distant disease progression during administration or within 180 days of discontinuing combination therapy with taxane based chemotherapy and anti-HER2 therapy (trastuzumab or pertuzumab) in the adjuvant disease.
    • Note: Patients who began treatment with this combination and discontinued taxane-based chemotherapy due to intolerability before distant disease progression are eligible. For patients who received taxane based chemotherapy and antiHER2 therapy (trastuzumab or pertuzumab) in the neo-adjuvant setting and underwent surgical resection of primary breast disease: Distant disease progression during or within 180 days of discontinuing anti-HER2 therapy (trastuzumab or pertuzumab) in the adjuvant setting.
• Cohort B (one of the following must be true):
  • Distant disease progression during administration of combination therapy with endocrine therapy and anti-HER2 therapy (trastuzumab or pertuzumab) for metastatic disease. Permissible endocrine therapies include an aromatase inhibitor or fulvestrant.
    • NOTE: Tamoxifen is not permissible.
  • Distant disease progression during administration of combination therapy with endocrine therapy and anti-HER2 therapy (trastuzumab or pertuzumab) in the adjuvant setting. Permissible endocrine therapies include an aromatase inhibitor or fulvestrant.
    • NOTE: Tamoxifen is not permissible.
• Willingness to provide mandatory tumor tissue specimens for correlative research.
  • NOTE: If insufficient or no tissue is obtained by the pre-registration biopsy, an archival tissue specimen (preferably from a metastatic site) from procedure performed ≤ 2 years prior to pre-registration must be available to submit for Central Laboratory review prior to registration.
  • Exception: If there is no medically safe site for biopsy, Study Chair (Dr Haddad) may waive this requirement.

Exclusion Criteria
•Pre-Registration:

Cardiac Exclusion Criteria

• Patients who previously discontinued trastuzumab due to unacceptable cardiac toxicity/
• Patients with a history of LVEF decline to below 50% during or after prior trastuzumab or other HER2 directed therapy ≤ 6 months prior to preregistration.
• Patients with any class of New York Heart Association (NYHA) CHF or heart failure with preserved ejection fraction (HFPEF).
• Patients with a history of known coronary artery disease or a myocardial infarction within 12 months prior to pre-registration.
• Patients with persistently uncontrolled hypertension (systolic BP > 160 mm Hg or diastolic BP > 100 mm Hg) despite optimal medical therapy.
• Patients with known unstable angina pectoris.
• Patients with a known history of serious cardiac arrhythmias requiring treatment (exception: controlled atrial fibrillation, paroxysmal supraventricular tachycardia).
• Patients with a prolonged QTc interval (≥ 450 ms).
• Leptomeningeal disease or uncontrolled brain metastasis.
  • NOTE: Metastases treated by surgery and/or radiotherapy such that patient is neurologically stable and off steroids ≥ 4 weeks prior to preregistration are eligible.
• Failure to recover from acute, reversible effects of prior therapy regardless of interval since last treatment.
  • EXCEPTION: Grade 1 peripheral (sensory) neuropathy that has been stable for at least 3 months since completion of prior treatment.
• Tumors involving spinal cord or heart.
• Visceral crisis or lymphangitic spread.
  • NOTE: Visceral crisis is not the mere presence of visceral metastases, but implies severe organ dysfunction as assessed by symptoms and signs, laboratory studies, and rapid progression of disease.
• Uncontrolled intercurrent non-cardiac illness including, but not limited to:
  • ongoing or active infection;
  • psychiatric illness/social situations;
  • dyspnea at rest due to complications of advanced malignancy or other disease that requires continuous oxygen therapy;
  • or any other conditions that would limit compliance with study requirements.
• Immunocompromised patients and patients known to be HIV positive and currently receiving antiretroviral therapy.
  • NOTE: Patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial.
• Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm.
• History of myocardial infarction ≤ 6 months, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias.
• Prior history of hypersensitivity, drug or radiation-induced, or other immunemediated pneumonitis.
• Patient is unable to swallow oral medications or has impairment of GI function or GI disease that may significantly alter drug absorption (e.g. active inflammatory bowel disease, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome).
  • Note: Concomitant therapy with proton pump inhibitors and/or H2- receptor antagonists is permissible.
• Patient has a history of clinically significant dry eye (xerophthalmia) or other corneal abnormality, or if a contact lens wearer, does not agree to abstain from contact lens use from baseline through the last TVB-2640 dose.
• Patients with a history of intolerance to trastuzumab (i.e., a grade 3 or 4 infusion reaction) are excluded.
  • Note: Patients with a history of mild infusion reaction to trastuzumab who have previously been successfully re-challenged after an infusion reaction with or without prophylactic medication are allowed.
• Other invasive malignancy ≤ 3 years prior to pre-registration.
  • EXCEPTIONS: Non-melanoma skin cancer, papillary thyroid cancer, or carcinoma-in-situ of the cervix which has been adequately treated.
  • NOTE: If there is a history of prior malignancy, patients must not be receiving other antineoplastic treatment for their cancer and the disease must be inactive/stable.

Inclusion Criteria
•Registration:

• Registration must be completed ≤ 28 days of pre-registration.
• ECOG Performance Status (PS) 0 or 1.
• Disease characteristics.
• Histological confirmation of HER2-positive advanced breast cancer. HER2+ is defined by 2013 ASCO/CAP guidelines.
• For Cohort B only: Histologic confirmation of ERα positive disease (≥ 1% expression).
• The following laboratory values obtained ≤ 14 days prior to registration:
  • Hemoglobin ≥ 9.0 g/dL;
  • Absolute neutrophil count (ANC) ≥ 1500/mm^3; Platelet count
  • ≥ 100,000/mm^3;
  • Direct bilirubin ≤ 1.5 x ULN;
  • Aspartate transaminase (AST) ≤ 3 x ULN (≤ 5 x ULN for patients with liver involvement);
  • Calculated creatinine clearance ≥ 45 ml/min using the Cockcroft-Gault formula below:
• Cockcroft-Gault Equation:
• Creatinine clearance for males = (140
  •age)(weight in kg) (72)(serum creatinine in mg/dL).
• Creatinine clearance for females = (140
  •age)(weight in kg)(0.85) (72)(serum creatinine in mg/dL).
• Cardiac ejection fraction (LVEF) ≥ 50% by echocardiogram ≤ 28 days prior to registration.
• Provide written informed consent.
• Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study).
• Negative urine pregnancy test done ≤ 7 days prior to registration, for women of childbearing potential only.
  • NOTE: If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• Patient and his/her partner agree to use adequate contraception after providing written informed consent through 3 months after the last dose of TVB-2640, as follows:
  • For women: Compliant with a medically-approved contraceptive regimen during and for 3 months after the treatment period or documented to be surgically sterile or postmenopausal;
  • For men: Compliant with a medically-approved contraceptive regimen during and for 3 months after the treatment period or documented to be surgically sterile. Men whose sexual partners are of child-bearing potential must agree to use 2 methods of contraception prior to study entry, during the study, and for 3 months after the treatment period.
• Willingness to provide mandatory tumor tissue and/or blood specimens for correlative research.

Exclusion Criteria
•Registration:

• Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:
  • Pregnant women;
  • Nursing women;
  • Men or women of childbearing potential who are unwilling to employ adequate contraception.
• Any of the following therapies prior to registration:
  • Chemotherapy ≤ 3 weeks;
  • Immunotherapy ≤ 3 weeks;
  • Biologic therapy ≤3 weeks;
  • Monoclonal antibodies ≤ 3 weeks;
  • Radiation therapy ≤ 2 weeks;
  • CDK 4/6 inhibitors ≤ 4 weeks;
  • mTOR inhibitors ≤ 4 weeks.

• Subjects who have entered and completed Study M16-006 or Study M15-991 or Study M15-989.
• Subjects have completed the study M16-006 or M15-991 and have achieved clinical response.
• Main entry criteria for Study M16-006 and Study M15-991:
  • Males and females aged ≥ 18 to ≤ 80 years of age, or minimum age of adult consent according to local regulations, at the Baseline Visit. Where locally permissible ≥ 16 to < 18 years of age who meet the definition of Tanner stage 5 development;
  • Moderately to severely active CD, defined as average daily SF ≥ 4 and/or average daily AP score ≥ 2;
  • Endoscopic evidence of mucosal inflammation (Simple Endoscopic Score for CD [SES-CD], excluding the presence of narrowing component, ≥ 3 as confirmed by a centrally read endoscopy. During the COVID-19 pandemic the final endoscopy post-induction treatment may not be conducted due to local regulation prohibiting endoscopy and subjects may be allowed to enroll in SS 3 should they meet clinical response.
• Main entry criteria for all other subjects:
  • Patients with Crohn's disease, who have successfully completed another AbbVie risankizumab Crohn's disease study.

• Subject is considered by the Investigator, for any reason, to be an unsuitable candidate for the study.
• Subject who has a known hypersensitivity to risankizumab or the excipients of any of the study drugs or the ingredients of CHO, or had an AE during Studies M16-006, M15-991 or M15-989 that in the Investigator's judgment makes the subject unsuitable for this study.
• Subject is not in compliance with prior and concomitant medication requirements throughout Studies M16-006, M15-991 or M15-989.
• Confirmed positive urine pregnancy test at the Final Visit of Study M16-006, Study M15-991 or Study M15-989.
• Have a known history of lymphoproliferative disease, including lymphoma, or signs and symptoms suggestive of possible lymphoproliferative disease, such as lymphadenopathy and/or splenomegaly.

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

Eligibility last updated 9/15/23. Questions regarding updates should be directed to the study team contact.