• Males or female subjects 6 to 17 years of age, inclusive, at the time the informed consent form is signed by the legal guardian.
• Subjects must have a weight of ≥ 20 kg.
• Subjects must have an age and sex specific BMI value no lower in range than the 5th percentile on the Centers for Disease Control (CDC) growth chart for children and adolescents (CDC, 2000).
• Subject is able to swallow the study medication tablet.
• Able to sign an age-appropriate assent with a legal guardian(s) who understand(s) and voluntarily sign(s) an informed consent prior to any study-related assessments/procedures being conducted.
• Be willing and able to adhere to the study visit schedule and other protocol requirements.
• Diagnosis of chronic plaque psoriasis for at least 6 months prior to Screening.
• Has moderate to severe plaque psoriasis at Screening and Baseline as defined by:
  • PASI score ≥ 12; and
  • Body surface area (BSA) ≥ 10%; and
  • sPGA ≥ 3 (moderate to severe).
• Disease inadequately controlled by or inappropriate for topical therapy for psoriasis.
• Candidate for systemic therapy or phototherapy.
• At Screening, laboratory values must be within the following ranges:
  • White blood cell (WBC) count
  • Age (years) | Males (x 10^3 /μL) | Females (x 10^3 /μL)
    • 6-11 | 3.5 – 13.5 | 3.5 – 13.5
    • 12-18 | 3.5 – 13.5 | 3.5 – 13.5
  • Platelet count
  • Age (years) | Males (x 10^3 /μL) | Females (x 10^3 /μL)
    • 6-11 | 125 – 400 | 125 – 400
    • 12-18 | 125 – 400 | 125 – 400
  • Serum creatinine ≤ 1.2 x upper-limit of normal (ULN) for age and gender.
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) ≤ 1.5 x ULN for age and gender. If initial test of ALT or AST is > 1.5 x ULN, one repeat test is allowed during Screening. Please see the reference ranges of the central laboratory.
  • Total bilirubin ≤ 2 mg/dL (≤ 34 μmol/L). If initial test result is > 2 mg/dL, one repeat test is allowed during the Screening period 
  • Hemoglobin (Hb)
  • Age (years) | Males (g/dL) | Females (g/dL)
    • 6-11 | 10.0 – 15.0 | 10.0 – 15.0
    • 12-18 | 11.0 – 16.5 | 10.5 – 15.5
• All females of childbearing potential (FCBP) must either practice abstinence* from heterosexual contact or use one of the approved contraceptive options as described below while on apremilast and during any dose interruption, and for at least 28 days after administration of the last dose of apremilast. For the purpose of this study, a female subject is considered of childbearing potential if she is ≥ 12 years old or has reached menarche, whichever occurred first.
• At the time of study entry, and at any time during the study when a female subject of childbearing potential’s contraceptive measures or ability to become pregnant changes, the Investigator will educate the subject regarding abstinence or contraception options and the correct and consistent use of effective contraceptive methods in order to successfully prevent pregnancy.
• Females of childbearing potential must have a negative pregnancy test at Screening and Baseline. All FCBP who engage in activity in which conception is possible must use one of the approved contraceptive+ options described below:
  • Option 1: Any one of the following highly effective methods: hormonal contraception (for example, birth control pills, intravaginal ring, transdermal patch, injection, implant); intrauterine device (IUD); tubal ligation; or partner’s vasectomy; OR
  • Option 2: Male or female latex condom or nonlatex condom NOT made out of natural (animal) membrane (for example,  polyurethane); PLUS one additional barrier method:
    • diaphragm with spermicide;
    • cervical cap with spermicide; or
    • contraceptive sponge with spermicide

  • NOTE: Option 2 may not be acceptable as a highly effective contraception option in all countries per local guidelines/regulations.

• * True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
• + If a female subject is a FCBP when entering the study, the chosen form of contraception must be effective by the time the female subject is randomized into the study (for example, hormonal contraception should be initiated at least 28 days before randomization).

• Other than psoriasis, history of any clinically significant (as determined by the Investigator) cardiac, endocrinologic, pulmonary, neurologic, psychiatric, hepatic, renal, hematologic, immunologic disease, or other major uncontrolled disease.
• Any condition, including the presence of laboratory abnormalities, or psychiatric illness, that would place the subject at unacceptable risk if he/she were to participate in the study.
• Any condition that confounds the ability to interpret data from the study.
• Evidence of skin conditions, other than psoriasis, that would interfere with clinical assessments.
• Pregnant or breastfeeding.
• Guttate, erythrodermic, or pustular psoriasis at Screening and Baseline.
• Psoriasis flare or rebound within 4 weeks prior to Screening.
• Positive Hepatitis B surface antigen, or anti-hepatitis C antibody, at Screening.
• History of positive human immunodeficiency virus infection (HIV), congenital and acquired immunodeficiencies (eg, common variable immunodeficiency, immunoglobulin A deficiency).
• Active tuberculosis (TB) or a history of incompletely treated TB.
• History of recurrent significant infections.
• Active infection or infection treated with antibiotic treatment within 2 weeks of first dose.
• Any history of or active malignancy.
• History of allergy/intolerance to any component of the investigational product; i.e., apremilast, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, hypromellose 15cP, titanium dioxide, polydextrose food chemical color, talc, maltodextrin, medium chain triglycerides, iron oxide red, iron oxide yellow, and iron oxide black.
• Deficiencies in lactose metabolism, ie, galactose-1-phosphate uridylyltransferase, UDPgalactose 4-epimerase, galactokinase or Fanconi Bickel syndrome, including congenital lactase deficiencies, and glucose-galactose malabsorption.
• Prior history of suicide attempt at any time in the subject’s lifetime prior to Screening or randomization in the study, or major psychiatric illness requiring hospitalization within 3 years prior to signing the assent and informed consent.
• Answer “Yes” to any question on the Columbia-Suicide Severity Rating Scale during Screening or at Baseline.
• Current or planned concurrent use of the following therapies that may have a possible effect on psoriasis. 
  • Topical therapy within 2 weeks prior to randomization including, but not limited to, topical corticosteroids, topical retinoid or vitamin D analog preparations, tacrolimus, pimecrolimus, or anthralin/dithranol.
    • Exceptions*:
      • Low potency or weak corticosteroids (please refer to the Investigators’ Manual) will be allowed as background therapy for treatment of the face, axillae and groin in accordance with manufacturer’s suggested usage;
      • unmedicated skin moisturizer (eg, Eucerin®) will also be permitted for body lesions.
      • *Subjects should not use these topical treatments within 24 hours prior to the clinic visit.
  • Conventional systemic therapy for psoriasis within 4 weeks prior to randomization (including but not limited to cyclosporine, corticosteroids, methotrexate, oral retinoids, mycophenolate, thioguanine, hydroxyurea,  sirolimus, sulfasalazine, azathioprine, and fumaric acid esters).
  • Phototherapy treatment (ie, ultraviolet B [UVB], PUVA) within 4 weeks prior to randomization.
  • Biologic therapy:
    • Etanercept (or biosimilar) treatment four weeks prior to randomization;
    • Adalimumab (or biosimilar) treatment ten weeks prior to randomization;
    • Other TNF or IL-17 blockers (such as infliximab, certolizumab pegol, secukinumab, ixekizumab, brodalumab, or their biosimilars) within 12 weeks prior to randomization;
    • Anti-IL-12 or anti-IL-23 treatment (such as ustekinumab, guselkumab, or tildrakizumab) within 24 weeks prior to randomization.
  • Use of any investigational drug within 4 weeks prior to randomization, or 5 pharmacokinetic/pharmacodynamic half-lives, if known (whichever is longer).
• Prolonged sun exposure or use of tanning booths or other ultraviolet (UV) light sources.
• Children in Care: a child who has been placed under the control or protection of an agency, organization, institution or entity by the courts, the government or a government body, acting in accordance with powers conferred on them by law or regulation.
• Prior treatment with apremilast.

• Age ≥ 18 years old
• Histological confirmation of melanoma of any mucosal site including (but not limited to) anus/rectum, vulvar/vaginal, sinonasal.
  • NOTE: Melanomas of cutaneous origin and/or ocular origin are ineligible.
• R0 or R1 resection of primary melanoma tumor (no gross disease can be left behind, but microscopically positive margins are acceptable).
• Surgery within ≤ 90 days of registration.
• ECOG Performance Status (PS) ≤ 1.
• The following laboratory values obtained ≤ 14 days prior to registration:
• Hematological
  • Absolute Neutrophil Count (ANC) ≥ 1500/mm^;3
  • Hemoglobin (Hgb) ≥ 9 g/dL (may be transfused);
  • Platelet (Plt) 100,000/mm^3.
• Renal
  • Serum Creatinine ≤ 1.5 x ULN.
• Hepatic
  • Alkaline Phosphatase (Alk Phos) ≤ 1.5 x upper limit of normal (ULN);
  • Total and Direct Bilirubin ≤ 1.5 × (ULN);
  • Aspartate aminotransferase (AST) ≤ 1.5 × ULN.
• Negative pregnancy test done within 7 days prior to registration, for women of childbearing potential only.
  • NOTE: Females are considered of child bearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months.
• Written informed consent and HIPAA authorization for release of personal health information prior to registration.
  • NOTE: HIPAA authorization may be included in the informed consent or obtained separately.
• Willing to return to enrolling institution for follow-up.
• Willing to provide archival tissue prior to C1D1 if available and blood samples for correlative research purposes

• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the subject inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
• Immunocompromised patients and subjects known to be HIV positive and currently receiving antiretroviral therapy.
  • NOTE: Subjects known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial.
• 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.
• Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm.
• Other active malignancy ≤ 3 years prior to registration.
  • EXCEPTIONS: Malignancies with a very low (< 5%) risk of recurrence such as non-melanotic skin cancer or carcinoma-in-situ of the cervix.
• History of myocardial infarction ≤ 6 months, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias.
• Active autoimmune disease -including but not limited to:
  • Subjects with a history of inflammatory bowel disease, including ulcerative colitis and Crohn’s Disease;
  • Subjects with a history of symptomatic autoimmune disease requiring systemic treatment within the past 2 years with the use of disease modifying agents, corticosteroids, or immunosuppressive drugs:
  • rheumatoid arthritis;
  • systemic progressive sclerosis (scleroderma);
  • systemic lupus erythematosus;
  • psoriasis;
  • autoimmune vasculitis (e.g., Wegener’s Granulomatosis);
  • CNS or motor neuropathy considered of autoimmune origin (e.g., GuillainBarre Syndrome and Myasthenia Gravis, multiple sclerosis).
    • EXCEPTION: autoimmune conditions that are only requiring replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• Any radiation within 2 weeks prior to study initiation. Neoadjuvant and adjuvant radiation are allowed, but must be completed > 2 weeks prior to registration.
• Any prior systemic therapy for melanoma (chemotherapy, immunotherapy, targeted therapy).
• Women of childbearing potential (WOCBP) must be willing to abstain from heterosexual intercourse or to use 2 forms of effective methods of contraception from the time of informed consent until 5 months after the last dose of study drug. The two contraception methods can be comprised of two barrier methods, or a barrier method plus a hormonal method. Examples include: intrauterine device (IUD), vasectomy of a female subject’s male partner, contraceptive rod implanted into the skin, or use of two of the following: diaphragm with spermicide (cannot be used in conjunction with cervical cap/spermicide), cervical cap with spermicide (nulliparous women only), contraceptive sponge (nulliparous women only), male condom or female condom (cannot be used together), hormonal contraceptive.

*Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.

• NOTE: Male subjects are not required to utilize contraception. The study regimen is not genotoxic and systemic concentrations sufficient to produce a risk of fetal toxicity are not expected in WOCBP partners from exposure to a male participant’s seminal fluid.
• Pregnant or breastfeeding.
  • NOTE: breast milk cannot be stored for future use while the mother is being treated on study.

• Male or female, aged ≥ 18 years.
• Confirmed diagnosis of:
  • For the monotherapy cohorts: Metastatic or unresectable BC, NSCLC, CRC, ovarian cancer, or acral melanoma that is refractory to standard therapy or for which no standard therapy exists. Participants who are considered intolerant of or ineligible for standard therapy(ies), as well as participants who have been offered but refused standard therapy(ies), may also be eligible;
  • For the pembrolizumab combination therapy cohort: Metastatic or unresectable NSCLC, CRC (only MSI-H or dMMR), melanoma (with the exception of uveal melanoma), HCC, HNSCC, ESCC, or UC with prior or ongoing pembrolizumab treatment and have progressed or have achieved stable disease and who, in the judgment of their treating physicians, could benefit from the addition of ATRC-101 to improve or maintain their response:
  • Individuals with BRAF mutant melanoma must have received BRAF inhibitors alone or in combination with a MEK inhibitor, if indicated;
  • Individuals with NSCLC should have received platinum-based therapy unless contraindicated.
  • For the PLD combination therapy cohort: Metastatic or unresectable high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer that is platinum resistant, defined as progression during or within 6 months of the last dose of platinum-based chemotherapy OR BC that is refractory to other standard therapies.
• Measurable disease based on RECIST v1.1, as assessed by the local site investigator/radiologist. Lesions situated in an area treated with radiation or other locoregional therapy are considered measurable only if the progression has been demonstrated in such lesions following loco-regional therapy.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
• Adequate organ and marrow function (i.e., without chronic, ongoing growth factor or transfusion support) at Screening as defined by the following laboratory parameters:
  • Absolute neutrophil count (ANC) ≥ 1000/µL;
  • Absolute lymphocyte count (ALC) ≥ 500/ µL;
  • Platelet count ≥ 75,000/µL;
  • Hemoglobin ≥ 9.0 g/dL;
  • PT/INR, aPTT ≤ 1.5 x ULN unless participant is receiving a stable dose of therapeutic anticoagulation;
  • Albumin ≥ 3.0 g/dL;
  • Creatinine clearance or eGFR ≥ 30 mL/min as estimated by the Cockcroft-Gault equation;
  • AST/ALT ≤ 2 x ULN. If documented liver metastases, then ≤ 5 x ULN;
  • Bilirubin ≤ 2 x ULN; or bilirubin ≤ 3 x ULN if due to Gilbert’s or Crigler-Najjar disease.
• Available representative tumor specimens in paraffin blocks (preferred) or ≥ 20 unstained slides, with an associated pathology report, obtained after last systemic anti-cancer therapy and within 60 days prior to the planned first dose of investigational product. If fewer than 20 unstained slides are available, a discussion with the Medical Monitor is required prior to enrollment. If an archived sample is not available, participant must have a tumor that is amenable to biopsy without unacceptable risk of a major procedural complication and consent to have a tumor biopsy. Tumor lesions used for biopsy should not be lesions used as RECIST 1.1 target lesions unless there are no other lesions suitable for biopsy. If a RECIST target lesion is used for biopsy, the lesion must be ≥ 2cm in longest diameter:
  • For the pembrolizumab combination therapy cohort:
  • A biopsy collected within 60 days of the planned first dose of investigational product while the participant is receiving pembrolizumab is acceptable.
• Women of childbearing potential (WOCBP) and fertile males with partners who are WOCBP must use highly effective contraception (per CTFG 2014) from first dose and through 90 days after final dose of investigational product.
• Willing and able to provide written informed consent and able to comply with all trial procedures.

• Disease that is suitable for local therapy administered with curative intent.
• Malignant disease other than the malignancy to be investigated in this trial within the last 5 years with the exception of basal or squamous cell carcinoma of the skin OR curatively treat in situ disease.
• Autoimmune disease requiring systemic treatment (e.g., with disease modifying agents, corticosteroids, or immunosuppressive drugs) in the past 2 years. Hormone replacement therapy (e.g., insulin, thyroxine, and replacement-dose hydrocortisone) is not considered systemic treatment.
• Active or prior paraneoplastic neurologic disorder of the central nervous system (CNS).
• Prior allograft.
• Clinically significant cardiovascular disease; e.g., cerebral vascular accident/stroke or myocardial infarction, within 6 months prior to the first dose of investigational product, unstable angina, congestive heart failure (New York Heart Association ≥ Class III), or unstable cardiac arrhythmia requiring medication.
• Presence of active, symptomatic, or untreated CNS metastasis; or CNS metastasis that requires local directed therapy or increasing doses of corticosteroids within the 2 weeks prior to the planned first dose of investigational product. Individuals with treated and/or asymptomatic CNS disease may be enrolled if neurologically stable over the prior 2 weeks (and after consultation with the Medical Monitor).
• HIV infection with an AIDS-defining  opportunistic infection within the past 12 months or with a CD4+ T cell count < 350/µL
• Hepatitis B surface antigen (HBsAg) positive OR anti-Hepatitis B core (anti-HBc) positive and HBV viral load above the lower limit of quantification.
• Hepatitis C antibody positive with HCV viral load greater than or equal to the lower limit of quantification.
• Infection requiring intravenous antibacterial, antiviral, or antifungal therapy within 2 weeks prior to the planned first dose of investigational product.
• Ongoing ≥ Grade 2 toxicity(ies) due to a previously administered anticancer agent with the following exceptions:
  • Grade 2 neuropathy or alopecia;
  • For the monotherapy cohorts: Grade 2 immune-related endocrinopathy attributed to a checkpoint inhibitor and controlled with hormone replacement alone.
• Treatment with biological agents (including monoclonal antibodies) within 28 days of the planned first dose of investigational product with the following exception:
  • For the pembrolizumab combination therapy cohort: Pembrolizumab treatment within 28 days of the planned first dose of investigational product.
• Treatment with radiation, chemotherapy or anticancer small molecule therapy within 14 days or 5 half-lives (whichever is longer) prior to the planned first dose of investigational product. Treatment with nitrosoureas or mitomycin C require a 42-day washout prior to the planned first dose of investigational product.
• Receipt of any investigational drug or device not otherwise specified above within 28 days or 5 half-lives (whichever is longer) prior to the planned first dose of investigational product.
• Pregnant or breastfeeding; negative pregnancy status in WOCBP must be confirmed by serum pregnancy test at Screening.
• History of ≥ Grade 3 infusion-related reaction associated with antibody administration; or:
  • For the monotherapy cohorts: Known allergy/intolerance to ATRC-101 or its excipients;
  • For the pembrolizumab combination therapy cohort: Known allergy/intolerance to ATRC-101, pembrolizumab, or their excipients.
• Major surgery or significant traumatic injury occurring within 28 days prior to the planned first dose of investigational product. If major surgery occurred > 28 days prior to Cycle 1-Day 1, individual must have recovered adequately from the toxicity and/or complications from the intervention prior to Cycle 1-Day 1.
• Prior treatment with ATRC-101.
• Intercurrent illness that is either life-threatening or of clinical significance such that it might limit compliance with trial requirements, or in the Investigator’s assessment would place the participant at an unacceptable risk for participation.
• Receipt of a live vaccine within 30 days of planned Cycle 1-Day 1. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed. Intranasal influenza vaccines (e.g., FluMist) are live attenuated vaccines and are not allowed.

For the pembrolizumab combination therapy cohort ONLY:

• Experienced ≥ Grade 3 or higher immune related adverse events while on immunotherapy prior to enrollment.
• Have not recovered from ≥ Grade 2 immune related adverse events attributed to immunotherapy prior to enrollment.
• NSCLC with epidermal growth factor receptor (EGFR) or anaplastic lymphoma receptor tyrosine kinase (ALK) genomic tumor alterations.
• Isolated intracranial relapse.
• Interstitial lung disease or active, non-infectious pneumonitis.
• Signs and symptoms consistent with clinically significant, decreased pulmonary function: (1) blood saturation oxygen level (SpO2) < 90% at rest on room air; (2) dyspnea at rest (CTCAE ≥ Grade 3) or required supplemental oxygenation within 14 days prior to the planned first dose of investigational product.
• Ongoing immune-related toxicity or immune-related toxicity at any time requiring systemic corticosteroids.

Patients may be enrolled prior to, during, or following neoadjuvant systemic therapy provided they meet the following eligibility and ineligibility requirements noted below:

• Pathologically confirmed unicentric invasive breast cancer defined as radiologic clinical stage T1 or T2 (≤ 5 cm), N0 or N1 (≤ 4 abnormal axillary nodes on initial ultrasound), clinical stage M0.
• HER2 positive (IHC 3+ and or FISH amplified) or triple receptor negative (TN, ER/PR < 10% HER2 negative (IHC 1+ or 2+ FISH non-amplified) receiving any standard routine clinical NST regimen.
• Patient desires breast conserving therapy.
• Age 40 years or older.  This age cutoff is justified because breast cancers in women under the age of 40 are known to have a significantly higher risk of IBTR presumably due to underlying biologic differences [104, 105].
• Female sex.
• If the patient has a history of a prior non-breast  cancer, all treatment for this cancer must have been completed prior to study registration and the patient must have no evidence of disease for this prior non-breast cancer.
• Patient must have an initial nodal ultrasound that does not demonstrate more than four suspicious lymph nodes, any suspicious lymph nodes should be biopsied to determine if nodal metastatic disease present.

• Radiologic evidence for a stage T3 or clinical stage T4 breast cancer.
• Clinical or pathologic evidence for distant metastases.
• Prior diagnosis of invasive or ductal carcinoma in situ breast cancer in the ipsilateral breast.
• Clinical evidence of progression of disease > 20% in the breast or new evidence of nodal metastases.
• Patient is known to be pregnant.
• Patient is participating in a NST protocol in which surgical excision of the breast and or lymph nodes are required.

• Patients must have inflammatory breast cancer without distant metastases. All biomarker subtype groups (estrogen receptor [ER], progesterone receptor [PR], HER2) are eligible. Inflammatory disease will be defined per American Joint Committee on Cancer (AJCC) 8th edition with documentation by history/exam and pathology at the time of diagnosis. 
• All patients must have completed neoadjuvant chemotherapy prior to mastectomy. The chemotherapy regimen is at the discretion of the treating physician but it is recommended that it include at least 4 cycles of anthracycline and/or taxane-based therapy (plus targeted therapy for patients with HER2+ disease). Response to chemotherapy is not a criterion for eligibility (both complete responders and those with residual disease are eligible). Please note that although pathologic complete response (pCR) is not required or excluded, pCR status must be determined post-surgery prior to randomization.
• All patients must have undergone modified radical mastectomy (with negative margins on ink) with pathologic nodal evaluation (from level I and II axillary lymph node dissection) at least 3 weeks and no more than 12 weeks prior to randomization, unless they receive additional chemotherapy after mastectomy. Patients must not have gross residual tumor or positive microscopic margins after mastectomy. 
• Additional adjuvant chemotherapy after surgery is allowed at the discretion of the treating physician, either completed prior to randomization or planned for after completion of protocol treatment. If adjuvant chemotherapy is administered after mastectomy, the patient must be randomized at least 3 weeks but no more than 12 weeks after the last dose of adjuvant chemotherapy. 
• Patients must not have a history of radiation therapy to the ipsilateral chest wall and/or regional nodes. Prior radiation therapy to other body sites is allowed.
• Patients must not be planning to receive any other investigational agents during radiation therapy. Prior therapy, including prior treatment with olaparib or other PARP inhibitor, is allowed. 
• Patients must not have a known hypersensitivity to olaparib or any of the excipients of the product.
• Patients must not have unresolved or unstable grade 3 or greater toxicity from prior administration of another investigational drug and/or prior anti-cancer treatment. 
• Patients must not be planning to receive strong or moderate CYP3A inhibitors or inducers while on olaparib treatment. Patients receiving strong or moderate CYP3A inhibitors must agree to discontinue use at least 2 weeks prior to receiving olaparib. Patients receiving strong or moderate CYP3A inducers must agree to discontinue use at least 5 weeks prior to receiving olaparib. 
• Patients must not be planning to receive live virus or live bacterial vaccines while receiving olaparib and during the 30 day follow up period.
• Patients must not be planning to receive any additional anti-cancer therapy (chemotherapy, endocrine therapy, immunotherapy, biological therapy or other novel agent) while receiving radiotherapy with or without study medication. If a patient is receiving concurrent anti-HER2 targeted therapies, they must not take these medications during the period of radiotherapy (with or without study drug) while enrolled on the study. 
• Patients must be ≥ 18 years of age.
• Patients must have Zubrod performance status 0-2. 
• Patients must have adequate hematologic function as evidenced by all of the following within 28 days prior to registration:
  • Absolute neutrophil count (ANC) >= 1000/mm^3 (within 28 days prior to registration);
  • Platelet count >= 100,000/mm^3 (within 28 days prior to registration);
  • Hemoglobin >= 9.0 g/dL (after transfusion if required and within 28 days prior to registration).
• Patients must have adequate renal function as evidenced by calculated creatinine clearance >= 51 mL/min by Cockcroft-Gault equation, within 28 days prior to registration.
• Calculated creatinine clearance = [(140
  •age) x wt (kg) x 0.85 (if female)]/[72 x creatinine (mg/dl)].
• Patients must have adequate hepatic function as evidenced by all of the following within 28 days prior to registration:  
  • Total bilirubin =< 1.5 x upper limit of normal (ULN) (within 28 days prior to registration).
  • Patients with documented Gilbert's disease may have bilirubin up to 2.5 mg/dL.
  • Serum glutamic-oxaloacetic transaminase (SGOT) =< 2.5 x ULN (within 28 days prior to registration).
  • Serum glutamate pyruvate transaminase (SGPT) =< 2.5 x ULN (within 28 days prior to registration) .
  • Alkaline phosphatase =< 2.5 x ULN (within 28 days prior to registration). 
• Patients must not have a history of other prior malignancy except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for five years.
• Female patients must be postmenopausal or have a negative urine or serum pregnancy test within 28 days prior to registration. Female patients of childbearing potential and male patients with partners of childbearing potential, who are sexually active, must agree to the use of two highly effective forms of contraception. 
• Patients who are breastfeeding must agree to discontinue breastfeeding before receiving olaparib due to potential risk for adverse events in nursing infants secondary to treatment of the mother with olaparib. 
• Patients must not have active uncontrolled infection, symptomatic congestive heart failure, unstable angina pectoris or cardiac arrhythmia. 
• Patients must be able to swallow and retain oral medications and have no known gastrointestinal disorders likely to interfere with absorption of the study medication. 
• Patients must not have a history of a resting electrocardiography (ECG) indicating uncontrolled, potentially reversible cardiac conditions (such as unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, Fridericia's formula corrected QT interval [QTcF] prolongation > 500 ms, electrolyte disturbances) or congenital long QCYP3T syndrome. 
• Patients must not have myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or with features suggestive of MDS/AML. 
• Patient must not have had major surgery within 2 weeks of starting study treatments and patients must have recovered from any effects of any major surgery. 
• Patients must not have a history of uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, or extensive interstitial bilateral lung disease on high resolution computed tomography (HRCT) scan. 
• Patients must not have had previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT). 
• Patients must not have had whole blood transfusions in the last 120 days prior to randomization.

• Age ≥ 18 years < 90 years.
• Patients identified with decompensated heart failure (DHF) and diagnosed clinically with volume overloaded by the primary admitting provider or ED evaluation.
• New York Heart Association functional Class III-IV status/Stage C-D HF.
• ischemic or non-ischemic etiology of HF.
• LVEF < 70% measured within 6 months of study data collection.

• Known significant intrinsic chronic kidney disease (baseline GFR < 15 ml/min/1.73m²) patients.
• Receiving hemodialysis.
• Known renal artery stenosis disease.
• Females who are pregnant or of childbearing potential.

Eligibility last updated 5/25/22. Questions regarding updates should be directed to the study team contact.

Participants with a physician diagnosis of COPD who meet the following criteria: 

• Current or former smokers with a smoking history of ≥ 10 pack-years.
• Moderate-to-severe COPD (post-bronchodilator FEV1/ forced vital capacity [FVC] ≤ 70% and post-bronchodilator FEV1 % predicted > 30% and ≤ 70%). 
• Medical Research Council (MRC) Dyspnea Scale grade ≥ 2. 
• Patient-reported history of signs and symptoms of chronic bronchitis (chronic productive cough) for 3 months in the year up to screening in the absence of other known causes of chronic cough. 
• Documented history of high exacerbation risk defined as exacerbation history of ≥ 2 moderate* or ≥ 1 severe** within the year prior to inclusion. At least one exacerbation should have occurred while the patient was taking ICS/LAMA/LABA (or LAMA/LABA if ICS is contradicted).
  • *Moderate exacerbations are recorded by the investigator and defined as AECOPD that require either systemic corticosteroids (intramuscular (IM), intravenous, or oral) and/or antibiotics. One of the two required moderate exacerbations has to require the use of systemic corticosteroids.
  • **Severe exacerbations are recorded by the investigator and defined as AECOPD requiring hospitalization or observation > 24 hours in emergency department/urgent care facility.
• Background triple therapy (ICS + LABA + LAMA) for 3 months prior to randomization with a stable dose of medication for ≥ 1 month prior to Visit 1: (Double therapy: LABA + LAMA allowed if ICS is contraindicated).
• Evidence of Type 2 inflammation: Patients with blood eosinophils ≥ 300 cells/microliter at Visit 1.
• Body mass index (BMI) ≥ 16 kg/m^2.
• Male or female.
• Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
• Female participants: A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
  • Not a woman of childbearing potential (WOCBP); OR
  • A WOCBP who agrees to follow the contraceptive guidance during the intervention period and for at least 12 weeks after the last dose of study intervention.
• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

• COPD diagnosis for less than 12 months prior to randomization.
• A patient with current diagnosis of asthma or history of asthma according to the 2018 Global Initiative for Asthma (GINA) guidelines or other accepted guidelines.
• Significant pulmonary disease other than COPD (e.g., lung fibrosis, sarcoidosis, interstitial lung disease, pulmonary hypertension, bronchiectasis, Churg-Strauss Syndrome, etc.) or another diagnosed pulmonary or systemic disease associated with elevated peripheral eosinophil counts.
• Cor pulmonale, evidence of right cardiac failure.
• Treatment with oxygen of more than 12 hours per day.
• Hypercapnia requiring BiPAP.
• Acute exacerbation of COPD (AECOPD, as defined above in I 02) within 4 weeks prior to or during the screening period.
• Respiratory tract infection within 4 weeks prior to screening, or during the screening period.
• History of, or planned pneumonectomy or lung volume reduction surgery. Patients who are participating in the acute phase of a pulmonary rehabilitation program; i.e., who started rehabilitation < 4 weeks prior to screening.
  • Note: patients in the maintenance phase of a rehabilitation program can be included.
• Diagnosis of α-1 anti-trypsin deficiency.
• Inability to follow the procedures of the study (e.g., due to language problems, psychological disorders) or unable to read, understand and fill out a questionnaire or use an e-Diary without any help.
• Anti-immunoglobulin E (IgE) therapy (omalizumab) within 130 days prior to Visit 1 or any other biologic therapy (including anti-IL5 mAb) or immunosuppressant to treat inflammatory disease or autoimmune disease (e.g., rheumatoid arthritis, inflammatory bowel disease, primary biliary cirrhosis, systemic lupus erythematosus, multiple sclerosis, etc.) as well as other diseases within 2 months or 5 half-lives prior to Visit 1, whichever is longer.
• Exposure to another investigative drug (small molecules as well as monoclonal antibodies) within a time period prior to Visit 1 that is less than 6 months. The minimum interval since exposure to any other (non-antibody) investigative study medication is 30 days prior to Visit 1.
• History of systemic hypersensitivity or anaphylaxis to any biologic therapy, including any excipients.
• Patients receiving medication or therapy that are prohibited as concomitant therapy.
• Patient is the Investigator, or any Sub-investigator, research assistant, pharmacist, study coordinator, other staff or relative thereof directly involved in the conduct of the study.
• Clinically significant abnormal electrocardiogram (ECG) at randomization that may affect the conduct of the study in the judgment of the investigator, prolonged QTc interval [male > 450 msec, female > 470 msec, Fredericia correction].
• A patient with a history of clinically significant renal, hepatic, cardiovascular, metabolic, neurologic, hematologic, ophthalmologic, respiratory (other than COPD), gastrointestinal, cerebrovascular disease/condition, substance and/or alcohol abuse disorder, active or prior history of malignancy or active malignancy, including lymphoproliferative diseases (except successfully-treated carcinoma in-situ of the cervix, non-metastatic squamous cell or basal cell carcinoma of the skin) within 5 years prior to baseline, or history of or current other significant medical illness or disorder which, in the judgment of the investigator.
• Active tuberculosis or non-tuberculous mycobacterial infection, latent untreated tuberculosis or a history of incompletely treated tuberculosis will be excluded from the study unless it is well documented by a specialist that the patient has been adequately treated and can now start treatment with a biologic agent, in the medical judgment of the investigator and/or infectious disease specialist. Tuberculosis testing will be performed on a country-by-country basis, according to local guidelines if required by regulatory authorities or ethics boards.
• Acute myocardial infarction < 6 months from screening visit.
• TIA or stroke < 6 months from screening visit.
• Hospitalization for any CV or cerebrovascular event < 6 months from screening visit.
• Heart failure NYHA Class III or IV.
• Patients on cardiac medications not on a stable dose during the last 6 months; e.g., antiarrythmics, antihypertensives, and antidiuretics, etc. Dose modification of cholesterol-modifying agents and anticoagulants is allowed.
• Cardiac arrhythmias including paroxysmal (e.g., intermittent) atrial fibrillation are excluded.
• Patients with persistent atrial fibrillation as defined by continuous atrial fibrillation for at least 6 months and controlled with a rate control strategy (i.e., selective beta blocker, calcium channel blocker, pacemaker placement, digoxin or ablation therapy) and stable appropriate level of anticoagulation for at least 6 months may be considered for inclusion.
• Unstable ischemic heart disease or other relevant cardiovascular disorder such as pulmonary embolism, deep vein thrombosis within ≤ 6 months from enrollment that in Investigator's judgment may put the patient at risk or negatively affect the study outcome.
• Patients who are < 80% compliant with controller therapy during screening.
• Previous use of dupilumab.
• Females who are lactating, breastfeeding or who are pregnant.
• Women of childbearing potential (pre-menopausal female biologically capable of becoming pregnant) who:
  • Do not have a confirmed negative serum beta-hCG test at Visit 1 or negative urine pregnancy test at Visit 2;
  • Who are not willing to use one of the acceptable forms of effective contraception for the duration of the study;
  • Postmenopausal women (defined as at least 12 consecutive months without menses) are not required to use additional contraception.
• Diagnosed active parasitic infection (helminthes), suspected or high risk of parasitic infection, unless clinical and (if necessary) laboratory assessments have ruled out active infection before randomization.
• History of HIV infection or positive HIV 1/2 serology at Visit 1.
• Known or suspected history of immunosuppression, including history of invasive opportunistic infections (e.g., tuberculosis, histoplasmosis, listeriosis, coccidioidomycosis, penumocystosis, aspergillosis), despite infection resolution; or unusually frequent, recurrent or prolonged infections, per investigator’s judgment.
• Evidence of acute or chronic infection requiring treatment with antibacterials, antivirals, antifungals, antiparasitics, or antiprotozoals within 4 weeks before Visit 1, significant viral infections within 4 weeks before Visit 1 that may not have received antiviral treatment (e.g., influenza receiving only symptomatic treatment).
• Live, attenuated vaccinations within 4 weeks prior to Visit 1 or planned live, attenuated vaccinations during the study.
• Patients with active autoimmune disease or patients using immunosuppressive therapy for autoimmune disease (e.g., inflammatory bowel disease, primary biliary cirrhosis, systemic lupus erythematosus, multiple sclerosis, etc.).
• Patients with any of the following result at screening:
  • Positive (or indeterminate) HBsAg;
  • Positive IgM HBc Ab; or
  • Positive total HBc Ab confirmed by positive HBV DNA; or
  • Positive HCV Ab confirmed by positive HCV RNA.
• Clinically significant laboratory tests at screening/randomization (Visit 1):
  • Alanine transaminase (ALT) > 3 times upper limit of normal range (ULN);
  • Hemoglobin < 10g /100 mL for male and < 9g/ 100 mL for female;
  • Platelets < 100 000/mm^3;
  • Creatinine ≥ 150 μmol/L.
• Patients on macrolide (e.g., azithromycin) therapy, unless on stable therapy for >12 months.
• Patient who has withdrawn consent before enrollment/randomization.
• Despite screening of the patient, enrollment/randomization is stopped at the study level.

• All patients between the ages of 18 and 65 years old.
• Endotracheal tube or tracheostomy in place and mechanically ventilated for ≤ 7 days.
• Admitted to a participating ICU.
• Radiologic evidence of bilateral pulmonary infiltrates not fully explained by pleural  effusions, atelectasis, or hydrostatic pulmonary edema  
• P/F ratio < 200 with PEEP ≥ 8 cm H2O; If ABG values are not available, the P/F ratio may be inferred from SpO2 values as long as following conditions are met:  
  • SpO2 values are 80-96%;
  • SpO2 is measured ≥10 min after any change in FIO2;  
  • PEEP is ≥ 8 cm H2O;
  • The pulse oximeter waveform tracing is adequate;
  • The qualifying inferred P/F ratio is confirmed 1-6h after initial determination.
• Access to an LAR to provide consent.  
• Criteria 3 AND 4 must be met within 48h of enrollment and randomization, not be fully  explained by hydrostatic pulmonary edema, and must have occurred within 7 days onset  of a condition associated with ARDS.
• Patients may be enrolled and decision about randomization delayed if all criteria other than P/F ratio < 200 are met and then randomized if and when the P/F ratio < 200 (as long as this occurs within 48h of randomization).

• ​Missed ARDS window (> 48hrs).  
• Missed NMB window: (> 12 hrs).
• Missed mechanical ventilation window (> 7 days).
• Refractory hypotension (> 0.2 mcg/kg/min of norepinephrine or equivalent dose for 6 h or longer).
• Core temperature < 35.5°C while not receiving CRRT.
• Patient is unable to give consent and no Legally authorized representative is available.
• Significant, active bleeding (>3u blood products and/or surgical/IR intervention).  
• Platelets <10K/mm^3 (uncorrected).
• Active hematologic malignancy.  
• Skin process that precludes cooling device.  
• Moribund, not likelyto survive 72 hours.  
• Pre-morbid condition makes it unlikely that patient will survive 28 days.  
• Do Not Resuscitate status. 
• Not likely to remain intubated for ≥ 48h.  
• Physician of record unwilling to participate.  
• Severe underlying lung disease:  
  • On home O2;
  • On BIPAP (except for OSA);  
  • Prior lung transplantation.
• Pregnant.
• BMI > 50 kg/m2.  
• Known NYHA class IV heart disease.  
• Acute Coronary Syndrome past 30 days (MI, unstable angina).  
• Cardiac arrest within 30 days of enrollment.  
• Burns over > 20% of the body surface.  
• Severe chronic liver disease (Child-Pugh score 12-15).  
• Previously randomized in CHILL study.

• Clinical and radiographic evidence of a brain tumor.
  • This includes gliomas, ependymomas and medulloblastomas or low grade glioma or gliosis. The pathology will be confirmed after the sample is obtained during the surgery.
• Tissue sample of the suspected lesion(s) is to be obtained by means of elective surgery as part of clinical management.

• Emergency surgery.

• Patients coming to Mayo Clinic’s Genetic Heart Rhythm Clinic for evaluation or follow-up for their GHD.  
• Patients 18 years and older.

• Patient inability or unwillingness to participate in the study.
• Patients 17 years and under.

• 18 years of age or older.
• Able to read, write and understand English.
• Undergoing chemotherapy, radiation therapy, CAR-T, or bone marrow transplant for a cancer diagnosis within the previous 3 years or have metastatic cancer.
• A mean score of at least 1.1 on the Cancer and Treatment Distress (CTxD) or at least one item rated at a 3 (often true) or 4 (nearly all the time).
• A minimum score of 3 on the PC-PTSD-5.
• Denial of suicidal ideation or intent, with no evidence of psychotic behavior.
• Participants must be willing and able to travel to Mayo Clinic outside of normally scheduled visits to participate in the study.

• Individuals under 18 years of age.

• Norepinephrine > 0.05mcg/kg/min.;
• Dopamine > 10 mcg/kg/min.;
• Phenylephrine > 0.4 mcg/kg/min.;
• Epinephrine > 0.05 mcg/kg/min.;
• Vasopressin > 0.03 units/min.;
• Vasopressin (any dose) in combination with another vasopressor listed above.

3. The subject must have received intravenous fluid resuscitation of a minimum of 30mL/kg
administered within 24 hours of eligibility.

4. Documented or suspected infection defined as definitive or empiric intravenous
antibiotic administration.

5. The subject must have a screening multi-organ dysfunction score (MODS) > 9 OR a
sequential organ failure assessment (SOFA) >11, in the event a complete MODS cannot be
obtained due to missing measurements.

6. Endotoxin Activity Assay between ≥ 0.60 to <0.90 EA units.

7. Evidence of at least 1 of the following criteria for new onset organ dysfunction that
is considered to be due to the acute illness:

• Requirement for positive pressure ventilation via an endotracheal tube or tracheostomy tube;
• Thrombocytopenia defined as acute onset of platelet count < 150,000µ/L or a reduction of 50% from prior known levels;
• Acute oliguria defined as urine output < 0.5mL/kg/hr for at least 6 hours despite adequate fluid resuscitation.

• Acute pulmonary embolus;
• Transfusion reaction;
• Severe congestive heart failure (e.g., NYHA Class IV, ejection fraction < 35%).

6. Subject has had chest compressions as part of CPR during this hospitalization without
immediate return to communicative state.

7. Subject has had an acute myocardial infarction (AMI) within the past 4 weeks.

8. Subject has uncontrolled hemorrhage (acute blood loss requiring > 3 UPC in the past 24
hours).

9. Major trauma within 36 hours of screening.

10. Subject has severe granulocytopenia (leukocyte count less than 500 cells/mm3) or
severe thrombocytopenia (platelet count less than 30,000 cells/mm^3).

11. HIV infection in association with a last known or suspected CD4 count of < 50/mm^3.

12. Subject's baseline state is non-communicative.

13. Subject has sustained extensive third-degree burns within the past 7 days.

14. Body weight < 35 kg (77 pounds).

15. Known hypersensitivity to Polymyxin B.

16. Subject has known sensitivity or allergy to heparin or has a history of heparin
associated thrombocytopenia (H.I.T.).

17. Subject is currently enrolled in an investigational drug or device trial.

18. Subject has been previously enrolled in the current trial.

19. Any other condition, that in the opinion of the investigator, would preclude the
subject from being a suitable candidate for enrollment, such as end-stage chronic
illness (e.g., lack of source control and bowel necrosis) with no reasonable expectation
of survival to hospital discharge.

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

Eligibility last updated 10/3/22. Questions regarding updates should be directed to the study team contact.

Inclusion Criteria

• At least 18 years of age
• Able to provide informed consent
• Has diagnosed or suspected blood disorders associated with immune cytopenia (primary or secondary) including, though not restricted, to the following better-defined diseases
  • Immune hemolytic anemia
    • Cold-agglutinin disease
    • Evans syndrome
    • Paroxysmal cold hemoglobinuria
    • Warm autoimmune hemolytic anemia
  •  Immune neutropenia
  •  Immune thrombocytopenia
  •  Pure red cell aplasia
  •  Thrombotic thrombocytopenic purpura (acquired)
• Hemoglobin levels greater than 8

• Patients with perihilar or intrahepatic CCA undergoing liver transplant will be evaluated.
• Single lesion ≤3 cm.
• Absence of vascular invasion.
• No evidence of extrahepatic disease.
• No attempted prior resection with violation of tumor plane.
• General eligibility as a liver transplant candidate.
• No attempted prior resection with violation of tumor plane.

• None.

• Histologically confirmed CD30-positive PTCL (most subtypes allowed) or TMF per the revised World Health Organization 2016 classification (Swerdlow, 2016).
  Note: Patients must wait for central results before first dose of study drug.
• Cohorts A and B (PTCL cohorts):
  • measurable by the modified Lugano Classification (Cheson, 2014);
  • measurable disease of ≥1.5 cm diameter by computed tomography (CT), assessed locally for eligibility.
    • Note: Confirmation by fluorodeoxyglucose (FDG) avid disease by positron emission tomography (PET) recommended, if possible.
• Cohort C (TMF cohort):
  • measurable by the Olsen Criteria (Olsen, 2011) including at least 1 cutaneous lymphoma lesion ≥2 cm in diameter, assessed locally for eligibility.

Patients must have relapsed or refractory disease AND the following: 

• Cohorts A and B (PTCL cohorts):
  • patients must have received at least 1 prior line of systemic therapy. For patients with systemic ALCL, patients must have failed or be intolerant to brentuximab vedotin [BV]; Adcetris®.
• Cohort C (TMF cohort):
  • patients must have received at least 1 prior line of systemic therapy; and have exhausted systemic therapies with full approval for their treatment of transformed mycosis fungoides 
• Completion of treatment with any radiotherapy, chemotherapy, antibody, immunoconjugates and/or another investigational drug ≥4 weeks (or 5 half-lives of the drug, whichever is shorter) prior to first dose of study drug.
  Note: patients may be enrolled after a minimum of 2 weeks of radiation if radiation was for palliative intent to a single cutaneous lesion or single nodal region after discussion with the sponsor.
• Completion of an autologous hematopoietic stem cell transplantation at least 3 months prior to first dose of study drug (if applicable). 
• Resolution of any clinically significant previous therapy-related toxicity to ≤Grade 1 or to baseline if pre-existing condition (exception: patients with all grade alopecia and ≤Grade 2 peripheral neuropathy.
• Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1 (Appendix B).
• Life expectancy ≥12 weeks.
• Adequate laboratory functional values. Note: transfusions and growth factors allowed during screening; however, transfusion-dependency defined as requiring blood products ≥once per week is not allowed.

• Patients with the following subtypes of lymphoma:
  • T-cell prolymphocytic leukemia;
  • T-cell large granular lymphocytic leukemia;
  • Chronic lymphoproliferative disorder of NK cells;
  • Aggressive NK-cell leukemia;
  • Extranodal NK-/T-cell lymphoma;
  • Indolent T-cell lymphoproliferative disorder of the GI tract.
  • Adult T-cell leukemia/lymphoma (ATLL)
• Current evidence of central nervous system involvement.
• Has had an allogenic tissue hematopoietic cell/solid organ transplant within the last 3 years. Note: Patients who have had a transplant >3 years ago are eligible as long as there are no signs/symptoms of graft versus host disease (GvHD).
• Requirement for chronic systemic immunosuppressive therapy <12 weeks prior to the first dose of study drug for prophylaxis or management of conditions such as GvHD (e.g. mycophenolate, methotrexate, calcineurin inhibitor-based therapy, steroid doses that would require prolonged tapering for discontinuation).
• Major surgery ≤4 weeks prior to first dose of study drug.
• Any active, concurrent, significant illness or disease (other than T-cell lymphoma) or clinically significant findings including psychiatric and behavioral problems, medical history, and/or physical examination findings that would preclude the patient from participation in the study such as:
  • active infection requiring systemic therapy ≤10 days before the first dose of study drug
  • unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction ≤6 months prior to first study drug, uncontrolled cardiac arrhythmia e.g. atrial fibrillation/flutter, cerebrovascular accidents ≤6 months before first dose of study drug
  • any severe or uncontrolled other disease or condition which might increase the risk associated with study participation
  • active Hepatitis B or Hepatitis C. Antiviral prophylaxis for chronic Hepatitis B virus infection may be used at the discretion of the investigator.
• Diagnosis of Human Immunodeficiency Virus (HIV) i.e. presence of HIV 1/2 antibodies
• Diagnosis of immunodeficiency or requirement for systemic steroid therapy or any other form of immunosuppressive therapy (outside of samples already mentioned in Exclusion Criterion number 4) <7 days prior to the first dose study drug. Topical steroid creams for symptomatic relief for patients in Cohort C (TMF) are exceptions to this rule. Also, the use of physiologic doses of corticosteroids may be approved after consultation with the Sponsor/Medical Monitor.
• Any other malignancy known to be active, with the exception of treated cervical intraepithelial neoplasia and non-melanoma skin cancer.
• General intolerance of any protocol medication or its excipients
• Patient´s inability to appreciate the nature, meaning and consequences of the trial and to formulate his/her own wishes correspondingly.
• Patient is unwilling to comply with the protocol; including the required biopsies and PK sampling.
• Prior treatment with AFM13.

• Patient is able to communicate well with the Investigator, understands and is willing to comply with all requirements of the study, and understands and signs the written informed consent form (ICF).
• At least 18 years of age.
• Cirrhosis and ascites.
• AKI stage 2 or 3. AKI defined by any of the following:
  • increase in SCr (SCr) ≥ 0.3 mg/dl (or ≥ 26.5 micromolar/L) within 48 h; or
  • increase ≥ 50% in baseline SCr, which is known or presumed to have occurred within the prior seven days.
• QLY SCr ≥ to 1.5 mg/dl.
• No sustained improvement in renal function (less than 20% decrease in SCr and SCr ≥ 1.5 mg/dL) after 48 h of diuretic withdrawal and the beginning of plasma volume expansion with albumin.
• Female patients as well as female partners of male patients must be willing to avoid pregnancy for the duration of the study (> 90 days).

• Significant co-morbidities that in the opinion of the Investigator would preclude study participation.
• QLY SCr level > 5 mg/dL.
• AKI stage 1.
• ACLF stage 3.
• Model for End-Stage Liver Disease (MELD) score > 35.
• At least one event of large volume paracentesis (LVP) > 4 Liters in the last 4 days before enrollment.
• Current or recent (within 4 weeks) treatment with nephrotoxic drugs (e.g., aminoglycosides, amphotericin, cyclosporine, NSAIDS (e.g., ibuprofen, naproxen, celecoxib), significant exposure to radiographic contrast agents (large doses or multiple injections of iodinated contrast media).
• Shock (hypovolemic-, cardiogenic-, or vasodilatory/distributive shock) with mean arterial blood pressure (MAP) ≤ 70 mmHg or systolic blood pressure ≤ 90 mmHg along with hypoperfusion. 
• Sepsis or uncontrolled bacterial infection (e.g., persisting bacteremia, persisting ascitic fluid leucocytosis, fever, increasing leucocytosis with vasomotor instability) as measured with the quick sepsis-related organ dysfunction assessment (qSOFA) score.
• Fewer than two days of anti-infective therapy for documented or suspected infection.
• Superimposed acute liver injury induced by drugs, herbal preparation or dietary supplements, with the exception of alcoholic hepatitis.
• Estimated life expectancy less than 5 days.
• Hypoxia (< 90%) or worsening respiratory symptoms.
• Proteinuria > 500 mg/day.
• Tubular epithelial casts, heme granular casts.
• Haematuria or microhaematuria (more than 50 red blood cells per high power field).
• Abnormal renal ultra-sonography unless there is a known chronic structural disease (e.g., diabetic or hypertensive nephropathy).
• Current or recent (within 4 weeks) renal replacement therapy (RRT).
• Severe cardiovascular and pulmonary diseases including, but not limited to, unstable angina, pulmonary edema, congestive heart failure requiring increasing doses of drug therapy, persisting symptomatic peripheral vascular disease, or any other cardiovascular disease judged by the Investigator to be severe. 
• Transjugular intra-hepatic systemic shunt (TIPS) unless it is known to be non-functioning or occluded.
• Ongoing use of vasopressors, unless used for only 48 h before screening; in this case a wash-out period of 8 h before enrollment will be necessary. Patients receiving midodrine and octreotide may be enrolled but treatment must be discontinued prior to enrollment.
• Known allergy or hypersensitivity to terlipressin or other component of the study treatment.
• Subject is not suitable to participate in the study for any reason (including, but not limited to co-morbidities, history of non-compliance with study visits, procedures, or drug administration) in the opinion of the Investigator.
• Females of childbearing potential (those who are not surgically sterilized or post-menopausal for at least 1 year) are excluded from participation in the study unless they agree to use highly effective contraception.
• Males who have no sterilization history and whose female partners have child-bearing potential must agree to use a highly effective method of contraception during the  period from the time of signing the informed consent form (ICF) through 90 days after the last dose of study drug. A male patient must agree to immediately inform the Investigator if his partner becomes pregnant during the study.

Eligibility last updated 5/30/23. Questions regarding updates should be directed to the study team contact.

• Diagnosis of chronic kidney disease (CKD) and active candidate on the kidney donor waitlist at the time of screening.
• Body mass index (BMI) ≤ 40 kg/m^2.
• Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
• Capable of giving signed informed consent.

For Participants in Cohort A

• Active candidates on the kidney waitlist with living donor.

For Participants in Cohort B

• Active candidates on the kidney waitlist with no living donor cleared for donation.

• Significant cardiac dysfunction.
• Known active, recurrent, or chronic infection.
• Active lupus or uncontrolled diabetes.
• Prior treatment with rituximab within 6 months from SAR650984 administration.
• Inadequate organ and bone marrow function at screening.
• Pregnant or breastfeeding women or women who intend to become pregnant during participation in the study.
• Known intolerance or hypersensitivity to any component of SAR650984 or premedications.
• Participants who are not suitable for participation as judged by the Investigator.

The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

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

Eligibility last updated 10/4/23. Questions regarding updates should be directed to the study team contact.

- Study participant has positive TB test at the Screening Visit unless it is determined by a TB specialist that the positive result is related to an adequately treated latent TB infection).

Participant meets any of the following TB exclusion criteria:

• Known active TB disease;
• History of active TB involving any organ system unless adequately treated according to World Health Organization (WHO)/Centers for Disease Control and Prevention (CDC) therapeutic guidance and proven to be fully recovered upon consult with an appropriate specialist;
• Latent TB infection (LTBI) (unless appropriate treatment is initiated at least 4 weeks prior to IMP dosing and will be continued to completion). Tuberculosis preventive therapy should be in accordance with applicable clinical guidelines and appropriate specialist judgment.

- High risk of exposure to TB infection, as assessed by the investigator

- Current pulmonary nontuberculous mycobacterial (NTM) infection or history of pulmonary NTM infection unless proven to be fully recovered. For further information relating to definitions of known active TB, past history of TB, LTBI, high risk of acquiring TB infection and NTM infection, see Appendix 12, Section 10.12.

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

Eligibility last updated 12/7/23. Questions regarding updates should be directed to the study team contact.

• Female patient volunteers aged 18 years and older 
• Without a history of mastectomy or implants 
• Which are identified to have findings suspicious for breast cancer, or not suspicious, and may be referred to Radiology for clinical MRI and/or ultrasound, and may have had a baseline MRI, will be candidates for enrollment
• Have biopsy proven breast cancer and are planning to be treated with neo-adjuvant chemotherapy and had their baseline MRI and/or ultrasound. VA/SDUV/CUSE will be performed after diagnostic biopsy in this group of patients

• Having any condition that does not allow proper use of our imaging devices 
• History of mastectomy or implants

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

Eligibility last updated 4/12/23. Questions regarding updates should be directed to the study team contact.

• Male and female subjects 18 years of age and older.
• Have a primary diagnosis, or a high clinical suspicion, of cancer in the lung warranting surgery based on CT/PET or other imaging.
• Are scheduled to undergo surgical thoracoscopy for diagnostic wedge resection followed by anatomic lung resection.
• Female subjects of childbearing potential or less than 2 years postmenopausal agree to use an acceptable form of contraception from the time of signing informed consent until 30 days after study completion.
• Ability to understand the requirements of the study, provide written informed consent and authorization of use and disclosure of protected health information, and agree to abide by the study restrictions and to return for the required assessments .

• Previous exposure to OTL38.
• Any medical condition that in the opinion of the investigators could potentially jeopardize the safety of the subject.
• History of anaphylactic reactions to folate, including synthetic folic acid (pteroylmonoglutamic acid) and contrast agents containing indocyanine green for near infrared imaging. Subjects with a medical history of 'idiopathic anaphylaxis' will require evaluation.
• History of allergy to any of the components of OTL38, including folic acid.
• A positive serum pregnancy test at Screening or a positive urine pregnancy test on the day of surgery or day of admission for female subjects of childbearing potential.
• Clinically significant abnormalities on electrocardiogram (ECG) at screening.
• Presence of any psychological, familial, sociological condition or geographical challenges potentially hampering compliance with the study protocol and follow-up schedule.
• Impaired renal function defined as eGFR < 50 mL/min/1.73m^2. Impaired liver function defined as values > 3 x the upper limit of normal (ULN) for alanine aminotransferase (ALT) or aspartate aminotransferase (AST), alkaline phosphatase (ALP), or > 2 x ULN for total bilirubin except in subjects with Gilbert's syndrome.
• Received an investigational agent in another investigational drug or vaccine trial within 30 days prior to the administration of study drug.
• Known sensitivity to fluorescent light.

Select

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

Eligibility last updated 11/17/22. Questions regarding updates should be directed to the study team contact.

Eligibility last updated 7/8/22. Questions regarding updates should be directed to the study team contact.

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

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

• Subject scheduled for vaginal birth.
• Subject gestating a single fetus.
• Subject nulliparous, or had a previous pregnancy terminated within 24 weeks gestation.
• Subject able and willing to comply with the protocol required follow-up visits.
• Subjects able and willing to provide written informed consent prior to enrollment.
• In the opinion of the investigator, the subject has sufficient mental capacity to understand the informed consent form (ICF), comply with the protocol requirements, and provide clinically relevant and reliable feedback regarding their experience with the device.
• Subject receives epidural anesthesia during labor prior to using the device.
• Subject 18 years of age or older at time of consent.

• Subject has high likelihood of less than 1 hour of potential device dilation time after she arrives at the hospital.
• Subject has need for or is planning a Caesarean-section.
• Subject begins labor with less than 36 weeks gestation.
• Subject has neurological diseases; e.g., Multiple Sclerosis, that may result in unrelated pelvic disorders, or has been diagnosed with HIV.
• Subject has muscular or skin disorder that affects elasticity of tissue, such as scleroderma or lupus.
• Subject has evidence of local or systemic infection, or has active herpes infection.
• Subject has any prior surgical procedures to the vaginal anatomy which could lead to pelvic dysfunction, pelvic fractures, or pelvic soft tissue injuries.
• Subject has any general health condition or systemic disease that may represent, in the opinion of the investigator, a potential increased risk associated with device use or pregnancy.
• Subject has placenta previa or vasa previa.
• Known significant chromosomal or structural fetal anomalies.
• Category 2 and/or 3 fetal tracing that is unresolved.

Eligibility last updated 9/2/21. Questions regarding updates should be directed to the study team contact.

• Is a known carrier of a heterozygous loss-of-function GRN mutation causative of FTD with a global CDR® plus NACC FTLD score of 0 to 2; and
  • A CDR® plus NACC FTLD-SB score ≤ 0.5 with an elevated level of serum NfL; or
  • A CDR® plus NACC FTLD-SB score of > 0.5 with 1 or more of the 6 behavioral/cognitive symptoms required for a diagnosis of possible bvFTD (Rascovsky 2011), or a diagnosis of PPA (Gorno-Tempini 2011).
• Age 25 to 85 years, inclusive, at Screening.
• At Screening, women must be nonpregnant and nonlactating, and one of the following conditions must apply:
  • Not a woman of childbearing potential (WOCBP) (either surgically sterilized or physiologically incapable of becoming pregnant, or at least 1-year postmenopausal [amenorrhea duration of 12 consecutive months with no identified cause other than menopause]);
  • Is a WOCBP and agrees to use an acceptable contraceptive method from Screening until 10 weeks after the last dose of study treatment. Acceptable contraception is defined as using hormonal contraceptives (e.g., combined oral contraceptive pill) or an intrauterine device combined with at least 1 of the following forms of contraception: a diaphragm or cervical cap, or a condom. In addition, total abstinence, if in accordance with the lifestyle of the participant, is acceptable;
  • A WOCBP must have a serum pregnancy test conducted at screening. Additional requirements for pregnancy testing during and after study intervention are described in the Schedules of Assessments.
• Men must agree to use acceptable contraception and not donate sperm from Day 0 until 10 weeks after the last dose of study treatment. Acceptable contraception for the male participant when having sexual intercourse with a WOCBP who is not currently pregnant is defined as using a condom. In addition, WOCBP partners must use hormonal contraceptives (e.g., combined oral contraceptive pill) or an intrauterine device.
• Agrees not to donate blood or blood products for transfusion for the duration of the study and for 1 year after the final dose of study treatment.
• Willing to and can comply with the study protocol requirements, in the opinion of the investigator.
• Willing and able to give informed consent. If the patient is not competent, a legally authorized representative must provide informed consent on their behalf, and the patient must provide assent, in accordance with local regulations, guidelines, and institutional review board (IRB) or independent ethics committee (IEC).
• Patient has the availability of a person (“study partner”) who has frequent and sufficient contact with the patient (at least 5 hours per week of in-person contact) and who can provide accurate information to the study site regarding the patient's behavior, cognitive, and functional abilities, as well as their health, throughout the study. Requirements for the study partner include:
  • Willing and able to provide informed consent to participate in the study as a study partner;
  • The study partner must have sufficient cognitive capacity to accurately report upon the participant’s behavior, cognitive, and functional abilities, in the opinion of the investigator;
  • The study partner should be in sufficiently good general health to have a high likelihood of maintaining the same level of interaction with the participant and participation in study procedures throughout the study duration;
  • The same study partner should participate throughout the duration of Part 1 of the study. If a change in study partner is necessary, the medical monitor must be contacted;
  • Study partner agrees to provide information at investigational site visits that require partner input for COA completion;
  • Study partner agrees to accompany the participant at COA visits, as follows:
    • At-risk participants (CDR® plus NACC FTLD-SB score ≤ 0.5) require the study partner at the COA visits only;
    • . − Symptomatic participants (CDR® plus NACC FTLD-SB score > 0.5) require the study partner at each visit;
    • At-risk participants who become symptomatic (CDR® plus NACC FTLDSB > ) during the study treatment period require the study partner at each visit moving forward through Study Completion. Inclusion criteria applicable to those participants participating in the optional Winterlight Labs Speech Assessment (WLA) only:
    • Has available and willing study partner to administer the WLA;
    • Has WiFi access in their residence or WiFi access in a private area where the testing can take place;
    • Participants and study partners must be proficient in English, Spanish, French, or German in the investigator’s opinion.

• Dementia due to a condition other than FTD including, but not limited to, Alzheimer’s disease, Parkinson’s disease, dementia with Lewy bodies, Huntington disease, or vascular dementia.
• Known mutation causative of neurodegenerative disorder(s) other than heterozygous loss-of-function GRN mutations causative of FTD.
• Known history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric, human, or humanized antibodies or fusion proteins.
• Signs or symptoms of progressive supranuclear palsy or bulbar dysfunction, such as postural instability, eye problems, and swallowing difficulties.
• History of moderate or severe substance use disorder within the past 2 years, with the exception of nicotine, as defined by the Diagnostic and Statistical Manual of Mental Disorders, fifth edition criteria (American Psychiatric Association 2013).
• Currently has or has had an acute illness that requires or required systemic antibiotics within 30 days prior to first study treatment administration.
• Clinically significant vitamin B12 or folate deficiency (if treated, must be on a stable regimen for at least 3 months prior to first study treatment administration).
• Untreated hypothyroidism (if treated, thyroid supplementation dose must be stable for at least 3 months with a normal thyroid-stimulating hormone level prior to study treatment administration).
• Insufficiently controlled diabetes mellitus (e.g., hemoglobin A1C ≥ 8%).
• Any surgery (major or emergent) or hospitalization within 30 days prior to first study treatment administration.
• History of cancer within the last 5 years with the exception of basal cell or squamous cell carcinoma.
• Positive for hepatitis B surface antigen, human immunodeficiency virus-1 or -2 antibodies or antigen, or history of spirochetal infection of the CNS (e.g., syphilis, borreliosis, or Lyme disease). Participants with a positive hepatitis C virus antibody will be allowed if hepatitis C RNA is negative.
• Significant kidney disease as indicated by either of the following:
  • Estimated glomerular filtration rate (eGFR) 95 mm Hg or systolic BP > 150 mm Hg) at screening.
• History or presence of an abnormal ECG that is clinically significant, including complete left bundle branch block, second- or third-degree atrioventricular block, or evidence of acute or subacute myocardial infarction or ischemia.
• History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias such as structural heart disease (e.g., severe left ventricular systolic dysfunction, left ventricular hypertrophy) or clinically significant electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia).
  • Note: Participants with premature ventricular contractions are eligible to participate.
• For participants who consent to lumbar puncture, participant has contraindication to lumbar dural puncture, including coagulopathy, concomitant anticoagulation medication (except for a platelet inhibitor such as aspirin), thrombocytopenia, or other factor(s) that precludes safe lumbar puncture.
• History or presence of clinically evident vascular disease potentially affecting the brain (e.g., clinically significant carotid or vertebral artery stenosis or plaque; cerebral hemorrhage or infarct greater than 1 cm3; 3 or more lacunar infarcts in any location; cerebral contusion; encephalomalacia; intracranial aneurysm; arteriovenous malformation; subdural hematoma); hydrocephalus; space-occupying lesions (e.g., abscess or brain tumor such as meningioma) that have the potential to affect cognitive function; or intracranial tumor that is clinically relevant (e.g., glioma, cerebral metastasis).
• History of a clinically significant, persistent neurologic deficit, structural brain damage, or CNS trauma.
• Resides in a skilled nursing facility, convalescent home, or long-term care facility at screening; or requires continuous nursing care (i.e., > 3 months).
• Unable to tolerate MRI procedures (e.g., due to anxiety or claustrophobia) or has a contraindication to MRI, including, but not limited to, the presence of pacemakers, aneurysm clips, artificial heart valves, ear implants, or foreign metal objects in the eyes, skin, or body that are not compatible with an MRI scan; or any other clinical history or examination finding that would pose a potential hazard in combination with MRI.
• Has a medical condition or extenuating circumstance that, in the opinion of the investigator, might compromise their ability to comply with the protocol-required testing or procedures, or compromise the participant’s well-being, safety, or clinical interpretability.

Eligibility last updated 1/4/22. Questions regarding updates should be directed to the study team contact.

• Subjects must provide written informed consent.
• Be a female or male, at least 18 years of age.
• Have a medically confirmed diagnosis of classic 21-hydroxylase deficiency CAH based on standard medically accepted criteria such as elevated 17-OHP level, confirmed CYP21A2 genotype, positive newborn screening with confirmatory second-tier testing, or cosyntropin stimulation.
• Be on a stable, supraphysiologic glucocorticoid dose regimen (defined as > 13 mg/m^2/day in hydrocortisone dose equivalents) that has been stable for at least 1 month prior to screening, is intended for chronic use, and consists of 1 or more of the following glucocorticoids: hydrocortisone (except sustained release), prednisone, prednisolone, methylprednisolone, or dexamethasone. 
• If treated with fludrocortisone, dose should be stable for at least 1 month prior to screening with an upright plasma renin activity (PRA) during screening within the normal range on the subject’s usual sodium intake. If PRA is not within the normal range, the subject must have systolic blood pressure > 100 mmHg, without orthostatic hypotension, and with serum sodium and potassium in the normal range.
• Female subjects of childbearing potential with fertile male partners must agree to use contraception consistently from screening until the final study visit or 30 days after the last dose of study drug, whichever is longer. A female who is not of childbearing potential must meet one of the following:
  • Postmenopausal, defined as no menses for 12 months without an alternative medical cause and confirmed by elevated follicle-stimulating hormone (FSH) consistent with a postmenopausal range;
  • Permanent sterilization procedure, such as hysterectomy, bilateral salpingectomy; or bilateral oophorectomy;
  • Acceptable methods of contraception include the following:
    • Condom with spermicide (cream, spray, foam, gel, suppository, or polymer film);
    • Diaphragm with spermicide (with or without condom);
    • Cervical cap with spermicide (with or without condom);
    • Vaginal sponge impregnated with spermicide used with condom;
    • Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS);
    • Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation, which may be oral, intravaginal, or transdermal, at least 2 months prior to screening;
    • Progestogen-only hormonal contraception associated with inhibition of ovulation, which may be oral, injected, or implanted, at least 2 months prior to screening;
    • Bilateral tubal ligation;
    • Sexual partner(s) who had been vasectomized at least 3 months prior to screening or medically confirmed successful procedure;
    • Progesterone only, where inhibition of ovulation is not the primary mode of action.

• Have a known or suspected diagnosis of any of the other forms of classic CAH including 11-β-hydroxylase deficiency, 17-α-hydroxylase deficiency, 3-β-hydroxysteroid dehydrogenase deficiency, P450 side-chain cleavage deficiency, or P450 oxidoreductase deficiency.
• Have a history of bilateral adrenalectomy, hypopituitarism, or other condition requiring chronic therapy with oral, inhaled, or intranasal glucocorticoids.
• Evidence of glucocorticoid overtreatment during screening, as evidenced by preglucocorticoid morning 17-OHP less than the ULN, post-glucocorticoid morning 17-OHP less than the lower limit of normal, or morning androstenedione level less than the lower limit of normal, based on normal ranges for age and sex.
• At increased risk of developing adrenal crisis in the Investigator’s opinion, based on, for example, repeated history of adrenal crisis in the past, prior history of adrenal crisis precipitated by reducing glucocorticoid dose, recent episode(s), etc.
• Have a clinically significant medical condition or chronic disease (including history of neurological, hepatic, renal, cardiovascular, gastrointestinal, significant malabsorption, hematologic, pulmonary, psychiatric, or endocrine disease [excluding CAH]) that in the opinion of the investigator would preclude the subject from participating in and completing the study or that could confound interpretation of study outcome.
• History of malignancy, unless successfully treated with curative intent and considered to be cured.
• Have a known history of clinically concerning cardiac arrhythmia (including long QT syndrome) or prolongation of screening (pre-treatment) QT interval corrected for heart rate using Fridericia’s correction (QTcF) of > 450 msec (males) or > 470 msec (females).
• Known sensitivity (i.e., hypersensitivity) or allergy to any corticotropin-releasing hormone (CRH) receptor antagonist.
• Have evidence of chronic renal or liver disease based on any of these screening laboratory test abnormalities:
  • Serum creatinine > 1.5 × ULN;
  • Aspartate aminotransferase (AST) > 3 × ULN;
  • Alanine aminotransferase (ALT) > 3 × ULN;
  • Total bilirubin > 1.5 × ULN unless due to a documented diagnosis of Gilbert's syndrome.
• Have any of the following hematologic abnormalities at screening:
  • Hemoglobin 1.3, unless the subject is on anticoagulant treatment that affects INR;
  • White blood cell (WBC) count < 3.0 × 10^3 /mm^3;
  • Platelet count < 100,000/mm^3;
  • Absolute neutrophil count < 1.0 × 103 /mm^3.
• Have any of the following abnormal coagulation abnormalities at screening:
  • Activated partial thromboplastin time (aPTT) that exceeds ULN values by more than 5 seconds;
  • Prothrombin time (PT) expressed as international normalized ratio (INR) > 1.3, unless the subject is on anticoagulant treatment that affects INR.
• Used any active investigational drug within 30 days or 5 half-lives (whichever is longer) before screening, or plans to use an investigational drug (other than the study drug) during the study.
• Are using any excluded concomitant medication and cannot discontinue use of these medications for the duration of the study.
• Has current substance dependence or substance or alcohol abuse (drugs including controlled substance or non-prescribed use of prescription drugs; nicotine and caffeine dependence are not exclusionary).
• Have a significant risk of suicidal or violent behavior. Subjects with any suicidal ideation of type 4 (active suicidal ideation with some intent to act, without specific plan) or type 5 (active suicidal ideation with specific plan and intent) in the past 6 months before screening or any history of suicidal behavior within the past year based on the Columbia-Suicide Severity Rating Scale (C-SSRS) should be excluded.
• Have had a blood loss ≥ 550 mL or donated blood or blood products within 8 weeks before Day 1 (baseline).
• Females who are pregnant or lactating.
• In the Investigator’s opinion, the subject is not capable of adhering to the protocol requirements.

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