• Age ≥ 18 years.
• Women with an initial pathologically confirmed diagnosis of stage I-III, hormone receptor positive, HER2-neu negative, invasive breast cancer within 18 months prior to enrollment.
• Women who have undergone neo-adjuvant chemotherapy who have no residual invasive disease post-surgery are eligible based on an initial pathologically confirmed diagnosis.
• Hormone receptor positive is defined as estrogen receptor (ER) and/or progesterone receptor (PR) of > 1%.
• HER2-neu negative is defined as 0-1+ by immunohistochemical (IHC) analysis, or non-amplified by fluorescence in situ hybridization (FISH) analysis.
• Patients must have received cancer-directed surgery, and/or completed all other adjuvant therapy, except reconstruction.
• Patients must have initiated an endocrine therapy drug within the 6 months prior to registration, OR have received a prescription with stated intent to initiate within 6 weeks after registration.
• No history of previous cancer as follows:
  • Invasive or non-invasive breast cancer at any time.
  • Non-breast cancer, within the past 5 years, excluding non-melanoma skin cancer.
• Patients must be willing to use a smart phone for study activities.
• Patient is NOT to be deemed ineligible during the recruitment process if they do not have a smart phone.
• If a participant does not own a smart phone or has limited data or texting capabilities or their smart phone cannot support the Alliance electronic patient reported outcomes (ePRO) survey application (app), a smart phone and service can be provided to the participant at no cost through the Ohio State University (OSU) partnership with Verizon Wireless for the duration of the study activities.
• The CRP is ONLY to discuss this option with those patients who self-identify a phone-related barrier to participation, including: lack of a smart phone, insufficient phone plan (minutes/text/data), or a smart phone incompatible with the Alliance ePRO app.
• For OSU provided phones, charges will be paid by the grant through the intervention period. At the end of the 12-month intervention period, patients will be responsible for paying monthly fees, if continued service is desired. The physical phones will belong to the patients at the end of their study activities.
• Patients must be willing to use a Pillsy medication event monitoring system for the duration of study participation.
• In order to complete the mandatory patient-completed measures, participants must be able to speak and read English.

• Age 18 years or older at the onset of Screening.
• Biopsy confirmed diagnosis of IgAN within 8 years prior to Screening.
• Proteinuria of > 1 g/day within 6 months prior to Screening or uPCR > 0.75 by spot urine at Screening .
• Mean of two proteinuria measurements > 1 g/day at baseline. 
• Estimated glomerular filtration rate of ≥ 30 mL/min/1.73 m^2 at Screening and baseline.

• Treatment with immunosuppressants (e.g., azathioprine or cyclophosphamide), or cytotoxic drugs, for IgA within 8 weeks prior to Screening. Treatment with immuno-suppressants or cytotoxic drugs for IgAN is not allowed during the Run-In Period. Treatment with immunosuppressants are allowed if such treatment is for indications other than IgAN. 
• Treatment with eculizumab within 8 weeks prior to Screening. Treatment with eculizumab is not allowed during the Run-In Period. 
• Treatment with systemic corticosteroids within 8 weeks prior to Screening. Treatment with systemic corticosteroids is not allowed during the Run-In Period.
• Uncontrolled BP, a systolic BP of > 150 mmHg and a diastolic BP of > 100 mmHg at rest despite the combination of two or more anti-hypertensives including ACEIs, ARBs, or direct renin inhibitors at Screening and baseline.
• Female patients who are pregnant, breast feeding, or planning to become pregnant up through 12 weeks after the last dose of study drug, including possible retreatments.
• Clinical or biological evidence of Type 1 diabetes mellitus (DM), or poorly controlled DM with hemoglobin A1c > 7.5 or with evidence of diabetic nephropathy on biopsy, systemic lupus erythematosus, IgA vasculitis (Henoch-Schonlein purpura), secondary IgAN, or other renal disease during Screening and Run-In.
• History of renal transplantation. 
• Have a known hypersensitivity to any constituent of the investigational product.
• Rapidly progressive glomerulonephritis.
• Significant abnormalities in clinical laboratory values.
• History of human immunodeficiency virus (HIV), evidence of immune suppression, active HCV infection (patients with positive anti-HCV antibody but a non-detected HCV RNA PCR can enroll), HBV infection (patients with positive HBsAg are excluded. For patients with isolated positive anti-HBc antibody, HBV DNA test by PCR must be non-detectable to enroll). 
• Diagnosis of a malignancy except for adequately treated and cured basal or squamous cell skin cancer, curatively treated in situ disease, or other cancer from which the patient has been disease-free for ≥ 5 years.
• Have received any other investigational drug or device or experimental procedures within 30 days of the Screening Visit (SV).

• Male and female subjects aged 18 to 75 years, inclusive.
• IPAA for UC completed at least 1 year prior to screening.
• Active signs and symptoms of pouchitis, as follows:
  • Modified Pouchitis Disease Activity Index (mPDAI) score ≥ 5; and
  • Increased stool frequency, defined as 3 more stools per day above “normal” (after IPAA) and an absolute total of ≥ 6 stools per day.
• Chronic or recurrent pouchitis, defined by:
  • ≥ 2 episodes within 1 year prior to or including the screening period treated with antibiotic or other prescription therapy; or
  • Maintenance antibiotic therapy taken continuously for ≥ 4 weeks immediately prior to the screening endoscopy.
• Antibiotic-resistant pouchitis, defined as disease remaining active despite at least 2 weeks of antibiotic therapy.
• Histologic inflammation in the pouch, defined by a Geboes score of 3.1 or greater.
• Unlikley to conceive.
• Women of childbearing potential (WOCBP) must have a negative pregnancy test at screening and at the randomization visit prior to the first dose of study drug.
• Able to participate fully in all aspects of this clinical trial.
• Written informed consent must be obtained and fully documented.

• Known Crohn’s disease (CD) or suspected CD of the pouch, defined as complex perianal/pouch fistula and/or extensive length of pre-pouch ileitis with deep ulceration.
• Diagnosed or suspected irritable pouch syndrome (IPS).
• Isolated or predominant cuffitis.
• Mechanical complications of the pouch such as stricture or fistula(e) that preclude evaluation of the pouch and terminal ileum.
• Fecal incontinence due to anal sphincter dysfunction.
• Pelvic sepsis within 12 months prior to screening.
• Planned surgery for UC, or any other elective surgery within the time frame of the study.
• Diverting stoma.
• Current bacterial or parasitic pathogenic enteric infection, including Clostridium difficile, active tuberculosis infection, known infection with hepatitis B or C virus, known infection with human immunodeficiency virus, infection requiring hospitalization or intravenous antimicrobial therapy, or opportunistic infection within 6 months prior to screening, any infection requiring antimicrobial therapy within 2 weeks prior to screening, history of more than 1 episode of herpes zoster or any episode of disseminated zoster.
• Prior biologic use restrictions and exclusions:
  • No more than 25% of enrolled subjects (in each phase) may have prior failure of any biologics;
  • Subjects who have used prior biologic therapies must have discontinued within 8 weeks of screening (or within 4 weeks if drug levels are undetectable).
• Use of any of the following prohibited therapies, except under the stated conditions (if applicable):
  • Opioids within 4 weeks prior to screening;
  • Chronic use of nonsteroidal anti-inflammatory drugs;
  • Oral 5-aminosalicylate (5-ASA), unless the dose is ≤ 4.8 g/day and has been stable for at least 4 weeks prior to screening;
  • Oral budesonide within 6 weeks of screening;
  • Other oral corticosteroids at daily doses > 20 mg prednisone or equivalent, or who started oral corticosteroids within 6 weeks prior to screening; stable doses < 20 mg prednisone or equivalent for at least 4 weeks prior to screening are permitted;
  • Any rectal compounds;
  • Immunosuppresant therapy (azathioprine, 6-mercaptopurine, methotrexate, cyclosporin) within 8 weeks prior to screening;
  • Fecal transplant within 12 weeks prior to screening;
  • Any investigational therapy within 4 weeks prior to screening.
• Diagnosed with any immune deficiency.
• History of malignancy, except for basal cell carcinoma, nonmetastatic squamous cell carcinoma of the skin, or prior malignancy with curative therapy completed at least 5 years prior to screening and no recurrence. 
• Clinically meaningful laboratory abnormalities at screening that would affect subject safety, as judged by the investigator from local testing.
• A concurrent, clinically significant, serious, unstable, or uncontrolled underlying cardiovascular, pulmonary, hepatic, renal, gastrointestinal, genitoruinary, hematological, coagulation, immunological, endocrine/metabolic, or other medical disorder that, in the opinion of the investigator, might confound study results, pose additional risk to the subject, or interfere with the subject’s ability to participate fully in the study.
• Current or recent history of alcohol dependence or illicit drug use that, in the opinion of the investigator, may interfere with the subject’s ability to comply with the study procedures.
• Pregnant or lactating females.
• Any surgical procedure requiring general anesthesia within 1 month prior to screening, or planned elective surgery during the study.
• Mental or legal incapacitation or a history of clinically significant psychiatric disorders at the time of the screening visit that would impact the ability to participate in the trial according to the investigator.
• Concurrent participation in any other interventional study or received any investigational therapy within 1 month prior to screening.
• Previous exposure to AMT-101.
• A known hypersensitivity to AMT-101 or its excipients.

• Confirmed diagnosis of NPC (NPC1 or NPC2) and at least one neurological symptom.
• The patient is two years of age or above.
• The patient is a permanent resident of US. -If taking miglustat (Zavesca®), the patient must have been on the target dose for the past six weeks.
• If the patient is sexually active, it is agreed to use effective contraception.
• Confirmed negative urine pregnancy test for sexually active female of child-bearing potential (post-menarche).
• If the patient has a history of seizures, the condition must be adequately controlled; i.e., the pattern of seizure activity must be stable, and the patient must be on a stable dose and regimen of antiepileptic medication during one month prior to screening.
• Patient or parent/guardian must provide written informed consent to participate in EAP.

• Severe liver insufficiency.
• Renal insufficiency.
• Known or suspected allergy or intolerance to arimoclomol or its constituents.
• The patient is pregnant, planning to become pregnant (while on the study) or is currently breastfeeding.
• The patient will undergo treatment with another investigational drug, whilst participating in the program or in the 4 weeks prior to commencing treatment with arimoclomol.
• The patient is either eligible and able to participate in or is currently participating in an active interventional clinical trial within the indication. The patient, in the opinion of the clinician, is unable to comply with the treatment or has a medical condition that would potentially increase the risk to the patient by participation.
• The patient has a medical condition which hinders the clinician's assessment of arimoclomol safety and efficacy (e.g., certain epileptic conditions or severe cataplexy).

• Informed consent/assent:
  • For adult participants (≥ 18 years of age), ability to comprehend and willingness to sign an ICF;
  • For adolescent participants (≥ 12 to < 18 years of age), written informed consent of the parent(s) or legal guardian and written assent from the adolescent participant.
    • Note: Adolescents who during the course of the study become legal adults will be asked for their consent to participate in the study.
• Female and male adults and adolescents ≥ 12 years of age.
• Clinical diagnosis of FOP (based on findings of congenital malformation of the great toes, episodic soft-tissue swelling, and/or progressive HO).
• Participant-reported FOP disease activity within 1 year of the screening visit. This is defined as pain, swelling, and other signs and symptoms associated with FOP flare-ups or wosening of joint function or radiographic progression of HO (increase in site or number of HO lesions) with or without an association with flare-up episodes.
• Ability to swallow and retain orally administered tablets, either whole or crushed and dispersed in foods or liquids.
• Willingness to avoid pregnancy or fathering children based on the criteria below.
  • Male participants with reproductive potential must agree to take appropriate precautions to avoid fathering children from screening through 90 days after the last dose of study drug and must refrain from donating sperm during this period. Permitted methods in preventing pregnancy (see Appendix A) should be communicated to the participants and their understanding confirmed.
  • Female participants of childbearing potential must have a negative pregnancy test at screening (serum) and before the first dose on Day 1 (urine). Female participants of childbearing potential must agree to take appropriate precautions to avoid pregnancy from screening through 190 days after the last dose of study drug and must refrain from donating oocytes during this period. Permitted methods in preventing pregnancy should be communicated to the participants and their understanding confirmed.
  • Women without childbearing potential (ie, surgically sterile with a hysterectomy and/or bilateral oophorectomy OR ≥ 12 months of amenorrhea and at least 50 years of age) are eligible.
• Willing and able to undergo low-dose WBCT (excluding the head) imaging without requiring intubation.
• Willing and able to comply with study procedures and requirements and attend all study visits as defined in this Protocol.

• Pregnant or breast-feeding.
• CAJIS score ≥ 24.
• FOP disease severity that in the investigator's opinion precludes participation (e.g., ankyloses of most or all joints, symptomatic thoracic insufficiency syndrome, or recurrent respiratory infections).
• History of uncontrolled or unstable cardiovascular, respiratory, renal, gastrointestinal, endocrine, hematopoietic, psychiatric, and/or neurological disease within 6 months of screening.
• Any clinically significant medical condition other than FOP that would, in the investigator's judgment, interfere with full participation in the study, pose a significant risk to the participant, or interfere with interpretation of study data.
• Presence of a clinically significant finding on echocardiogram (as assessed by the investigator).
• Presence of an abnormal finding on ECG at screening that in the investigator's opinion is clinically significant and/or the following ECG parameters: QTcF interval > 450 milliseconds, QRS interval > 120 milliseconds, PR interval > 220 milliseconds, ECG evidence of Brugada syndrome, atrial fibrillation or atrial flutter, or Mobitz II or higher grade atrioventricular block.
• Current treatment with a potent/strong inhibitor or inducer of CYP3A4 within 5 half-lives before the first dose of study treatment or expected to receive such treatment during the study.
  • Note: Topical ketoconazole is allowed.
• Use of the following medications:
  • Imatinib 30 days prior to baseline (Day 1 visit);
  • Any medication that might interfere with HO formation in the 90 days before baseline (Day 1 visit);
  • Bisphosphonates within 1 year of screening.
• Participation in an investigational drug study for the treatment of FOP or any other indication within 30 days or 5 half-lives (whichever is longer) before baseline (Day 1 visit).
• Planning to receive a live vaccine during the course of the study or within 6 weeks after the last dose of study drug.
• Known or suspected allergy to INCB000928 or any component of the study drug.
• Known history of clinically significant drug or alcohol abuse as defined by the investigator in the l year before baseline (Day 1 visit).
• Chronic or current active infectious disease requiring systemic antibiotic, antifungal, or antiviral treatment.
• HIV, HBV, or HCV infection.

Note: Successfully treated HCV is allowed.

• Participants with laboratory values at screening defined in Table 7.

Eligibility last updated 2/7/22. Questions regarding updates should be directed to the study team contact.

Screening

• The participant must be at least 18 years of age at the time of informed consent.
• The participant must provide written informed consent prior to any study procedures.
• The participant must meet diagnostic criteria for Gorlin Syndrome (GS) including major criterion #3a plus 1 additional major criterion or plus 2 additional minor criteria listed below. While not required for study entry, if participant has genetic testing results available at study entry or any time during the study, the testing result will be collected.

Major Criteria

• > 2 histologically confirmed BCCs or 1 for participant under age 20.
• Odontogenic keratocysts of the jaw confirmed histologically.
• ≥ 3 palmar and/or plantar pits seen at the Screening Visit.
• Bilamellar calcification of the falx cerebri present at less than 20 years of age. Fused, bifid, or markedly splayed ribs.
• First degree relative with GS.
• Patched protein 1 (PTCH1) mutation predicted to be of functional significance in normal tissue.

Minor Criteria

• Macrocephaly.
• Congenital malformations including frontal bossing, cleft lip or palate, "coarse face", moderate to severe hypertelorism.
• Skeletal abnormalities detectable clinically: Sprengel deformity, marked pectus deformity, or marked finger syndactyly.
• Skeletal abnormalities detectable radiographically: bridging of the sella turcica; vertebral abnormalities such as hemivertebrae, fusion or elongation of the vertebral bodies; modeling defects of the hands and feet; flame shaped lucencies of the hands or feet.
• Ovarian fibroma.
• Medulloblastoma.
• The participant is willing to have blood collected for safety and PK testing.
• The participant is willing to abstain from application of a non-study topical medication (prescription or over the counter) to face for the duration of the trial. Moisturizers and emollients are allowed. Participant will be encouraged to use their preferred sunscreen with a sun protector factor (SPF) of at least 30 daily on all exposed skin on the face.
• Participants of childbearing potential must agree to use a medically acceptable, highly effective form of contraception for the entire duration of the study including through the follow-up period.
• The participant is willing to forego treatment of BCCs with anything other than the study IP except when the Investigator believes that delay of treatment of a BCC potentially might
  compromise the health of the participant. During the trial, the only allowed form of BCC treatment is surgical.

Screening

• The participant has previously participated in a clinical trial evaluating sirolimus topical gel within the last 5 years.
• Participants with known hypersensitivity to any of the ingredients in the study medication formulation.
• Participants with current, recent (within five half-lives of the experimental drug or if half-life not known, within the past 6 months prior to Day 0), or planned participation in an experimental drug study while enrolled in this study.
• Participants who are pregnant, breastfeeding or planning to become pregnant during the study including through the follow-up period.
• Participants of childbearing potential who are unwilling or unable to comply with contraception measures.
• The participant has any condition or situation which, in the Investigator's opinion, may put the participant at significant risk, could confound the study results, including disease activity, or could interfere significantly with participation in the study.
• Participants deemed by the investigator as unwilling or unable to remain compliant with all tests and procedures, including photographs of their face, if needed, adherence to the study drug administration regimen, and other protocol-required activities.

Baseline

Participants are eligible to be included in the study only if all the following criteria apply at Day 0, Baseline:

• The participant must have had at least a history of 10 BCCs present on the face, scalp, ears and/or neck (clinically diagnosed and/or biopsy confirmed) within 24 months prior to Randomization/Day 0.
• Female participants of childbearing potential must have a negative urine pregnancy test to participate in the study.

Baseline

Participants are excluded from the study if any of the following criteria apply at Day 0, Baseline:

• The participant has > 20 clinically suspicious lesions on the face at time of randomization.
• The participant has used topical or systemic treatment that might interfere with the evaluation of the study IP.  Among these are use of the following:
  • 5-fluorouracil, imiquimod, diclofenac, ingenol mebutate (topical); itraconazole, SUBA-itraconazole (systemic) within the 3 months prior to Day 0;
  • Hedgehog inhibitors (glasdegib, vismodegib, sonidegib, patidegib) systemically within the 6 months prior to Day 0. Topical Hedgehog inhibitors within the 3 months prior to Day 0;
  • Systemic chemotherapy of any kind within 1 year prior to Day 0;
  • Known inhibitors of the mTOR signaling pathway or systemically within 2 months prior to Day 0;
  • Photodynamic therapy (PDT) to target lesions within 3 months prior to Day 0;
  • Nicotinamide orally (500mg/2 time daily) within 3 months prior to Day 0.
• The participant has previously participated in a clinical trial evaluating an investigational product for treatment of BCCs or GS within 3 months prior to Day 0.
• Participants with an ECOG > 2 at Day 0.
• Participants previously treated for invasive cancer within the past 5 years excluding nonmelanoma skin cancer, Stage I cervical cancer, in situ ductal cell carcinoma of the breast, or chronic lymphocytic leukemia (CLL) Stage 0, at Day 0.

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

Eligibility last updated 8/3/22. Questions regarding updates should be directed to the study team contact.

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

Eligibility last updated 3/28/23. Questions regarding updates should be directed to the study team contact.

Eligibility will be determined based on clinicopathologic data derived from patient medical records and established by two or more board-certified Mayo Clinic pathologists.

CASES and CONTROLS

• Inclusion criteria are age ≥ 18 years.

CASES

• Eligible if unequivocally confirmed diagnosis of metastatic melanoma, either by histology or patient history + imaging.

CASES and CONTROLS

• History of an internal malignancy other than melanoma or non-melanoma skin cancer within 5 years prior to blood draw.
• Ambiguous pathology.
• Insufficient or poor quality DNA retrievable from blood sample.

CASES

• Excluded if:
  • all metastatic lesion(s) surgically removed
  • exposed to radiation therapy 7 days prior to blood draw,
  • transplant prior to blood draw iv) surgery or biopsy of any lesion in the 7 days prior to blood draw.

CONTROLS:

• Excluded if internal malignancy other than melanoma or non-melanoma skin cancer is documented within 3 years after blood draw.

Inclusion Criteria

1. First allogeneic HSCT, in ≤ CR2, and MRD negative prior to transplant (including
matched sibling, MUD with at least 6 of 8 HLA markers, or haploidentical with at least
5 of 10 HLA markers) as:

- Adjuvant therapy for AML (Group 1) at 90 days (±10 days) post-HSCT defined as
patients with CRMRD; or

- Treatment for refractory/relapsed AML (first relapse post-HSCT) when disease
occurs after transplant (Group 2) defined as

- First relapse (MRD+ or frank relapse) post-HSCT

- Patients in Arm 1B (SOC) who experience first relapse (MRD+ or frank
relapse) post HSCT

- Safety Lead-in defined as patients who fit all the criteria for Group 2 only

2. Are ≥18 years of age

3. Karnofsky/Lansky score of ≥60

4. Life expectancy ≥12 weeks

5. Adequate blood, liver, and renal function

- Blood: Hemoglobin ≥7.0 g/dL (can be transfused)

- Liver: Bilirubin ≤2X upper limit of normal; aspartate aminotransferase ≤3X upper
limit of normal

- Renal: Serum creatinine ≤2X upper limit of normal or measured or calculated
creatinine clearance ≥45mL/min

7. Patients are allowed to be on experimental conditioning regimens prior to transplant if
no planned maintenance therapy post-transplant.

8. In Group 2, patients may receive bridging therapy at the investigators' discretion in
situations where MT-401 is not ready for administration or the treating physician believes
the patient would benefit

Exclusion Criteria

1. Clinically significant or severely symptomatic intercurrent infection

2. Pregnant or lactating

3. For Group 1, anti-neoplastic therapy after HSCT and prior to or during dosing of
MT-401

4. For Group 2, concomitant anti-neoplastic therapy during or after dosing of MT-401

5. Evidence of acute or chronic GVHD ≥Grade 2 (exception: acute or chronic Grade 2 GVHD
of skin allowed if stable) within one week prior to receiving MT-401

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

Eligibility last updated 12/27/22. Questions regarding updates should be directed to the study team contact.

• Patients must have histologically confirmed (biopsy-proven) diagnosis of mantle cell lymphoma (MCL), with documented cyclin D1 (BCL1) expression by immunohistochemical stains and/or t(11;14) by cytogenetics or FISH. 
• Patients must have measurable or evaluable disease as defined as a lymph node measuring >1.5 cm in any dimension or splenomegaly with spleen >15 cm in craniocaudal dimension. 
• Age ≥ 60 years. 
• No intention to undergo consolidation with high dose chemotherapy and autologous stem cell rescue (Autologous Stem Cell Transplant) in first remission
• ECOG performance status of 0-2. 
• Ability to understand and willingness to sign Institutional Review Board (IRB)-approved informed consent. 
• Willing to provide mandatory tissue samples (if sufficient tissue available), bone marrow and blood samples for research purposes. 
• Adequate organ function as measured by the following criteria, obtained ≤ 2 weeks prior to registration: 
  • Absolute Neutrophil Count (ANC) ≥ 1000/mm³;
  • Hemoglobin ≥ 8 g/dL;
  • Platelets ˃75,000/mm³;
  • Creatinine clearance ≥ 40 mL/min, calculated with the use of 24-hour creatinine clearance or by Cockcroft-Gault formula;
  • Total Bilirubin ≤ 1.5 x Upper Limit of Normal (ULN) or ≤ 3 x ULN for patients with documented Gilbert's syndrome;
  • Aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) ≤ 2.5 x ULN. 
• All females of childbearing potential (not surgically sterilized and between menarche and 1 year post menopause) must have a blood test to rule out pregnancy within 2 weeks prior to registration. 
• Women must not be pregnant or breastfeeding. Females of childbearing potential who are sexually active with a non-sterilized male partner and sexually active men must agree to use 2 methods of adequate contraception (hormonal plus barrier or 2 barrier forms) prior to study entry, for the duration of study participation, and for 12 months after last dose of therapy. Method of contraception must be documented. 
• Patients should not have prior chemotherapy, radiotherapy or immunotherapy for lymphoma.
• Corticosteroids used for other non-lymphomatous conditions will be allowed.
• Corticosteroids no greater than 1 mg/kg prednisone (or equivalent) given for ≤ 14 days will be allowed for treatment of lymphoma related symptoms.

• Patients should not have prior chemotherapy, radiotherapy or immunotherapy for lymphoma. 
• Patients must have no recent (< 1 year) history of malignancy except for the following:
  • adequately treated non-melanoma skin cancer;
  • adequately treated Stage I melanoma of the skin;
  • in situ cervical cancer;
  • low grade prostate adenocarcinoma (Gleason grade ≤ 6) managed with observation and stable for 6 months. 
• Patients should not have known evidence of central nervous system (CNS) lymphoma. 
• Patients must not have received a prior allogeneic stem cell transplant or solid organ transplant (except for cornea) for any indication. 
• Patients must have no active, uncontrolled infections. 
• Patients must not have active hepatitis B or be chronic carriers of hepatitis B. This is defined as patients with hepatitis B surface antigen (HBsAg) positive. Patients with prior exposure to hepatitis B (hepatitis B core antibody (anti-HBc) positive AND HBsAg negative) are allowed with a protective level hepatitis B surface antibody AND a negative hepatitis B viral load by polymerase-chain reaction (PCR). 
• Patients must not have active hepatitis C (HCV) as defined by a hepatitis C viral load detectable by PCR. Patients with a negative HCV antibody are assumed to have a negative HCV viral load. Patients with a positive HCV antibody must have a negative hepatitis C viral load by PCR. Prior treatment for an active HCV infection will be allowed as long as the hepatitis C viral load by PCR is negative.
• Patients must not have known active Human Immunodeficiency Virus (HIV). Testing not required in absence of clinical suspicion. 
• Patients must not have evidence of significant, uncontrolled concomitant diseases, including psychiatric diseases, that could affect compliance with the protocol or interpretation of results or that could increase risk to the patient.
• Patients must not have conditions that preclude oral administration or absorption of medications through the GI tract, including but not limited to the inability to swallow pills or malabsorption syndromes. 
• Patients must not have known allergies to both xanthine oxidase inhibitors and rasburicase. 
• Patients must not require the use of warfarin. Blood thinners of other classes are permitted.
• Patient may not receive the following agents within 7 days prior to the first dose of venetoclax: 
  • Strong and moderate CYP3A inhibitors
  • Strong and moderate CYP3A inducers
  • Strong and moderate P-gp inhibitors 
• Patients must not have consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges), or star fruit within 3 days prior to the first dose of venetoclax.

Inclusion criteria:

• Pathological diagnosis CNS inflammatory demyelinating disease (IIDD) consistent with MS, confirmed by a pathologist
• FFPE tissue with sufficient area for pathological analyses

Eligibility last updated 8/19/22. Questions regarding updates should be directed to the study team contact.

- Prior treatment with > 1 line of a BRAF and/or MEK inhibitor for metastatic disease  

- Serious cardiac condition =< 6 months prior to registration, such as uncontrolled arrhythmia, myocardial infarction, unstable angina, or heart disease defined by the
New York Heart Association (NYHA) class III or class IV

- Failure to recover from acute, reversible effects of prior therapy regardless of interval since last treatment

- Uncontrolled intercurrent non-cardiac illness including, but not limited to:

- Ongoing or active infection requiring IV antibiotic usage within the last week prior to study treatment

- Any other conditions that would limit compliance with study requirements or confound the interpretation of study results

- Immunocompromised patients and patients known to be human immunodeficiency virus (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

- Any of the following, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects:

- Pregnant persons

- Nursing persons

- Persons of childbearing potential who are unwilling to employ adequate contraception

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

Eligibility last updated 6/28/23. Questions

• Women ≥ 35 years old and ≤ 75 years old.
• Women that meet at least one of the following:
  • NCI-BCRAT 5-year risk (> 3%) or that shows at least moderate evidence of treatment benefit outweighing risk according to the US Preventative Services Task Force or IBIS (version 8) risk calculator (> 8% for the 10-year risk);
  • History of atypical hyperplasia (30% lifetime risk for developing breast cancer);
  • LCIS (approximately 20% lifetime risk for developing breast cancer);
  • Status post-surgery (lumpectomy or unilateral mastectomy) for ER positive DCIS;
  • Status post-surgery (lumpectomy or unilateral mastectomy) for pleomorphic LCIS.

Exclusion Criteria:

• Women whose BCRAT falls below the threshold moderate according to the US Preventative Task Force or IBIS (version 8) 10 year risk of < 8%; OR do not have a surgical finding that demonstrates increased risk of developing invasive breast cancer.
• Women with known BRCA1 and BRCA2 mutations.
• Women with known contraindications to tamoxifen, raloxifene, exemestane or anastrozole.
• Women unable to give informed consent.
• Prior history of invasive breast cancer.
• At-risk women due to prior radiation therapy to the chest.
• Prior use of preventive medications (tamoxifen, raloxifene, exemestane or anastrozole) for breast cancer prevention.

• At least 18 years of age, at the time of signing the informed consent. 
• Signs and symptoms of CDI including diarrhea such that in the Investigator's opinion CDI antimicrobial therapy is required. Diarrhea is defined as a change in bowel habits, with ≥ 3 Unformed Bowel Movements (UBMs) (5, 6 or 7 on the Bristol Stool Chart) in the 24 hours prior to randomization. 
• The presence of either toxin A and/or B of C. difficile in the stool determined by a positive free toxin test, produced within 72 hours prior to randomization. 
• Male or Female
  •Male must agree to use contraception as detailed in the protocol during the treatment period and for at least 5 days after study treatment and refrain from donating sperm during this period.
• Female patient is eligible to participate if she is not pregnant, not breastfeeding, and either:
• Not a woman of childbearing potential (WOCBP). A WOCBP who agrees to follow the contraceptive guidance per protocol during the treatment period and for at least 5 days after study treatment. 
• Documented signed informed consent and any authorizations required by local law (e.g., Protected Health Information [PHI]).

• More than one prior episode of CDI in the previous 3 months or more than 3 episodes in the past 12 months.
• A history of chronic diarrheal disease including inflammatory bowel disease (Crohn's disease or ulcerative colitis). 
• Positive diagnostic test for other gastro intestinal (GI) pathogens within 2 weeks of randomization. 
• Major gastrointestinal (GI) surgery (e.g., significant bowel resection) within 3 months of randomization (except appendectomy). Presence of a colostomy or ileostomy or likely requirement of an ostomy during the study. 
• Life threatening or fulminant CDI with evidence of hypotension, septic shock, peritoneal signs or absence of bowel sounds, or toxic megacolon. 
• Current history of significantly compromised immune system:
  • HIV positive with a CD4<200 cells/mm3 within 6 months of randomization;
  • Severe neutropenia with neutrophil count < 500 cells/mL;
  • Concurrent immunosuppressive therapy for recent (within previous 6 months) or anticipated solid organ transplant or bone marrow transplant;
  • Concurrent chemotherapy, radiotherapy or biologic for active malignancy. Or active malignancy with ablative chemotherapy within the past 3 months or anticipated during the study;
  • More than one day (24 hours) of dosing of antimicrobial treatment active against CDI for the current episode of CDI prior to randomization;
  • Prior or current use of anti-toxin antibodies including bezlotoxumab;
  • Unable to discontinue products used to affect bowel movement or disease progression;
  • Involved in a clinical trial and received an IMP for indications other than CDI within 1 month or five half-lives (whichever is longer) or within 3 months if the IMP was for CDI;
  • Received an investigational vaccine against C.difficile;
  • Patients that the Investigator feels are inappropriate for the study for any other reason; e.g., have any conditions that would make the patient unsuitable for inclusion, patients not likely to complete the study for whatever reason, known hypersensitivity or intolerance to study IMPs, patients unwilling or unable to comply with protocol requirements.

• Signed Informed Consent Form.
• Age 18 to 75 years at time of signing Informed Consent Form.
• Ability to comply with the study protocol, in the investigator's judgment.
• Diagnosis of pMN according to renal biopsy prior to or during screening.
  • Diagnosis should be based on light and immunofluorescence microscopy, and if possible, electron microscopy.
• UPCR ≥ 5 g from 24-hour urine collection despite best supportive care for ≥ 3 months prior to screening or UPCR ≥ 4 g despite best supportive care ≥ 6 months prior to screening.
  • Best supportive care comprises renin-angiotensin system blockade with ACE inhibitor and/or ARB at maximally tolerated approved dose.
• Systolic blood pressure ≤ 140 mmHg and diastolic blood pressure ≤ 90 mmHg at screening
• eGFR ≥ 40 mL/min/1.73m^2 or qualified endogenous creatinine clearance ≥ 40 mL/min based on 24-hour urine collection during screening. eGFR is calculated using the CKD-EPI equation (Levey, et al. 2009).
• Patients who previously responded to CNIs (CsA or tacrolimus), rituximab, or alkylating agents with either a CR or PR and subsequently relapsed are eligible but require discontinuation of CNIs or alkylating agents for ≥ 6 months and rituximab for ≥ 9 months prior to screening.
• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use adequate contraception during the treatment period and for 18 months after the final dose of obinutuzumab and for 28 days after the final dose of tacrolimus.
  • A woman is considered to be of childbearing potential if she is postmenarchal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and is not permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined by the investigator (e.g., Müllerian agenesis). The definition of childbearing potential may be adapted for alignment with local guidelines or regulations.
  • The following are examples of adequate contraceptive methods: bilateral tubal ligation; male sterilization; hormonal contraceptives; hormone-releasing intrauterine devices; copper intrauterine devices; male or female condom with or without spermicide; and cap, diaphragm, or sponge with spermicide.
  • The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of contraception. If required per local guidelines or regulations, locally recognized adequate methods of contraception and information about the reliability of abstinence will be described in the local Informed Consent Form.
• For men receiving tacrolimus:  agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, as defined below:
  • The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of preventing drug exposure. If required per local guidelines or regulations, information about the reliability of abstinence will be described in the local Informed Consent Form.
  • With a female partner of childbearing potential or pregnant female partner, men must remain abstinent or use a condom during the treatment period and for 28 days after the final dose of tacrolimus to avoid exposing the embryo.
  • For patients enrolled in the extended China enrollment phase at NMPA-recognized sites: current resident of mainland China and of Chinese ancestry.

• Patients with a secondary cause of MN (e.g., hepatitis B, SLE, medications, malignancies).
• Uncontrolled blood pressure, in the opinion of the investigator, during 3 months prior to screening.
• Evidence of ≥  50% reduction in proteinuria during the previous 6 months prior to randomization.
• Receipt of renal replacement therapy (e.g., renal transplantation, chronic dialysis).
• Type 1 or 2 diabetes mellitus (to exclude proteinuria secondary to diabetic nephropathy).
• Patients who have recent history of steroid-induced diabetes but no evidence on renal biopsy for diabetic nephropathy performed within 6 months of entry into the study are eligible.
• Pregnant or breastfeeding, or intending to become pregnant during the study or within 18 months after the final dose of obinutuzumab or 28 days after the final dose of tacrolimus.
• Women of childbearing potential, including those who have had a tubal ligation, must have a negative pregnancy test result within 1 day prior to each obinutuzumab infusion.
• History of resistance (no response) to CNIs or B-cell depleting antibodies.
• Patients with non-response to rituximab due to development of human anti-chimeric antibodies will be eligible.
• Receipt of previous therapies as follows:
  • Treatment with MMF or oral, intramuscular, or intravenous corticosteroids within 1 month prior to screening;
  • Any B-cell depleting therapy such as rituximab, ocrelizumab, or ofatumumab within 9 months prior to screening;
  • Treatment with cyclophosphamide or CNI within 6 months prior to screening;
  • Treatment with any biologic therapy (other than B-cell depleting agents) such as belimumab, ustekinumab, or anifrolumab (investigational) within 6 months prior to screening;
  • Treatment with an inhibitor of Janus-associated kinase, Bruton’s tyrosine kinase, or tyrosine kinase 2, including but not limited to tofacitinib, baricitinib, upadacitinib, filgotinib (investigational), ibrutinib, or fenebrutinib (investigational) within 3 months prior to screening;
  • Treatment with any investigational agent within 28 days of screening or 5 drug-elimination half-lives of the investigational drug, whichever is longer;
  • Receipt of a live vaccine within 28 days prior to screening or during screening.
• Thrombocytopenia, anemia, and/or coagulopathy with high risk for clinically significant bleeding or organ dysfunction or requiring plasmapheresis, IVIg, or acute blood product transfusions.
• Significant or uncontrolled medical disease which, in the investigator’s opinion, would preclude patient participation.
• Known HIV infection. 
• Tuberculosis (TB) infection:
  •  Testing for latent TB will be performed at screening if required by local regulations or in accordance with local clinical practice;
  •  Latent TB after completion of appropriate treatment is not exclusionary.
• Known active infection of any kind, excluding fungal infection of the nail beds.
• Any major episode of infection requiring hospitalization or treatment either with IV anti-infective treatments during the 2 months prior to or during screening or with oral anti-infective treatments during the 2 weeks prior to or during screening.
• History of serious recurrent or chronic infection.
• History of progressive multifocal leukoencephalopathy (PML).
• History of cancer, including solid tumors, hematological malignancies, and carcinoma in situ, except non-melanomatous carcinomas of the skin that have been treated or excised and have resolved.
• Major surgery requiring hospitalization within the 4 weeks prior to screening.
• Current active alcohol or drug abuse or history of alcohol or drug abuse within 12 months prior to screening.
• Intolerance or contraindication to study therapies, including:
  • Evidence of intolerance or toxicity associated with tacrolimus prior to screening;
  • History of severe allergic or anaphylactic reactions to monoclonal antibodies or known hypersensitivity to any component of the obinutuzumab infusion;
  • Intolerance or contraindication to oral or IV corticosteroids and premedications;
  • Intolerance or hypersensitivity to tacrolimus and its excipients;
  • Lack of peripheral venous access. 
• Laboratory parameters:
  • AST or ALT 2.5 > the upper limit of normal (ULN);
  • Amylase or lipase > 2 x ULN;
  • Neutrophils < 1.5 x 10^3 /µL;
  • CD19+ B cells < 5/µL;
  • Positive for hepatitis B surface antigen (HBsAg) at screening.
  • Patients who are HBsAg negative and hepatitis B core antibody positive with no detectable hepatitis B virus (HBV) DNA will be allowed into the study but will require regular HBV DNA monitoring;
  • Positive hepatitis C virus (HCV) antibody at screening.
  • Patients with positive hepatitis C antibody test result with no detectable HCV RNA for at least 12 months after completion of antiviral therapy are eligible but will require regular HCV RNA monitoring;
  • Hemoglobin < 9 g/dL;
  • Platelet count < 75,000/µL;
  • Positive serum human chorionic gonadotropin measured at screening.

Eligibility last updated 12/2/21. Questions regarding updates should be directed to the study team contact.

• 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.

• Has provided informed consent (signed by study patient or legally acceptable representative).
• Male or female adult ≥ 18 years of age (or country’s legal age of adulthood) at randomization.
• Laboratory-confirmed SARS-CoV-2 infection as determined by a RT-PCR result from any specimen (or other commercial or public health assay) ≤ 72 hours from randomization and no alternative explanation for current clinical condition.
• COVID-19 symptom onset ≤ 7 days.
• Hospitalized for COVID-19 illness for < 72 hours with at least 1 of the following at randomization; patients meeting more than one criterion will be categorized in the most severely affected category:
  • Cohort 1: Maintains O2 saturation > 93% on low-flow oxygen via nasal cannula, simple face mask, or other similar device;
  • Cohort 2: High-intensity oxygen therapy without mechanical ventilation, where high-intensity is defined as receiving supplemental oxygen delivered by 1 of the following devices:
    • Non-rebreather mask (with an SpO2 ≤ 96% while receiving an oxygen flow rate of at least 10 L/min).
    • High-flow device (e.g., AIRVO™ or Optiflow™) with at least 50% FiO2.
    • Non-invasive ventilator, including continuous positive airway pressure (CPAP), to treat hypoxemia (excluding isolated use for sleep-disordered breathing).
  • Cohort 3: On mechanical ventilation

• Phase 1 only: Patients maintaining O2 saturation > 94% on room air.
• In the opinion of the investigator, unlikely to survive for > 48 hours from screening.
• Receiving extracorporeal membrane oxygenation (ECMO).
• Has new-onset stroke or seizure disorder during hospitalization.
• Initiated on renal replacement therapy due to COVID-19.
• Has circulatory shock requiring vasopressors at randomization.
  • Note: Patients who require vasopressors for sedation-related hypotension or reasons other than circulatory shock may be eligible in this study.
• Patients who have received convalescent plasma or IVIG in the past 5 months or plan to receive during the study period for any indication.
• Participation in a clinical research study, including any double-blind study, evaluating an investigational product within 30 days and less than 5 half-lives of the investigational product prior to the screening visit.
  • Note: The use of remdesivir, hydroxychloroquine, or other treatments (except for COVID- 19 convalescent plasma or IVIG) being used for COVID-19 treatments in the context of the local standard-of-care or an open-label study or compassionate use protocol is permitted.
• Any physical examination findings, history of illness, and/or concomitant medications that, in the opinion of the study investigator, might confound the results of the study or pose an additional risk to the patient by their participation in the study.
• Known allergy or hypersensitivity to components of study drug.
• Pregnant or breastfeeding women.
• Continued sexual activity in women of childbearing potential (WOCBP)* or sexually active men who are unwilling to practice highly effective contraception prior to the initial dose/start of the first treatment, during the study, and for at least 6 months after the last dose.
• Highly effective contraceptive measures in women include:
  • Stable use of combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, transdermal) or progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation initiated 2 or more menstrual cycles prior to screening;
  • Intrauterine device (IUD);
  • Intrauterine hormone-releasing system (IUS);
  • Bilateral tubal ligation;
  • Vasectomized partner,† and/or;
  • Sexual abstinence‡,§;
  • Male study participants with WOCBP partners are required to use condoms unless they are vasectomized† or practice sexual abstinence.‡,§.

* WOCBP are defined as women who are fertile following menarche until becoming postmenopausal, unless permanently sterile. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient to determine the occurrence of a postmenopausal state. The above definitions are according to Clinical Trial Facilitation Group (CTFG) guidance. Pregnancy testing and contraception are not required for women with documented hysterectomy or tubal ligation. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy.

† Vasectomized partner or vasectomized study participant must have received medical assessment of the surgical success.

‡ Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study drugs. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient.

§ Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods of contraception. Female condom and male condom should not be used together.

• Confirmed diagnosis of CD for at least 3 months prior to Baseline. Appropriate documentation of biopsy results consistent with the diagnosis of CD, in the assessment of the investigator, must be available.
• SES-CD (excluding the presence of narrowing component) ≥ 6 (or ≥ 4 for subjects with isolated ileal disease), as confirmed by a central reader.
• Average daily liquid/very soft SF ≥ 4.0 AND/OR average daily AP score ≥ 2.0 at Baseline.
• Demonstrated an inadequate response or intolerance to one or more conventional and/or biologic therapies, in the opinion of the investigator, as defined below:
  • Oral locally acting steroids
  • Signs and symptoms of persistently active disease during or after a course of at least 4 weeks of treatment with 9 mg/day budesonide or 5 mg/day beclomethasone; OR
  • Inability to taper oral budesonide at or below 6 mg/day without recurrent active disease; OR
  • Intravenous or oral corticosteroids
  • Signs and symptoms of persistently active disease despite a history of at least one induction regimen consisting of a dose equivalent to prednisone (or equivalent) ≥ 40 mg/day orally for at least 3 weeks or intravenously for 1 week; OR
  • Inability to taper corticosteroids at or below a dose equivalent to prednisone 10 mg/day without recurrent active disease; OR
  • Immunosuppressants
  • Signs and symptoms of persistently active disease despite a history of at least one 12 weeks regimen of the following:
    • AZA: ≥ 2.0 mg/kg/day (≥ 1 mg/kg/day for subjects in Japan, Korea, Taiwan, Singapore, Hong Kong, or China), rounded to the nearest available tablet or half tablet formulation, OR a documented 6-thioguanine nucleotide (6-TGN) level of > 235 pmol/8 × 108 RBC at a dose < 2 mg/kg/day OR documentation that a dose reduction was required due to elevated 6-MP levels (> 5700 pmol/8 ×108  erythrocytes); OR
    • 6-MP: ≥ 1 mg/kg/day (≥ 0.6 mg/kg/day for subjects in Japan, Korea, Taiwan, Singapore, Hong Kong, or China), rounded to the nearest available tablet or half tablet formulation, (or a 6-TGN level of > 235 pmol/8 ×  108 RBC); OR
    • MTX (≥25 mg/week subcutaneous [SC] or intramuscular); OR
    • Tacrolimus (for subjects in Australia, Japan or Taiwan only): documented trough level of ≥5 ng/mL.
    • Note: Oral MTX use is allowed during the study, however prior or current use of oral MTX is not sufficient for inclusion into the study.
  • Biologic therapies for CD
    • At least one 6-week induction regimen of infliximab (≥5 mg/kg intravenous [IV] at Baseline and Weeks 2, and 6); OR
    • At least one 4-week induction regimen of adalimumab (one 160 mg subcutaneous [SC] dose at Baseline, followed by one 80 mg SC dose at Week 2 [or one 80 mg SC dose at Baseline, followed by one 40 mg SC dose at Week 2, in countries where this dosing regimen is approved]); OR
    • At least one 4-week induction regimen of certolizumab pegol (400 mg SC at Baseline and Weeks 2, and 4); OR
    • At least one 6-week induction regimen of vedolizumab (300 mg IV at Baseline and Weeks 2, and 6); OR
    • At least one 8-week induction regimen of ustekinumab [260 mg (≤55 kg) or 390 mg (> 55 to ≤85 kg) or 520 mg (> 85 kg) IV, followed by 90 mg SC at Week 8]; OR
    • Recurrence of symptoms during scheduled maintenance dosing following prior clinical benefit of the above biologics.
    • Intolerance to corticosteroids may include depression, severe insomnia, osteopenia, cushingoid features, etc. Intolerance to AZA/6-MP should include elevations of liver enzymes, pancreatitis, etc., and may include subjects with known thiopurine methyltransferase (TPMT) genetic mutation or low activity. Intolerance to a biologic may include, but not be limited to infusion-related reaction, rash, serum sickness, anaphylaxis,  elevated liver enzymes, demyelination, congestive heart failure, infection, etc. Demonstration of intolerance requires no minimum dose or duration of use.
    • Note: Non-bio-IR subjects who have received prior biologic for up to 1 year but have not failed may be enrolled; however, subjects must have discontinued the biologic for reasons other than  inadequate response or intolerance (e.g., change of insurance, well controlled disease), and must meet the criteria for intolerance or inadequate response to oral locally acting steroids, systemic steroids (prednisone or equivalent), and/or immunosuppressants as defined above.

• Subject on CD-related antibiotics who:
  • has not been on stable doses of these medications for at least 14 days prior to Baseline, or
  • has discontinued these medications within 14 days of Baseline.
• Subject on oral aminosalicylates who:
  • has not been on stable doses of these medications for at least 14 days prior to Baseline, or
  • has discontinued these medications within 14 days of Baseline.
• Subject on corticosteroids who meets the following:
  • prednisone or equivalent dose > 30 mg/day; or
  • budesonide > 9 mg/day; or
  • has not been on the current course for at least 14 days prior to Baseline and on a stable dose for at least 7 days prior to Baseline.
• Subject on MTX who:
  • has not been on the current course for ≥ 42 days prior to Baseline, and
  • has not been on a stable dose for ≥ 28 days prior to Baseline;
• Infection(s) requiring treatment with intravenous (IV) anti-infectives within 30 days prior to the Baseline Visit or oral/intramuscular (IM) anti-infectives within 14 days prior to the Baseline Visit
• Subject requiring or receiving any parenteral nutrition and/or exclusive enteral nutrition.
• Subject who received oral or parenteral traditional Chinese medicines within 30 days prior to Baseline.
• Subject who received any live vaccination within 30 days (or longer, if required locally [e.g., 8 weeks for Japan]) prior to Baseline, or who is expected to need live vaccination during study participation including at least 30 days (or longer, if required locally [e.g., 8 weeks for Japan]) after the last dose of study drug. 
• Subject who received cyclosporine, tacrolimus, mycophenolate mofetil, or thalidomide within 30 days prior to Baseline.
• Subject who received azathioprine (AZA) or 6-mercaptopurine (6-MP) within 10 days of Baseline.
• Subject who received fecal microbial transplantation within 30 days prior to Baseline.
• Subject who received nonsteroidal anti-inflammatory drugs (NSAIDs) within 7 days prior to Baseline, except topical NSAIDs and low dose aspirin for cardiovascular protection. 
• Systemic use of known strong cytochrome P450 (CYP)3A inhibitors or strong CYP3A inducers from Screening through the end of the study (refer to Table 1 for examples of commonly used strong CYP3A inhibitors and inducers).
• Subject who received any of the following agents:
  • adalimumab, certolizumab, golimumab, infliximab, natalizumab, vedolizumab, within 8 weeks prior to Baseline; or 
  • ustekinumab within 12 weeks prior to Baseline;
  • Note: If there is proper documentation of an undetectable drug level measured by a commercially available assay for any of the approved biologics above, there is no minimum washout prior to Baseline.
• Any investigational agent within 30 days or 5 half-lives prior to Baseline, whichever is longer, or is currently enrolled in another interventional study.
• Subject with previous exposure to a JAK inhibitor (e.g., tofacitinib, baricitinib, filgotinib) within 30 days from Baseline.
  • Note: Subjects who received a JAK inhibitor prior to study entry may be enrolled if they have not had inadequate response or loss of response.
•  Subject has been taking both oral budesonide (or oral beclomethasone) and oral prednisone (or equivalent) simultaneously, with the exception of topical or inhalers within 14 days prior to Screening or during the Screening Period.
• Subject received IV corticosteroids within 14 days prior to Screening or during the Screening Period.
• Subject has received therapeutic enema or suppository (i.e., rectal aminosalicylates/corticosteroids), other than required for endoscopy, within 14 days prior to endoscopy used for Screening or during the Screening period.
• Subject who received apheresis (e.g., Adacolumn apheresis) within 60 days prior to Screening or during the Screening Period. 
• Subject has cannabis use either recreational or for medical reasons within 14 days prior to Baseline or any history of clinically significant (per investigator's judgment) drug or alcohol abuse in the last 6 months.
• Subject who previously received stem cell transplantation except for local stem cell therapy for complex perianal fistula.
• Subject has been a previous recipient of an organ transplant which requires continued immunosuppression.
• Subject with the following ongoing known complications of CD:
  • abscess (abdominal or peri-anal);
  • symptomatic bowel strictures;
  • > 2 entire missing segments of the following 5 segments: terminal ileum, right colon, transverse colon, sigmoid and left colon, and rectum;
  • Confirmed COVID-19: the Baseline visit must be at least 14 days from onset of signs/symptoms or positive SARS-CoV-2 test, symptomatic subjects must have recovered, defined as resolution of fever without use of anti-pyretics and improvement in symptoms;
  • Suspected COVID-19: subjects with signs/symptoms suggestive of COVID-19, known exposure, or high risk behavior should undergo molecular (e.g., PCR) testing to rule out SARS-CoV-2 infection or must be asymptomatic for 14 days from a potential exposure;
  • fulminant colitis,
  • toxic megacolon;
  • or any other manifestation that might require surgery while enrolled in the study;
  • Subject with ostomy or ileoanal pouch;
  • Subject diagnosed with conditions that could interfere with drug absorption including but not limited to short gut or short bowel syndrome; 
  • Subject with surgical bowel resection within the past 3 months prior to Baseline, or a history of > 3 bowel resections.
  • Subject with positive Clostridium difficile (C. difficile) toxin stool assay during Screening. 
• Any active, chronic or recurrent infection that, based on the investigator's clinical assessment, makes the subject an unsuitable candidate for the study, including hepatitis B virus (HBV) or hepatitis C virus (HCV), recurrent or disseminated (even a single episode) herpes zoster, disseminated (even a single episode) herpes simplex, or HIV infection. Active HBV, HCV and HIV are defined as:
  • HBV: hepatitis B surface antigen (HBs Ag) positive (+) or detected sensitivity on the HBV deoxyribonucleic acid (DNA) polymerase chain reaction (PCR) qualitative test for hepatitis B core antibody (HBc Ab) positive (+) subjects;
• HCV: HCV ribonucleic acid (RNA) detectable in any subject with anti-HCV antibody (HCV Ab); 
  • HIV: confirmed positive anti-HIV antibody (HIV Ab) test;
  • Confirmed COVID-19: the Baseline visit must be at least 14 days from onset of signs/symptoms or positive SARS-CoV-2 test, symptomatic subjects must have recovered, defined as resolution of fever without use of anti-pyretics and improvement in symptoms;
  • Suspected COVID-19: subjects with signs/symptoms suggestive of COVID-19, known exposure, or high risk behavior should undergo molecular (e.g., PCR) testing to rule out SARS-CoV-2 infection or must be asymptomatic for 14 days from a potential exposure.
  • Subject has active TB or meets TB exclusionary parameters. 
  • History of any malignancy except for successfully treated nonmelanoma skin cancer (NMSC) or localized carcinoma in situ of the cervix.
  • Prior or current gastrointestinal dysplasia, other than completely removed low-grade dysplastic lesions in any biopsy performed during or before the Screening endoscopy.
  • History of gastrointestinal perforation (other than appendicitis or mechanical injury), diverticulitis or significantly increased risk for gastrointestinal perforation per investigator judgment.
  • Female who is pregnant, breastfeeding, or is considering becoming pregnant during the study or within 30 days after the last dose of study drug.
  • History of an allergic reaction or significant sensitivity to constituents of the study drug (and its excipients) and/or other products in the same.
  • Laboratory values meeting the following criteria within the Screening period prior to the first dose of study drug:
    • Serum AST or ALT > 2.0 × upper limit of normal (ULN); 
    • Total WBC count < 2500/µL;
    • Estimated glomerular filtration rate (eGFR) by simplified 4-variable Modification of Diet in Renal Disease (MDRD) formula < 30 mL/min/1.73 m^2;
    • Hemoglobin < 9 g/dL;
    • Platelet count < 100,000/µL; 
    • Absolute neutrophil count (ANC) < 1200/µL;
    •  Absolute lymphocyte count (ALC) < 750/µL. 37. Any of the following cardiovascular conditions or thrombotic conditions:
    • recent (within past 6 months) cerebrovascular accident, myocardial infarction, coronary stenting;
    • current uncontrolled hypertension as defined by a confirmed systolic blood pressure (BP) > 160 mmHg or diastolic BP > 100 mmHg;
    • prior history of thrombotic events including deep venous thrombosis and pulmonary embolism;
    • known inherited conditions that predispose to hypercoagulability. 
• History of clinically significant medical conditions or any other reason that in the opinion of the investigator would interfere with the subject's participation in this study or would make the subject an unsuitable candidate to receive study drug or would put the subject at risk by participating in the study.
• For Japan subjects only: positive result of beta-D-glucan or 2 consecutive indeterminate results of beta-D-glucan during the Screening Period.

Cases

• Women 14 years or older who are undergoing surgical evaluation for potential primary peritoneal, fallopian tube, or epithelial ovarian cancer  
• Women who have previously participated in the research study and are returning to MCR for secondary debulking surgery for these diseases will be re-consented for permission to use excess tissue from the second surgery.
• Women who are not considering surgery but who schedule consultations through medical oncology for ovarian, primary peritoneal, or fallopian tube cancer

Community Controls

• Women age 14 and older residing in the six state areas of MN, IA, WI, SD, ND and IL.
  • No prior bilateral oophorectomy
  • No prior diagnosis of ovarian, primary peritoneal, or fallopian tube cancer

• PRIOR TO STEP 1 REGISTRATION
• A diagnostic contrast-enhanced magnetic resonance imaging (MRI) (no other scan type allowed) of the brain must be performed postoperatively within 72 hours of resection; the enhancing tumor must have a maximal diameter of 5 cm; the tumor diameter will be the greatest diameter as measured on the contrast-enhanced postoperative MRI and will include residual disease and/or the postoperative surgical cavity as appropriate; for cases where residual disease or postoperative surgical cavity is NOT identifiable (e.g., polar glioblastomas [GBMs] where a polar lobectomy is performed), the patient will be excluded from the trial
• The GBM tumor must be located in the supratentorial compartment only (any component involving the brain stem or cerebellum is not allowed)
• Patients must provide study-specific informed consent prior to step 1 registration
• PRIOR TO STEP 2 REGISTRATION
• Histologically proven diagnosis of glioblastoma (World Health Organization [WHO] grade IV) confirmed by central review prior to step 2 registration
• Tumor tissue that is determined by central pathology review prior to step 2 registration to be of sufficient quantity for analysis of O6-methylguanin-DNA-methyltransferase (MGMT) status
  • Patients must have at least 1 block of tumor tissue; submission of 2 blocks is strongly encouraged to maximize the chances of eligibility; at least 1 cubic centimeter of tissue composed primarily of tumor must be present
  • Diagnosis must be made by surgical excision, either partial or complete; stereotactic biopsy or cavitron ultrasonic suction aspirator (CUSA) technique are not allowed
• History/physical examination within 28 days prior to step 2 registration
• The patient must have recovered from effects of surgery, postoperative infection, and other complications within 28 days prior to step 2 registration
• Documentation of steroid doses within 28 days prior to step 2 registration
• Karnofsky performance status ≥ 70 within 28 days prior to step 2 registration
• Age ≥ 18
• Absolute neutrophil count (ANC) ≥ 1,800 cells/mm^3
• Platelets ≥ 100,000 cells/mm^3
• Hemoglobin ≥ 10.0 g/dl (note: the use of transfusion or other intervention to achieve hemoglobin (Hgb) ≥ 10.0 g/dl is acceptable)
• Bilirubin ≤ 1.5 upper limit of normal (ULN)
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN
• Negative serum pregnancy test obtained for females of child-bearing potential within 28 days prior to step 2 registration

• Prior invasive malignancy (except non-melanomatous skin cancer) unless disease-free for a minimum of 3 years; (for example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible)
• Recurrent or multifocal malignant gliomas
• Any site of distant disease (for example, drop metastases from the GBM tumor site)
• Prior chemotherapy or radiosensitizers for cancers of the head and neck region; note that prior chemotherapy for a different cancer is allowable (except temozolomide)
• Prior use of Gliadel wafers or any other intratumoral or intracavitary treatment are not permitted
• Prior radiotherapy to the head or neck (except for T1 glottic cancer), resulting in overlap of radiation fields
• Severe, active co-morbidity, defined as follows:
  • Unstable angina at step 2 registration
  • Transmural myocardial infarction within the last 6 months prior to step 2 registration
  • Evidence of recent myocardial infarction or ischemia by the findings of S-T elevations of >= 2 mm using the analysis of an electrocardiogram (EKG) performed within 28 days prior to step 2 registration
  • New York Heart Association grade II or greater congestive heart failure requiring hospitalization within 12 months prior to step 2 registration
  • Serious and inadequately controlled arrhythmia at step 2 registration
  • Serious or non-healing wound, ulcer or bone fracture or history of abdominal fistula, intra-abdominal abscess requiring major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to step 2 registration, with the exception of the craniotomy for surgical resection
  • Acute bacterial or fungal infection requiring intravenous antibiotics at the time of step 2 registration
  • Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, however, that laboratory tests for coagulation parameters are not required for entry into this protocol
  • Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of step 2 registration
  • Acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition; note, however, that human immunodeficiency virus (HIV) testing is not required for entry into this protocol
  • Any other severe immunocompromised condition
  • Active connective tissue disorders, such as lupus or scleroderma, that in the opinion of the treating physician may put the patient at high risk for radiation toxicity
  • End-stage renal disease (ie, on dialysis or dialysis has been recommended)
  • Any other major medical illnesses or psychiatric treatments that in the investigator's opinion will prevent administration or completion of protocol therapy
• Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception
• Patents treated on any other therapeutic clinical protocols within 30 days prior to step 2 registration
• Inability to undergo MRI (e.g., due to safety reasons, such as presence of a pacemaker, or severe claustrophobia)
• Postoperative tumor plus surgical bed size exceeds 5 cm in maximum diameter.

• Resident of the United States.
• Age 18 years or older.
• Able to provide informed consent.
• Able to complete surveys in English or Spanish.
• Valid order for Cologuard screening.

• Provisions for inclusion of minorities:
  • Subjects will be included based upon a random selection from among all recipients of a Cologuard test.
  • Minorities will be invited without discrimination by this random process.

• Subject is male or female, ≥ 40 years of age at the time of enrollment. 
• Subject presents for a screening colonoscopy per standard of care. 
• Subject has no symptoms or signs that require immediate, or near term, referral for diagnostic or therapeutic colonoscopy. 
• Subject understands the study procedures and can provide informed consent to participate in the study and authorization for release of relevant protected health information (PHI) to the Study Investigator.

• Subject has a personal history of CRC or advanced precancerous lesions.
• Subject has a diagnosis or medical / family history of any of the following conditions, including:
  • Familial adenomatous polyposis (also referred to as "FAP", including attenuated FAP and Gardner’s syndrome);
  • Hereditary non-polyposis CRC syndrome (also referred to as "HNPCC" or "Lynch Syndrome");
  • Other hereditary cancer syndromes including but are not limited to Peutz–Jeghers Syndrome, MYH-Associated Polyposis (MAP), Turcot's (or Crail’s) Syndrome, Cowden's Syndrome, Juvenile Polyposis, Neurofibromatosis, or Familial Hyperplastic Polyposis.
• Subject has a diagnosis or personal history of inflammatory bowel disease (IBD) including chronic ulcerative colitis and/or Crohn’s disease.
• Subject has a diagnosis of Cronkhite-Canada Syndrome.
• Subject has had a positive Cologuard within the previous 2 years, or fecal occult blood test or FIT within the previous 6 months.
• Subject has undergone a colonoscopy within the previous 9 years, with the exception of a failed colonoscopy due to poor bowel preparation. Failed colonoscopy must have been within the past year and without therapeutic intervention.
• Subject has had overt rectal bleeding within the previous 30 days.
• Subject has any condition that in the opinion of the Investigator should preclude participation in the study.

Screening

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

Screening

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

Randomization Screening Inclusion Criteria :

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

Randomization

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

• Participants will be enrolled for this study from patients attending the Mayo Clinic Depression Center, Mayo Clinic Family Medicine clinics at Rochester and Kasson, MN;, Behavioral Health and Primary Care Clinic at Mayo Clinic Health System, Austin and Albert Lea, MN, with a diagnosis of major depression with a current moderate episode, with PHQ-9 scores 10-23.
• Participants will be required to be between 25 and 80 years old.
• Able to speak English.
• Able to provide written informed consent to participate in the study.
• Participants must have DSM-V diagnostic confirmation of major depressive disorder (MDD) (American Psychiatric Association 2013). 
• Participants will continue taking any prescribed medications from their clinical treatment team. 
• Participants with co-morbid secondary diagnoses of persistent depressive disorder and generalized anxiety disorders will be included in the study.
• Participants must consent to audio recording of random group sessions which will be disclosed at the final study session.
• Participants are willing to use the Mayo Clinic Patient Portal for communication purposes during the study.

• Participants with bipolar disorder, active psychosis, active suicidal ideations, and active substance abuse meeting criteria for substance use disorders except nicotine, obsessive compulsive disorder, active panic disorder with agoraphobia or other phobic disorder, active posttraumatic stress disorder, active severe personality disorders will be excluded.
• Participants with a severe major depressive episode- HAM-D scores ≥ 23.
• Pregnant women – because of time duration of the study.

• Participants will be enrolled for this study from patients attending the Mayo Clinic Depression Center, Mayo Clinic Family Medicine clinics at Rochester and Kasson, MN;, Behavioral Health and Primary Care Clinic at Mayo Clinic Health System, Austin and Albert Lea, MN, with a diagnosis of major depression with a current moderate episode, with PHQ-9 scores 10-23.
• Participants will be required to be between 25 and 80 years old.
• Able to speak English.
• Able to provide written informed consent to participate in the study.
• Participants must have DSM-V diagnostic confirmation of major depressive disorder (MDD) (American Psychiatric Association 2013). 
• Participants will continue taking any prescribed medications from their clinical treatment team. 
• Participants with co-morbid secondary diagnoses of persistent depressive disorder and generalized anxiety disorders will be included in the study.
• Participants must consent to audio recording of random group sessions which will be disclosed at the final study session.
• Participants are willing to use the Mayo Clinic Patient Portal for communication purposes during the study.

• Participants with bipolar disorder, active psychosis, active suicidal ideations, and active substance abuse meeting criteria for substance use disorders except nicotine, obsessive compulsive disorder, active panic disorder with agoraphobia or other phobic disorder, active posttraumatic stress disorder, active severe personality disorders will be excluded.
• Participants with a severe major depressive episode- HAM-D scores ≥ 23.
• Pregnant women – because of time duration of the study.