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

PRE-REGISTRATION ELIGIBILITY CRITERIA (STEP 0)

• Patients must have been diagnosed with CLL and have > 5000 B-cells per uL of peripheral blood at any point during the course of their disease.
• This blood submission is mandatory prior to registration/randomization to perform FISH centrally that will be used for stratification. It should be obtained as soon after preregistration as possible.

REGISTRATION ELIGIBILITY CRITERIA (STEP 1) 

• Patients must be diagnosed with CLL in accordance with 2018 IWCLL criteria [28] that includes all of the following:
  • ≥ 5 x10^9 B lymphocytes (5000/μL) in the peripheral blood measured by flow cytometry at any point in the course of the disease;
  • On local morphologic review, the leukemic cells must be small mature lymphocytes, and prolymphocytes must not exceed 55% of the blood lymphocytes;
  • CLL cells on immunophenotype (performed locally) must reveal a clonal B-cell population, which express the B cell surface markers of CD19 and CD20, as well as the T-cell antigen CD5. Patients with bright surface immunoglobulin expression or lack of CD23 expression in >10% of cells must lack t(11;14) translocation by interphase cytogenetics.
• Patients must be intermediate or high-risk Rai stage CLL.
  • Intermediate risk (formerly Rai stage I/II) is defined by lymphocytosis plus any of the following: enlarged lymph nodes, hepatomegaly, or splenomegaly'
  • High risk (formerly Rai stage III/IV) is defined by lymphocytosis with or without enlarged nodes and spleen plus disease-related anemia (hemoglobin < 11 g/dL) or thrombocytopenia (platelet count < 100 x 10^9/L) that is not attributable to autoimmune hemolytic anemia or thrombocytopenia.
• Patients must meet criteria for treatment as defined by 2018 IWCLL guidelines which includes at least one of the following criteria:
  • Evidence of marrow failure as manifested by the development or worsening of anemia or thrombocytopenia (not attributable to autoimmune hemolytic anemia or thrombocytopenia);
  • Massive (≥ 6 cm below the costal margin), progressive or symptomatic splenomegaly;
  • Massive nodes (≥ 10 cm) or progressive or symptomatic lymphadenopathy;
  • Progressive lymphocytosis with a lymphocyte doubling time < 6 months or an increase of ≥ 50% over a 2 month period;
  • Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard therapy;
  • Symptomatic or functional extranodal involvement (e.g., skin, kidney, lung, spine);
  • Constitutional symptoms, which include any of the following:
    • Unintentional weight loss of 10% or more within 6 months;
    • Significant fatigue;
    • Fevers >100.5 degrees F for 2 weeks or more without evidence of infection;
    • Night sweats ≥1 month without evidence of infection.
• Patients must not have had prior therapy for CLL (except palliative steroids or treatment of autoimmune complications of CLL with rituximab or steroids).
• Treatment with rituximab and/or high dose corticosteroids for autoimmune complications of CLL must be complete at least 4 weeks prior to enrollment. Palliative steroids must be at a dose not higher than 20 mg/day of prednisone or equivalent corticosteroid at the time of registration.
• Age ≥ 65 years.
• ECOG performance status 0-2.
• Required initial laboratory values.
• Absolute Neutrophil Count (ANC) ≥ 1,000/mm^3 except if due to bone marrow involvement.
• Platelet Count (untransfused) ≥ 30,000/mm^3.
• Calc. Creatinine Clearance ≥ 40 mL/min (by Cockcroft-Gault).
• Bilirubin ≤ 1.5 x upper limit of normal (ULN) except if due to liver involvement, hemolysis, or Gilbert’s disease.
• AST / ALT ≤ 2.5 x upper limit of normal (ULN) except if due to liver involvement.
• Patients must not have any history of Richter’s transformation or prolymphocytic leukemia (prolymphocytes in blood > 55%).
• If evidence of chronic hepatitis B virus (HBV) infection, HBV viral load must be undetectable on suppressive therapy if indicated.
  • Please note: IVIG can cause a false positive hepatitis B serology. If patients receiving routine IVIG have core antibody or surface antigen positivity without evidence of active viremia (negative hepatitis B DNA) they may still participate in the study, must have hepatitis serologies and hepatitis B DNA monitored periodically by the treating physician.
• If history of hepatitis C virus (HCV) infection, must be treated with undetectable HCV viral load.
• Patients with Class III or Class IV heart failure by New York Heart Association, those with unstable angina, and those with uncontrolled arrhythmia are not eligible.
• Patients who have had a myocardial infarction, intracranial bleed, or stroke within the past 6 months are not eligible.
• Human immunodeficiency virus (HIV)-infected patients on effective antiretroviral therapy with undetectable viral load within 6 months are eligible for this trial
• Patients must not be receiving active systemic anticoagulation with heparin or warfarin. Patients on warfarin must discontinue the drug for at least 10 days prior to registration on the study.
• Chronic concomitant treatment with strong inhibitors of CYP3A4/5 is not allowed on this study. Patients on strong CYP3A inhibitors must discontinue the drug for 14 days prior to registration on the study. 
• Chronic concomitant treatment with strong CYP3A4/5 inducers is not allowed.
• Patients must discontinue the drug 14 days prior to registration on the study.
• Patients must not require more than 20 mg prednisone or equivalent corticosteroid daily.
• Patients must not have uncontrolled active systemic infection requiring intravenous antibiotics.
• Central FISH blood results are mandatory prior to registration/randomization for it will be used for stratification.
• Patients must be able to swallow capsules and not have the following conditions:  disease significantly affecting gastrointestinal absorption, resection of the stomach or small bowel, partial or complete bowel obstruction.
• Patients must not have a known allergy to mannitol.
• Patients must not have prior significant hypersensitivity to rituximab (not including infusion reactions).
• Patients may not have had major surgery within 10 days prior to registration, or minor surgery within 7 days prior to registration. Examples of minor surgery include dental surgery, insertion of a venous access device, skin biopsy, or aspiration for a joint. The decision about whether a surgery is major or minor can be made at the discretion of the treating physician.
• Patients must be able to receive either a xanthine oxidase inhibitor or rasburicase for prophylaxis/treatment of TLS.

RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2)

• Completion of treatment through Cycle 14 Day 28, and remain on ibrutinib therapy.
• Receipt of central BM MRD results.
• Response assessment completed per Section 5.0 with CR determination.

Eligibility last updated 1/17/22. Questions regarding updates should be directed to the study team contact.

PRE-REGISTRATION ELIGIBILITY CRITERIA (STEP 0)

• Patients must have been diagnosed with CLL and have > 5000 B-cells per uL of peripheral blood at any point during the course of their disease.
• This blood submission is mandatory prior to registration/randomization to perform FISH centrally that will be used for stratification. It should be obtained as soon after preregistration as possible.

REGISTRATION ELIGIBILITY CRITERIA (STEP 1) 

• Patients must be diagnosed with CLL in accordance with 2018 IWCLL criteria [28] that includes all of the following:
  • ≥ 5 x10^9 B lymphocytes (5000/μL) in the peripheral blood measured by flow cytometry at any point in the course of the disease;
  • On local morphologic review, the leukemic cells must be small mature lymphocytes, and prolymphocytes must not exceed 55% of the blood lymphocytes;
  • CLL cells on immunophenotype (performed locally) must reveal a clonal B-cell population, which express the B cell surface markers of CD19 and CD20, as well as the T-cell antigen CD5. Patients with bright surface immunoglobulin expression or lack of CD23 expression in >10% of cells must lack t(11;14) translocation by interphase cytogenetics.
• Patients must be intermediate or high-risk Rai stage CLL.
  • Intermediate risk (formerly Rai stage I/II) is defined by lymphocytosis plus any of the following: enlarged lymph nodes, hepatomegaly, or splenomegaly'
  • High risk (formerly Rai stage III/IV) is defined by lymphocytosis with or without enlarged nodes and spleen plus disease-related anemia (hemoglobin < 11 g/dL) or thrombocytopenia (platelet count < 100 x 10^9/L) that is not attributable to autoimmune hemolytic anemia or thrombocytopenia.
• Patients must meet criteria for treatment as defined by 2018 IWCLL guidelines which includes at least one of the following criteria:
  • Evidence of marrow failure as manifested by the development or worsening of anemia or thrombocytopenia (not attributable to autoimmune hemolytic anemia or thrombocytopenia);
  • Massive (≥ 6 cm below the costal margin), progressive or symptomatic splenomegaly;
  • Massive nodes (≥ 10 cm) or progressive or symptomatic lymphadenopathy;
  • Progressive lymphocytosis with a lymphocyte doubling time < 6 months or an increase of ≥ 50% over a 2 month period;
  • Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard therapy;
  • Symptomatic or functional extranodal involvement (e.g., skin, kidney, lung, spine);
  • Constitutional symptoms, which include any of the following:
    • Unintentional weight loss of 10% or more within 6 months;
    • Significant fatigue;
    • Fevers >100.5 degrees F for 2 weeks or more without evidence of infection;
    • Night sweats ≥1 month without evidence of infection.
• Patients must not have had prior therapy for CLL (except palliative steroids or treatment of autoimmune complications of CLL with rituximab or steroids).
• Treatment with rituximab and/or high dose corticosteroids for autoimmune complications of CLL must be complete at least 4 weeks prior to enrollment. Palliative steroids must be at a dose not higher than 20 mg/day of prednisone or equivalent corticosteroid at the time of registration.
• Age ≥ 65 years.
• ECOG performance status 0-2.
• Required initial laboratory values.
• Absolute Neutrophil Count (ANC) ≥ 1,000/mm^3 except if due to bone marrow involvement.
• Platelet Count (untransfused) ≥ 30,000/mm^3.
• Calc. Creatinine Clearance ≥ 40 mL/min (by Cockcroft-Gault).
• Bilirubin ≤ 1.5 x upper limit of normal (ULN) except if due to liver involvement, hemolysis, or Gilbert’s disease.
• AST / ALT ≤ 2.5 x upper limit of normal (ULN) except if due to liver involvement.
• Patients must not have any history of Richter’s transformation or prolymphocytic leukemia (prolymphocytes in blood > 55%).
• If evidence of chronic hepatitis B virus (HBV) infection, HBV viral load must be undetectable on suppressive therapy if indicated.
  • Please note: IVIG can cause a false positive hepatitis B serology. If patients receiving routine IVIG have core antibody or surface antigen positivity without evidence of active viremia (negative hepatitis B DNA) they may still participate in the study, must have hepatitis serologies and hepatitis B DNA monitored periodically by the treating physician.
• If history of hepatitis C virus (HCV) infection, must be treated with undetectable HCV viral load.
• Patients with Class III or Class IV heart failure by New York Heart Association, those with unstable angina, and those with uncontrolled arrhythmia are not eligible.
• Patients who have had a myocardial infarction, intracranial bleed, or stroke within the past 6 months are not eligible.
• Human immunodeficiency virus (HIV)-infected patients on effective antiretroviral therapy with undetectable viral load within 6 months are eligible for this trial
• Patients must not be receiving active systemic anticoagulation with heparin or warfarin. Patients on warfarin must discontinue the drug for at least 10 days prior to registration on the study.
• Chronic concomitant treatment with strong inhibitors of CYP3A4/5 is not allowed on this study. Patients on strong CYP3A inhibitors must discontinue the drug for 14 days prior to registration on the study. 
• Chronic concomitant treatment with strong CYP3A4/5 inducers is not allowed.
• Patients must discontinue the drug 14 days prior to registration on the study.
• Patients must not require more than 20 mg prednisone or equivalent corticosteroid daily.
• Patients must not have uncontrolled active systemic infection requiring intravenous antibiotics.
• Central FISH blood results are mandatory prior to registration/randomization for it will be used for stratification.
• Patients must be able to swallow capsules and not have the following conditions:  disease significantly affecting gastrointestinal absorption, resection of the stomach or small bowel, partial or complete bowel obstruction.
• Patients must not have a known allergy to mannitol.
• Patients must not have prior significant hypersensitivity to rituximab (not including infusion reactions).
• Patients may not have had major surgery within 10 days prior to registration, or minor surgery within 7 days prior to registration. Examples of minor surgery include dental surgery, insertion of a venous access device, skin biopsy, or aspiration for a joint. The decision about whether a surgery is major or minor can be made at the discretion of the treating physician.
• Patients must be able to receive either a xanthine oxidase inhibitor or rasburicase for prophylaxis/treatment of TLS.

RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2)

• Completion of treatment through Cycle 14 Day 28, and remain on ibrutinib therapy.
• Receipt of central BM MRD results.
• Response assessment completed per Section 5.0 with CR determination.

Eligibility last updated 1/17/22. Questions regarding updates should be directed to the study team contact.

• Age ≥ 18 years.
• Patients meet criteria for IMPT treatment for Oropharyngeal Cancer as outlined in the procedure manual.
• If IMPT is declined by patient’s insurance, they can be treated with standard of care IMRT using the same applicable standard of care procedures outlined in the procedures manual.
• Meet criteria for adjuvant chemotherapy (if applicable).
• Histological confirmation of HPV+ squamous cell carcinoma as defined by neck node pathology. HPV positivity will be defined as positive staining for p16 and HPV DNA ISH. (If discordant, RNA ISH will be run for confirmatory testing).
• Clinical stage T0 N1-N3 and confirmed Pathologic stage T0 N1-N2 M0 (AJCC 8th edition) with one of the following risk factors:
  • lymph node ≥ 3cm;
  • ≥ positive lymph nodes;
  • presence of extracapsular extension;
  • > 1 nodal level involved.
• Absence of distant metastases on standard diagnostic workup, prior to registration (Chest CT, CXR, or PET/CT).
• Able to undergo pre-operative Q-clear series PET/CT head/neck for diagnostic workup of occult primary and nodal disease.
• Able to undergo Transoral Surgery and neck dissection by their ENT oncologist.
• Surgical exploration/sampling of all mucosal sites including ipsilateral wide field tonsillectomy and base of tongue resection.  Additional biopsies or surgical excision at the surgeon’s discretion. Any radiographic or clinically suspicious areas should be biopsied or removed. Bilateral neck dissection for high risk patients. Ipsilateral dissection only, for patients with contralateral cN0 necks and negative preoperative imaging.
• Final pathologic evaluation demonstrating all benign samplings without discernible primary.
• Documented smoking history.
• ECOG Performance Status (PS) 0 or 1. 
• Negative pregnancy test done ≤ 7 days prior to registration, for women of childbearing potential only.
• Following laboratory values obtained ≤ 35 days prior to registration:
  • Absolute neutrophil count (ANC) ≥ 1500/mm^3;
  • Platelet count ≥100,000/mm^3;
  • Hemoglobin  ≥8.0g/dL;
  • Creatinine ≤ 1.5 mg/dL or creatinine clearance ≥ 50 mL/min;
  • Total or direct bilirubin < 2 x institutional upper limit of normal (ULN);
  • AST (SGOT) or ALT (SGPT) < 3 x institutional ULN.
• Ability to complete questionnaire(s) by themselves or with assistance.
• Able to provide written informed consent.
• Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study).

• Any patient with positive retropharyngeal nodes on imaging.
• Any of the following because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects:
  • Pregnant women;
  • Nursing women;
  • Men or women of childbearing potential who are unwilling to employ adequate contraception.
• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
• 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.
• Other active malignancy ≤ 5 years prior to registration.
  • EXCEPTIONS: Non-melanotic skin cancer, breast cancer, prostate cancer, well-differentiated thyroid cancer, carcinoma-in-situ of the cervix.
  • NOTE: If there is a history or prior malignancy, they must not be receiving other specific treatment for their cancer.
• Immunocompromised patients and patients known to be HIV positive.
• Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm.
• History of connective tissue disorders such as scleroderma, rheumatoid arthritis, lupus, or Sjogren’s disease.
• Prior history of radiation therapy to the affected site.

Screening Period

• Signed written informed consent in accordance to ICH-GCP and national/local regulation before any protocol-related procedures that are not part of normal patient care.
• Female patients ≥ 18 years of age.
• Histologically confirmed high grade, stage IIIC or stage IV (FIGO staging) serous ovarian, fallopian or primary peritoneal carcinoma with abnormal CA-125 at diagnosis.
• Patients who have undergone primary debulking surgery or interval debulking surgery and completed a total of at least 5 cycles of taxane-platinum combination.
  • Note: patients may have received concurrent or maintenance bevacizumab or a PARP inhibitor.
• Patients must have achieved a complete response to therapy, as demonstrated by no residual disease on most recent CT scan and normal CA-125 not increasing by both the following: > 25% from nadir AND ≥ 10 UI/mL from nadir.
• Patient who remains disease free at least 6 months from last prior dose of cytotoxic chemotherapy (maintenance therapy with bevacizumab or a PARP inhibitor is allowed).
• Available tumor tissue, banked from previous abdominal debulking surgery and/or from a core needle biopsy performed at diagnosis if the patient received neoadjuvant chemotherapy, and peripheral blood samples for exome and transcriptome sequencing.

Treatment Period

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at treatment period initiation.
• Patients who have developed an asymptomatic relapse as defined by:
  • Cohort A: CA-125 ≥ 2 times ULN on 2 occasions at least 1 week apart (GCIG criteria) or low volume radiological disease and CA-125 > ULN. Low volume radiological disease is defined as radiologically visible disease excluding intra-hepatic or splenic metastases, ascites or pleural effusion thought to require drainage;
  • Cohort B: patient asymptomatic with measurable disease, excluding intra-hepatic or splenic metastases, ascites or pleural effusion thought to require drainage, whatever serum CA-125 level and for whom further treatment is not planned within 2 months.
  • Longest diameter on CT-scan must not exceed 2 cm for non-nodal lesions and 2.5 cm in short axis for nodal lesions.
• Adequate hematological, hepatic and renal functions:
  • Hemoglobin ≥ 9.0 g/dL;
  • Neutrophils count ≥ 1.5 x10^9 /L;
  • Lymphocytes count ≥ 0.9 x10^9 /L;
  • Platelets count ≥ 100 x10^9 /L;
  • Total bilirubin ≤ 1.5 x ULN (except for patients with Gilbert’s syndrome);
  • Aspartate aminotransferase (AST) ≤ 2.5 x ULN;
  • Calculated creatinine clearance ≤ 45 mL/min using the Cockroft & Gault formula or ≥ 45 mL/min/1.73m² using other methods.
• Patients who received standard maintenance therapy will stop before initiation of TG4050 administration. A free-interval of at least 30 days will be respected before first dosing of TG4050 except for PARP inhibitor (at least 14 days).

Screening Period

• Patient having received any cancer immunotherapy including cancer vaccines, any antibody/drug targeting T cell co-regulatory proteins such as anti-PD1, anti-PDL1 or anti-CTLA-4.
• Patients with other active malignancy ≤ 3 years prior to registration except non-melanoma skin cancer, stage 0 in situ carcinoma and recent early stage papillary thyroid cancer. If there is an history of prior malignancy, patient must not be receiving other specific treatment for their cancer.
• Patient post-organ transplantation, including allogeneic stem cell or bone marrow transplantation. History of blood transfusion within 3 weeks prior to study entry visit.
• Known history of positive testing for Human Immunodeficiency Virus (HIV) or known AIDS (Acquired Immune Deficiency Syndrome).
• Any known allergy or reaction to eggs or attributed to compounds of similar chemical or biological composition to therapeutic vaccines/immunotherapeutic products.
• Positive serology for Hepatis C Virus (HCV) or positive serum Hepatitis B surface antigen (HBsAg) within 3 months prior to or at study entry (tests required).

Treatment Period

• Measurable disease associated with the appearance of symptoms justifying initiation of further treatment.
• Major surgery within 4 weeks prior to treatment start.
• Treatment with another investigational agent within 30 days prior to TG4050 treatment initiation.
• Patients under chronic treatment with systemic corticosteroids or other immunosuppressive drugs for a period of at least 4 weeks and whose treatment was not stopped 2 weeks prior to TG4050 treatment initiation planned date, with the exception of patients with adrenal insufficiency who may continue corticosteroids at physiological replacement dose, equivalent to ≤ 10 mg prednisone daily. Steroids with no or minimal systemic effect (topical, inhalation) are allowed.
• Vaccination for the prevention of infectious diseases with a live vaccine during the four-week period prior to TG4050 treatment initiation planned date. Furthermore, patients should not receive any live vaccine during the period of study treatment administration.
• Patient with any underlying medical condition, that in the opinion of the investigator, could make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety or toxicity of the study treatment.
• 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 circumstances that could limit compliance with study requirements.
• History of myocardial infarction ≤ 6 months.

Eligibility last updated 4/20/22. Questions regarding updates should be directed to the study team contact.

• Provide written informed consent.
• Male or female aged ≥ 18 and ≤ 80 years at the time of signing consent.
• Average weekly score of ≥ 3 recorded for either abdominal pain, diarrhea, and/or nausea on the PRO questionnaire during at least 2 of the last 3 weeks of PRO collection during the Screening period. A minimum of 4 questionnaires must be completed each qualifying week.
• Eosinophilia of the gastric mucosa ≥ 30 eosinophils/HPF in 5 HPFs and/or eosinophilia of the duodenal mucosa ≥ 30 eosinophils/HPF in 3 HPFs from the EGD performed during the screening period, without any other cause for the gastric eosinophilia (e.g., parasitic or other infection or malignancy).
• Subjects must have failed or not be adequately controlled on standard of care treatments for EG and/or EGE symptoms (including but not limited to PPIs, systemic or topical corticosteroids, and/or diet).
• If on allowed treatments for EG and/or EGE at the time of enrollment, stable dose for at least 5 half-lives prior to screening and willingness to continue on that dose for the duration of the study.
• If patient is on pre-existing dietary restrictions, willingness to maintain dietary restrictions throughout the study, as much as possible.
• Able and willing to comply with all study procedures.
• Female subjects must be either post-menopausal for at least 1 year with FSH level >40 mIU/mL at screening or surgically sterile (tubal ligation, hysterectomy, or bilateral oophorectomy) for at least 3 months, or if of childbearing potential, have a negative pregnancy test and agree to use dual methods of contraception, or abstain from sexual activity from screening until the end of the study, or for 120 days following the last dose of study drug, whichever is longer.
• Male subjects with female partners of childbearing potential must agree to use a highly effective method of contraception from screening until the end of the study or for 120 days following the last dose of study drug, whichever is longer. All fertile men with female partners of childbearing potential should be instructed to contact the Investigator immediately if they suspect their partner might be pregnant at any time during study participation.

• Known hypersensitivity to any constituent of the study drug.
• Previous exposure to AK002.
• Diagnosis of celiac disease or active H. pylori infection as determined by screening EGD or a history of celiac disease diagnosed by prior EGD.
• Diagnosis of Hypereosinophilic Syndrome (HES), based on standard criteria (blood eosinophils > 1500/μL with involvement of either the heart, nervous system, and/or bone marrow).
• Presence of abnormal laboratory values considered by the Investigator to be clinically significant.
• Grade 2 or higher lymphopenia (< 0.8 × 109/L lymphocytes).
• Any disease, condition (medical or surgical), or cardiac abnormality, which, in the opinion of the Investigator, would place the subject at increased risk.
• History of malignancy, exempting carcinoma in situ, early stage prostate cancer, non-melanoma skin cancers, and cancers in remission for >5 years and considered cured (except for breast cancer). All history of malignancy (including diagnosis, dates, and compliance with cancer screening recommendations) must be documented and certified by the Investigator, along with the statement that in their clinical judgment the tissue eosinophilia is attributable to EGID, rather than recurrence of malignancy.
• Treatment with chemotherapy or radiotherapy in the preceding 6 months.
• Treatment for a clinically significant helminthic parasitic infection within 6 months of screening and/or a positive helminthic test at screening.
• Use of any medications that may interfere with the study such as immunosuppressive or immuno-modulatory drugs (including azathioprine, 6-mercaptopurine, methotrexate, cyclosporine, tacrolimus, anti-TNF, anti-IL-5, anti-IL-5 receptor, dupilumab, anti-IgE antibodies, omalizumab) or systemic corticosteroids with a daily dose >10 mg of prednisone or equivalent, during 5 half-lives prior to screening or during the screening period, except for omalizumab taken for asthma and/or urticaria when their asthma and/or urticaria cannot be controlled on other medications, If on omalizumab, the dose must have been stable for at least 4 weeks prior to screening.
• Vaccination with live attenuated vaccines within 30 days prior to initiation of treatment in the study, during the treatment period, or vaccination expected within 5 half-lives of the study drug administration.
• Known history of alcohol, drug, or other substance abuse or dependence.
• Participation in a concurrent interventional study with the last intervention occurring within 30 days prior to administration of study drug (or 90 days or 5 half-lives, whichever is longer, for biologic products).

• Adults, age > 18 years old.
• Subjects with wet and dry macular degeneration.
   
• Note:  Patients with all levels of cognitive ability will be enrolled.

• Patients who do not speak English.

• 18 years of age or older.
• Kidney transplant recipient.

• Neuropsychiatric condition causing patient to be unable to provide consent.
• Non-English speaking patient.
• Failed kidney transplant defined as return to dialysis.

• Subjects 18 years or older admitted to the IAP, an outpatient addiction treatment program.
• Primary diagnosis of moderate to severe Alcohol Use Disorder.
• If the subject qualifies for the CRU visit, they must agree to abstain from caffeine during the CRU visit to proceed.

• Currently on melatonin and unwilling to discontinue at least 2 weeks prior to completing the CRU visit.
• Currently on hypnotic medications (benzodiazepines and trazadone) and unwilling to discontinue for 5 days prior to the CRU visit and for the duration of the study if they meet requirements and begin melatonin treatment following the CRU visit.
• Unable or unwilling to provide informed consent.
• Pregnant or considering pregnancy.
• Diagnosis of any SUD, other than alcohol and mild cannabis use disorder, that has been active in the past 30 days.

Eligibility last updated 6/21/22. Questions regarding updates should be directed to the study team contact.

- Any patient considered to be vulnerable

• Subjects scheduled to elective and/or urgent median sternotomy for cardiac surgery, who are preoperative hemodynamically stable. 
• Males and females. 
• Subjects of age 18 years and older. 
• Subjects with both Diabetes Mellitus AND BMI ≥ 30 OR Diabetes Mellitus/BMI ≥ 30 AND at least one of the following: 
  • Current/Previous smoking history ≥ 30 pack year;
  • Chronic Obstructive Pulmonary Disease (COPD).
• Female of childbearing potential should have a negative serum pregnancy test prior to index procedure.
  • Note: All female of childbearing potential must agree to use a highly effective method of contraception (such as double barrier, oral or parenteral hormonal, intrauterine device and spermicide) consistently and correctly for the duration of the study. 
• Subject is willing and able to provide a signed Informed Consent Form and is willing and able to comply with study's procedures including follow-up visits.

• Subjects undergoing partial sternotomy. 
• Subjects with any preoperative active significant infection. 
• Subjects that received oral or IV doxycycline during the last 4 weeks prior to screening. 
• Subjects with sensitivity to doxycycline and/or to tetracycline family of drugs and/or other study drug ingredients. 
• Subjects with known allergies to more than 3 substances (an allergy questionnaire will be filled during the screening process). 
• Subjects with history of allergic/hypersensitivity reaction to any substance having required hospitalization and/or treatment with intra-venous steroids/epinephrine or in the opinion of the investigator the patient is at high risk of developing severe allergic/hypersensitivity reactions. 
• Subjects with uncontrolled Asthma (GINA III-IV). 
• Subjects with chronic urticaria. 
• Immunocompromised subjects from any reason, at screening. 
• Subjects with renal failure requiring dialysis. 
• Subjects scheduled to major organ transplantation and/or to other significant concomitant surgical procedure. 
• Subjects scheduled for mechanical assist device. 
• Subjects scheduled to be treated with preventive negative pressure devices.
• Subjects undergone Cerebro-Vascular Accident (CVA)/Transient Ischemic Attack (TIA) within the past 3 months prior to randomization. 
• Subjects that have undergone previously, any cardiac surgery through sternotomy. 
• Subjects with active or previous malignancy in the chest area. 
• Any subject with active malignancy or with malignancy that has not been in complete remission for at least 5 years. Subjects who have had carcinoma in situ of the cervix, squamous cell carcinoma of the skin and basal cell carcinoma of the skin, are eligible. 
• Pregnant or breast-feeding women or women of childbearing age not protected by an effective contraceptive method of birth control (such as double barrier, oral or parenteral hormonal, intrauterine device and spermicide). 
• Subjects enrolled in any intervention study with an investigational medicinal product and/or received any investigational medicinal product within 30 days or 5½ half-lives of the product prior to enrollment (whichever is longer). 
• In the opinion of investigator, subject is not eligible to participate in the study and/or to comply with protocol requirements (e.g., due to a cognitive, medical condition or residency distanced from site that may jeopardize Follow-Up visits attendance etc.).

Part 1 Dose Escalation:

• Histological or cytological diagnosis of solid tumor or Hodgkin’s Lymphoma who have relapsed or progressed and who are ineligible for all therapies with demonstrated clinical benefit.
  • Note: there is no limit to the number of prior treatment regimens; or
• Relapsed/refractory CD20 positive, B-cell NHL who have progressed following at least 2 prior systemic therapies. For aggressive histologies, frontline treatment must have included an alkylating agent; or
• Relapsed/refractory classical Hodgkin’s Lymphoma who have progressed following at least 2 prior systemic therapies and have progressed on checkpoint inhibitors (for Part 1B only);
• In Part 1A (45 mg/kg dose cohort only), Part 1B or Part 1C, archival tumor tissue and fresh post-treatment tumor biopsy obtained that allows preparation of the number of slides required in the separate study-specific specimen preparation instructions. Samples will be collected, processed and stored according to a separate laboratory manual.

Part 2 Dose Expansion for Combination Therapy with Rituximab:

• Relapsed/refractory DLBCL including histologically confirmed de novo (NOS) or transformed DLBCL (including transformation from follicular lymphoma of any grade, gastric MALT lymphoma and non-gastric MALT lymphoma) expressing CD20 by IHC (immunohistochemistry) or flow cytometry, primary mediastinal large B‐cell lymphoma, or T‐cell rich large B cell lymphoma, which are relapsed after at least 2 prior lines of systemic therapy including at least one rituximab-containing regimen or refractory disease to rituximab without better available choices.
• Confirmed marginal zone or follicular lymphoma (Grade 1-3a) expressing CD20+ by IHC or flow cytometry, relapsed after at least 2 prior line of systemic therapy including at least one rituximab-chemotherapy combination regimen or refractory to rituximab-containing regimen without better available choices; for indolent NHL histology, progression following prior treatment with an alkylating agent is allowed but not required.
  • NOTE: Refractory disease is defined as progression within 6 months of last dose of therapy. Relapsed disease is defined as disease recurrence or PD following a response after more than 6 months after last dose. Patients who received CAR-T therapy are allowed but cannot have progressive disease within 3 months of CAR-T therapy.
  • At least one measurable lesion as defined by Lugano criteria (version 2014).
  • Available fresh metastatic biopsy sample prior to study entry and one mandatory on-treatment tumor biopsy in US clinical sites, unless there is difficulty obtaining the sample (e.g., hard to reach tumors or biopsies requiring surgical intervention). Waiver of biopsy samples must be discussed with the medical monitor. Tumor biopsy samples collected should allow for sample preparation as detailed in the separate study-specific specimen preparation instructions. Mandatory archival pre-treatment or optional ontreatment FFPE tumor tissue that allow for sample preparation as detailed in the separate study-specific specimen preparation instructions will be collected from subjects enrolled at sites in China in the NHL cohort of Part 2.

Part 2 Dose Expansion for Combination Therapy with Pembrolizumab:

• Locally advanced or metastatic NSCLC that expresses PD-L1 (Tumor Proportion Score (TPS) ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum containing chemotherapy and checkpoint therapy.
• Patients with NSCLC must have progressed on treatment with one prior PD1/L1 inhibitor administered either as monotherapy or in combination with other checkpoint inhibitors or other therapies.
• Patients who have had more than 1 prior PD-(L)1 inhibitor may be considered after discussion with the Medical Monitor. PD-1/L1 inhibitor treatment progression is defined by meeting all of the following criteria:
  • has received at least 2 doses of the PD-1/L1 inhibitor (must be an approved PD-1/L1 inhibitor);
  • has been on a continuous regimen of the PD-1/L1 inhibitor for at least 4 months without disease progression;
  • has demonstrated radiographic disease progression after PD-1/L1.
• Epithelial ovarian cancer, fallopian tube, or primary peritoneal cancer with any high-grade serous component and immune-oncology (IO) treatment naive subjects with metastases progressed on or after platinum-containing therapy and are not eligible for further platinum-containing treatment. Patients must meet the following criteria:
  • platinum-refractory, platinum-resistant disease defined by progression of disease on a platinum-containing regimen or recurrence of disease within 180 days of receiving the last dose of platinum-based treatment;
  • must not have progressed during the first 3 months of first line platinum-based therapy or must not have progressed within 3 months after completing first line platinum-based therapy;
  • must not have evidence of bowel obstruction requiring hospitalization and decompression within the past 30 days;
  • must not have ascites that requires therapeutic paracentesis in the last 30 days;
  • must not have tumors with low malignant potential (ie. borderline tumors) or mucinous tumors.
  • Prior lines of therapy to include:
    • Patients must have had 1 to 3 prior lines of therapy including at least one bevacizumab-containing regimen or ineligible for all other available therapies; Or
    • Patients must be in the 4th or 5th line of treatment, irrespective of bevacizumab or who are ineligible for all therapies with demonstrated clinical benefit; Or
    • Patients with known BRCA-positive associated cancer or mutation, prior therapy must include PARP inhibitors (unless contraindicated)
  • At least one measurable lesion as defined by RECIST 1.1 solid tumors.
  • Available fresh metastatic biopsy sample prior to study entry and one mandatory on-treatment tumor biopsy, unless there is difficulty obtaining the sample (e.g., hard to reach tumors or biopsies requiring surgical intervention). Waiver of biopsy samples must be discussed with the medical monitor. Tumor biopsy samples collected should allow for sample preparation as detailed in the separate study-specific specimen preparation instructions.

All Subjects:

• Males or females, of any race, age ≥ 18 years;
• Be willing and able to provide written informed consent for the trial.
• Eastern Cooperative Oncology Group Performance Status 0 or 1.
• Subjects able to follow the requirements of the study protocol and complete the trial.
• Women of childbearing potential must:
  • Agree to use at least 2 effective contraceptive methods (1 highly effective method in combination with a barrier method; oral, injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier contraceptive with spermicide; or vasectomized partner), one of which must be barrier, from signing the ICF, throughout the study, and for up to 8 weeks following the last dose of TJ011133;
  • If using treatment with rituximab, women of childbearing potential should continue to use effective contraceptive methods for 12 months following treatment with rituximab;
  • If using treatment with pembrolizumab, women of childbearing potential should continue to follow contraceptive guidance during the treatment period and for at least 120 days after the last dose of study treatment;
  • Have a negative serum pregnancy test (sensitivity of at least 25 mIU/mL) at Screening; and have a negative serum or urine pregnancy test (Investigator’s discretion) within 72 hours prior to Cycle 1 Day -1 of study treatment (note that the screening serum pregnancy test can be used as the test prior to Day -1 study treatment if it is performed within the prior 72 hours);
  • Avoid conceiving for 8 weeks after the last dose of TJ011133;
  • Avoid donation of ova from signing the ICF until 8 weeks after the last dose of TJ011133 (12 months after the last dose of rituximab);
  • Agree to ongoing urine pregnancy testing, if clinically indicated, during the course of the study.
• Males must agree to use a condom (a latex condom is recommended) during sexual contact with a pregnant female or a female of childbearing potential and will avoid donation of sperm or having a female partner conceive from the time of signing the ICF, while participating in the study, during dose interruptions, and for at least 90 days after the last dose of study treatment, even if he has undergone a successful vasectomy.
• Subject with a QT interval corrected for heart rate using Fridericia's formula (QTcF) and/or QT interval corrected for heart rate using Bazett's formula of ≤ 450 msec for males, ≤ 470 msec for females.
• No systemic anti-cancer therapy within 4 weeks of starting study treatment or at least 5 half-lives (whichever is shorter) before study drug administration, and all AEs have either resolved or stabilized.
  • Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.
• A 28-day washout period after the completion of programmed death-1 (PD-1)/PD-L1 therapy.
• Adequate bone marrow function in subjects with solid tumors, including the following:
  • Part 1
  • Absolute neutrophil count ≥ 1500/μL (≥ 1.5 × 10^9 /L) without growth factor support for 7 days (14 days if on pegfilgrastim);
  • Platelet ≥ 100 × 10^3μL (≥ 100 ×10^9 /L) without transfusion within 2 weeks of the first study drug administration;
  • Hemoglobin ≥ 9 g/dL without transfusion within 2 weeks of the first study drug administration;
  • Part 2
  • Absolute neutrophil count ≥ 1500/μL (≥ 1.5 × 10^9 /L) without growth factor support for 7 days (14 days if on pegfilgrastim);
  • Platelet ≥ 75 × 10^3μL (≥ 75 × 109 /L) without transfusion within 2 weeks of the first study drug administration;
  • Hemoglobin ≥ 8 g/dL without transfusion within 2 weeks of the first study drug administration.
  • Adequate bone marrow function in subjects with NHL, including:
  • Part 1
  • Absolute neutrophil count ≥1000/μL (≥ 1.0 × 10^9 /L) without growth factor support for 7 days (14 days if on pegfilgrastim);
  • Platelet ≥ 100 × 10^3μL (≥ 100 × 10^9 /L) without transfusion within 2 weeks of the first study drug administration;
  • Hemoglobin ≥ 9 g/dL without transfusion within 2 weeks of the first study drug administration;
  • Part 2
  • Absolute neutrophil count ≥1000/μL (≥ 1.0 × 10^9 /L) without growth factor support for 7 days (14 days if on pegfilgrastim);
  • Platelet ≥ 50 × 10^3μL (≥ 50 ×10^9 /L) without transfusion within 2 weeks of the first study drug administration. For sites in China, Platelet ≥ 75 × 10^3μL (≥ 50 ×10^9 /L) without transfusion within 2 weeks of the first study drug administration;
  • Hemoglobin ≥ 8 g/dL without transfusion within 2 weeks of the first study drug administration. For sites in China, Hemoglobin ≥ 9 g/dL without transfusion within 2 weeks of the first study drug administration.
• Adequate renal function and serum creatine ≤ 1.5 × ULN or estimated serum creatinine clearance of ≥60 mL/min using the Cockcroft-Gault equation.
• Adequate liver function, including:
  • Total serum bilirubin ≤ 1.5 × ULN (≤ 3.0 × ULN if the subject has documented Gilbert syndrome);
  • AST and ALT ≤ 2.5 × ULN; ≤ 5.0 × ULN (if there is liver tumor present).
• Normal parameters within the following (unless the subject is receiving anticoagulant therapy):
  • Prothrombin Time ≤ 1.5 ULN, or 11 to 15 seconds in the absence of a normal range;
  • Partial thromboplastin time or activated partial thromboplastin time ≤ 1.5 × ULN;
  • International normalized ratio ≤1.5 × ULN.
• Resolved acute effects of any prior therapy to baseline severity or Grade ≤ 1 NCI CTCAE version 5.0 except for AEs not constituting a safety risk by Investigator judgment

• Has known active CNS metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are radiologically stable; i.e., without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment.
• Subjects with Burkitt’s lymphoma, lymphoblastic lymphoma, Richter's transformation, primary effusion lymphoma or chronic lymphocytic leukemia/small lymphocytic lymphoma.
• Subjects with mantle cell lymphoma with blastoid and TP53 alterations (applies to Part 1 only, all types of mantle cell lymphoma are excluded in Part 2).
• Impaired cardiac function or clinically significant cardiac diseases, including any of the following:
  • Left ventricular ejection fraction 25% of the bone marrow (non-lymphoma subjects only), or any subject who has received prior radiotherapy within 2 weeks of the start of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤ 2 weeks of radiotherapy) to non-CNS disease. For NSCLC subjects, radiation therapy to the lung that is > 30 Gy within 6 months of the first dose of trial treatment is not allowed (Parts 1B and Part 2 in combination with pembrolizumab only).
• Prior treatment with CD47 or SIRPα inhibitors;
• A woman of childbearing potential who has a positive urine pregnancy test (e.g., within 72 hours) prior to treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• Pregnant or nursing females or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 8 weeks for TJ011133, 120 days for pembrolizumab and 12 months for rituximab after the last dose of study treatment.
• Has a diagnosis of immunodeficiency (known active human immunodeficiency virus, hepatitis B virus/hepatitis C virus infection) or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study drug.
• Blood product transfusions within 14 days of Cycle 1 Day 1.
• Prior autologous stem cell transplant ≤3 months prior to starting TJ011133.
• Prior allogeneic stem cell transplant with either standard or reduced intensity conditioning.
• Has received chimeric antigen receptor (CAR) or chimeric antigen receptor T-cell (CAR-T) therapy within 90 days of starting TJ011133 OR has received prior CAR or CAR-T therapy and progressed within 90 days of infusion.
• Has received any experimental antibodies or a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.
• Received any vaccine within 7 days of planned start of study therapy. Exceptions may apply with SARS-CoV-2 (COVID-19) vaccine, I-Mab Biopharma will provide up-to-date guidance based on evolving current practices.
• History of AIHA or autoimmune thrombocytopenia.
• Any bleeding history within 6 months of planned start of study therapy.
• Any of the following in the previous 12 months: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident, transient ischemic attack, deep venous thrombosis, or pulmonary embolism.
• Any other significant medical condition, laboratory abnormality, or psychiatric illness that places the subject at unacceptable risk or that would prevent the subject from complying with the study.
• Second malignancy within the last 3 years (Part 2 dose expansion cohort only) with the exception of cutaneous squamous cell carcinoma or cutaneous basal cell carcinoma or cervical carcinoma in situ.
• Active graft versus host disease (GVHD) or ongoing immunosuppression for GVHD.
• Donation of blood from 3 months prior to Screening, plasma from 2 weeks prior to Screening, or platelets from 6 weeks prior to Screening.
• Has severe hypersensitivity (≥ Grade 3) to pembrolizumab or rituximab and/or any of its excipients;
• Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
• Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
• Has an active infection requiring systemic therapy.
• Not recovered (i.e., to ≤ Grade 1 or to baseline) from AEs emerging from previous treatments (except alopecia or neuropathy).
• Incomplete recovery from AEs and/or major surgery (must be ≤ Grade 1).
• History of a ≥ Grade 3 irAE with prior immunotherapy with the exception of non-clinically significant laboratory abnormalities.
• Unwilling or unable to comply with study procedures (including follow-up procedures).

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

• Adults aged 18 and over.
• Confirmed C. difficile infection based on positive C. difficile toxin PCR testing and clinical evidence of diarrhea.

• Known active pregnancy.
• Prior diagnosis of C. difficile infection within 2 months of this diagnosis.
• Other known active gastrointestinal infectious process.
• Vulnerable adults.
• Any other disease(s), condition(s) or habit(s) that would interfere with completion of study, or in the judgment of the investigator would potentially interfere with compliance to this study or would adversely affect study outcomes.

• Patients ≥ 18 years of age.
• One of the following progressive advanced or metastatic cancers:
  • Epithelial ovarian, fallopian tube, or primary peritoneal cancer (Part 1 and Part 2, Group 1 only) that is platinum refractory or platinum resistant;
  • Pancreatic adenocarcinoma (Part 2, Group 2 only) that is locally advanced, and now with progressive disease on or after front-line treatment;
  • Malignant mesothelioma with epithelioid histology, pleural or primary peritoneal (Part 2, Group 3 only) that is progressive disease following frontline platinum-based chemotherapy;
  • For Part 2 only
    •Measurable disease according to RECIST v1.1 for patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer, pancreatic adenocarcinoma, and peritoneal mesothelioma, and mRECIST v1.1 for patients with pleural mesothelioma;
  • Available archival tissue sample or fresh biopsy tissue sample must be obtained prior to enrollment;
  • For patients previously treated with systemic chemotherapy, targeted therapy, immunotherapy, or treatment with an investigational anticancer agent, discontinuation must have occurred ≥ 2 weeks, or at least 5 half-lives, whichever is longer, prior to start of study drug. The maximum washout period will not exceed 4 weeks;
  • ECOG performance status of 0 or 1;
  • Adequate bone marrow function, including:
    • Absolute neutrophil count (ANC) ≥ 1500/mm^3 or ≥ 1.5 x 10^9/L;
    • Platelets ≥ 100,000/mm3 or ≥ 100 x 10^9/L;
    • Hemoglobin (Hgb) ≥ 0 g/dL.
  • Adequate renal function, including estimated creatinine clearance ≥ 50 mL/min;
  • Adequate liver function, including:
    • Total serum bilirubin ≤ 1.5 x upper limit of normal (ULN) unless the patient has documented Gilbert syndrome in which case the maximum total serum bilirubin should be < 5 mg/dL;
    • Aspartate and alanine transaminase (AST and ALT) ≤ 2.5 x ULN or AST/ALT ≤ 5 x ULN for patients with liver metastases.
  • Serum albumin ≥ 30 mg/mL.

• Previously treated or current brain metastases.
  • Note: Patients with previously treated brain metastases may participate provided they are clinically stable for at least 4 weeks prior to study entry and have no evidence of new or enlarging brain metastases.
• Concurrent treatment with anti- TNFα therapies, systemic corticosteroids, or other immune suppressive drugs within the 2 weeks prior to Screening.
• History of or known or suspected autoimmune disease.
• History of clinically significant cardiovascular disease.
• Second primary malignancy that has not been in remission for greater than 3 years.
• Pulmonary, hematologic, renal, hepatic, gastrointestinal, neurological or psychiatric disease that would limit compliance with study requirements

• Patients age ≥ 18 years old.
• Either scheduled to receive or have received a kidney transplant (KT) at Mayo Clinic Rochester, Mayo Clinic Arizona, or Mayo Clinic Florida.

• Neuropsychiatric condition causing patient to be unable to provide consent.
• Scheduled to receive a combined organ transplant.

• Ages 65 and older.
• Presenting with type II odontoid fracture confirmed by CT scan to one of the study centers.
• Deemed appropriate by the attending surgeon involved for C1-2 posterior cervical fusion procedure if surgical management were to be indicated.
• Able to independently cooperate in the completion of all study consents, forms and documents.
• Able to speak, read and write English at an elementary school level.

• Those individuals with previously documented type II odontoid fracture.
• Those individuals whose odontoid fracture is related to malignancy or infection.
• Those individuals with associated spinal cord injury.
• Those individuals with other cervical, thoracic or lumbar injuries requiring surgical intervention.
• Those individuals with aberrant/anomalous local anatomy which precludes posterior placement of C1/2 instrumentation.

• Patient must be ≥ 18 years of age.                    
• Patient must be diagnosed with asymptomatic high-risk smoldering multiple myeloma (SMM) within the past 12 months. High-risk is defined by the presence of 2 or more of the following factors:
  • Abnormal serum free light chain (FLC) ratio of involved to uninvolved >20, but less than 100 if the involved FLC is >10 mg/dL by serum FLC assay;
  • Serum M-protein level > 2 gm/dL;
  • Presence of t(4;14) or del 17p or 1q gain by conventional cytogenetics or FISH studies;
  • > 20% plasma cells on biopsy or aspirate;
• A bone marrow aspirate and/or biopsy is required to be performed within 28 days prior to randomization and must demonstrate 10-59% clonal plasma cells.
• 1.  
• Patient must have measureable disease as defined by having one or more of the following, obtained within 28 days prior to randomization:
  • ≥ 1 g/dL on serum protein electrophoresis;
  • ≥ 200 mg of monoclonal protein on a 24 hour urine protein electrophoresis.
• NOTE: In the rare situation where the SPEP is felt to be unreliable, then quantitative immunoglobulin levels on nephelometry or turbidometry can be accepted. SPEP, UPEP, and serum FLC are required to be performed within 28 days prior to randomization.
• NOTE:      UPEP (on a 24-hour collection) is required; no substitute method is acceptable. Urine must be followed monthly if the baseline urine M-spike is ≥ 200 mg/24 hr, and urine in addition to serum must be followed in order to confirm a VGPR or higher response.
• Patient must have no lytic lesions, no known plasmacytoma, and no unexplained hypercalcemia (i.e., > 11 mg/dL or 1mg/dL above ULN). Specifically, local interpretation of MRI and PET scans will be used to exclude lytic lesions or plasmacytomas and must be obtained within 60 days prior to randomization.
• Patient must not have known COPD with FEV1 < 50% or known moderate or severe persistent asthma within 2 years prior to randomization.
• Patient must have adequate organ and marrow function as defined below (obtained within 28 days prior to randomization):
  • Hemoglobin ≥ 11 g/dL;
  • Platelet count ≥ 100,000 cells/mm^3;
  • Absolute neutrophil count ≥ 1500 cells/mm^3;
  • Calculated creatinine clearance ≥ 30 mL/min;
  • Bilirubin ≤ 1.5 mg/dL;
  • SGPT (ALT) and SGOT (AST) ≤ 2.5 times the upper limit of normal.
• Patient must not have any prior or concurrent systemic or radiation therapy for the treatment of myeloma. Patient must also not have contraindication to DVT prophylaxis/aspirin.
• Patient must not have more than one focal marrow lesion on MRI of either pelvis or spine.
• Concurrent use of erythropoietin is not allowed while on study therapy.
• Prior or glucocorticosteroid therapy for the treatment of multiple myeloma is not permitted.
• Prior systemic glucocorticosteroid use for the treatment of non-malignant disorders is permitted; concurrent use after registration on the study should be restricted to the equivalent of prednisone 10 mg per day. Prior or concurrent topical or localized glucocorticosteroid therapy to treat non-malignant comorbid disorders is permitted.
• Patient must not have active, uncontrolled seizure disorder. Patient must not have had a seizure in the last 6 months.
• Patient must not have uncontrolled intercurrent illness including uncontrolled hypertension, symptomatic congestive heart failure, unstable angina, uncontrolled cardiac arrhythmia, uncontrolled psychiatric illness or social situation that would limit compliance with the study, or a prior history of Stevens Johnson Syndrome.
• Patient must have an ECOG performance status 0, 1, or 2.
• Patients with monoclonal gammopathy of undetermined significance are not eligible.
• Patient must not have Grade 2 or higher peripheral neuropathy per CTCAE.
• Patient must not have active, uncontrolled infection.
• Patient may have a history of current or previous deep vein thrombosis or pulmonary embolism but are required to take some form of anti-coagulation as prophylaxis if they are not currently on full- dose anticoagulation.
• Patient should not have New York Heart Association classification III or IV heart failure at baseline.
• Patients with a history of prior malignancy are eligible provided they were treated with curative intent and have been free of disease for the time period considered appropriate for cure of the specific cancer.
• Patient must agree to register into the mandatory REMS program and be willing and able to comply with the requirements of REMS.
• Women must not be pregnant due to potential harm to the fetus from Daratumumab and Lenalidomide. All females of childbearing potential (FCBP) must have a blood test or urine study with a sensitivity of at least 25 mIU/mL within 10-14 days prior to the first dose of lenalidomide and again within 24 hours prior to the first dose of lenalidomide. FCBP must also agree to ongoing pregnancy testing while on treatment. A female of childbearing potential is defined as any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria:
  • has achieved menarche at some point;
  • has not undergone a hysterectomy or bilateral oophorectomy; or
  • has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).
  • Females of childbearing potential (FCBP) must either abstain from sexual intercourse for the duration of their participation in the study or agree to use TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME for 1) at least 28 days before starting study treatment; 2) while participating in the study; 3) during dose interruptions; and 4) for at least 28 days after the last dose of protocol treatment (FCBP who are assigned to Arm A and receive daratumumab must extend this contraception requirement to 3 months after the last dose of protocol treatment). Women must also agree to not breastfeed during this same time period. Men must agree to either abstain from sexual intercourse for the duration of their participation in the study or use a latex condom during sexual contact with a FCBP while participating in the study and for 28 days after the last dose of protocol treatment even if they have had a successful vasectomy (Men assigned to Arm A and receive daratumumab must extend this contraception requirement to 3 months after the last dose of protocol treatment).
  • Men must also agree to abstain from donating sperm while on study treatment and for 28 days after the last dose of protocol treatment even if they have had a successful vasectomy. Both women and men must both agree to abstain from donating blood during study participation and for at least 28 days after the last dose of protocol treatment.
  • Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of randomization are eligible for this trial. 
  • Patient should not have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to daratumumab, lenalidomide, or dexamethasone.
  • For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
  • Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.

• Patients must have the psychological ability and general health that permits completion of the study requirements and required follow up.
• All women will, by definition, be considered menopausal due to surgical removal of both ovaries prior to trial enrollment.
• Patients must have newly diagnosed, stage II-IV low-grade serous carcinoma (invasive micropapillary serous carcinoma or invasive grade I serous carcinoma) of the ovary or peritoneum. Tumors must be assessed for nuclear p53 staining.
• Appropriate stage for study entry based on the following diagnostic workup: 
  • History/physical examination within 14 days prior to registration; 
  • Contrast-enhanced imaging of the chest, abdomen and pelvis within 28 days prior to registration. 
• Patients must have undergone an attempt at maximal upfront cytoreductive surgery, with either optimal (< 1 cm diameter residual disease/nodule) or suboptimal residual disease (> 1 cm diameter residual disease/nodule) status allowed. 
• Patients must have undergone a bilateral salpingo-oophorectomy. 
• Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 within 14 days prior to registration .
• Patients must be within ≤ 8 weeks of primary cytoreductive surgery prior to initial randomization.
• Patients must be able to take per oral (P.O.) medications. 
• Absolute neutrophil count (ANC) greater than or equal to 1,500/mcl (within 14 days prior to registration). 
• Platelets greater than or equal to 100,000 cells/mcl (within 14 days prior to registration).
• Creatinine less than or equal to 1.5 x upper limit of normal (ULN) (within 14 days prior to registration).
• Patients whose serum creatinine is between 1.5 and 1.9 mg/dL are eligible if there is no hydronephrosis and the estimated creatinine clearance (CCr) is >= 30 ml/min (within 14 days prior to registration).
• Bilirubin less than or equal to 1.5 x ULN (within 14 days prior to registration).
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or equal to 3 x ULN (within 14 days prior to registration).
• Alkaline phosphatase less than or equal to 2.5 x ULN (within 14 days prior to registration). 
• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the United States (U.S.), authorization permitting release of personal health information.

• Patients with concomitant invasive malignancy or a history of other invasive malignancies, with the exception of non-melanoma skin cancer, are excluded if there is any evidence of other malignancy being present within the past five years. Patients are also excluded if their previous cancer treatment contraindicates this protocol. 
• Patients may not have received neoadjuvant chemotherapy or radiotherapy for the treatment of this disease. 
• Patients may not have received previous hormonal therapy for the treatment of this disease. 
• Patients with known hypersensitivity to letrozole or hypersensitivity/intolerance to carboplatin/paclitaxel therapy. 
• Patients with severe cardiac disease. 
• Myocardial infarction or unstable angina within 6 months prior to registration. 
• New York Heart Association (NYHA) Class II or greater congestive heart failure. 
• Patients with known central nervous system metastases.
• Patients with active or uncontrolled systemic infection. 
• Patients with ≥ Grade 2 baseline neuropathy. 
• Human immunodeficiency virus (HIV) positive with CD4 count < 200 cells/microliter. Note that patients who are HIV positive are eligible, provided they are under treatment with highly active antiretroviral therapy (HAART) and have a CD4 count ≥ 200 cells/microliter within 30 days prior to registration.
• Note also that HIV testing is not required for eligibility for this protocol. This exclusion criterion is necessary because the treatments involved in this protocol may be significantly immunosuppressive.

• Patient scheduled for open or laparoscopic liver surgery. 
• Age ≥ 18 years old. 

• Severe anemia (hemoglobin (Hgb) levels <90 g/l).
• Documented arterial or venous thrombosis at screening or in past three months (not including therapeutic portal vein embolization). 
• Anticoagulants (other than low-molecular-weight heparin (LMWH) or heparin in prophylactic doses to prevent deep vein thrombosis), direct thrombin inhibitors or thrombolytic therapy administered or completed within last week. 
• Known disseminated intravascular coagulation. 
• Severe renal insufficiency (creatinine clearance (CrCl) <30 ml/min).
• History of seizure disorder. 
• Pregnant or lactating (a negative urine pregnancy test must be obtained for women of child bearing potential during the pretreatment evaluation). 
• Acquired disturbance of colour vision
  •Hypersensitivity to TXA or any of the ingredients. 
• Unable to receive blood products (i.e., difficulty with cross matching, refuses blood transfusion, or a past history of unexplained severe transfusion reaction). 
• Previously enrolled in this study.

Key

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

• Able and willing to provide informed consent.
• Postmenopausal women (FSH > 20 IU/L).
• Aged 50-80 years old.
• Lean control subjects:  BMI < 25, Hemoglobin A1c <or= 5.9%
• Obese, non-diabetic subjects:  BMI ≥ 30, Hemoglobin A1c <or= 5.9%
• Obese, T2DM subjects:  BMI ≥ 30, Hemoglobin A1c > 6.5% (for at least the past 5 years).

• Clinical significant abnormality in any of the screening laboratory studies (see below).
• Presence of (documented clinical diagnosis of any of the following):
  • Significant liver or renal disease;
  • Malignancy (including myeloma);
  • Malabsorption (as defined by clinical diagnosis);
  • Hypoparathyroidism (as defined by clinical diagnosis);
  • Hyperparathyroidism (as defined by clinical diagnosis);
  • Acromegaly;
  • Cushing’s syndrome;
  • Hypopituitarism;
  • Severe chronic obstructive pulmonary disease;
  • History of cardiac failure;
  • Bleeding disorders or current use of therapeutic doses of anticoagulants other than aspirin.
• Undergoing treatment with any medications that affect bone turnover, including the following:
  • corticosteroids > 3 months at any time (inhaled steroids acceptable unless used year-round);
  • anticonvulsant therapy for seizures (carbamazepine or phenytoin within the previous year);
  • pharmacological doses of:
    • thiazolidinediones;
    • thyroid hormone (causing decline of thyroid stimulating hormone below normal);
    • Bisphosphonates (within the past 3 years);
    • denosumab, estrogen therapy or treatment with a selective estrogen receptor modulator, or teriparatide (within the past year).
  • Any history of fracture prior to screening.

• Age ≥ 18 years at the time of consent.
• Signed written informed consent.
• JCAR017 monotherapy and ibrutinib + JCAR017 combination cohorts must have diagnosis of:
  • CLL with an indication for treatment based on the Investigator’s opinion and measurable disease (any of the following: bone marrow involvement by ≥ 30% lymphocytes, peripheral blood lymphocytosis > 5 × 10^9 /L, and/or measurable lymph nodes ≥ 1.5 cm in the greatest transverse diameter and/or hepatomegaly or splenomegaly); or
  • SLL (lymphadenopathy and/or splenomegaly and < 5 × 10^9 CD19+ CD5+ clonal B lymphocytes/L [< 5000/µL] in the peripheral blood at diagnosis with measurable disease defined as at least one lesion ≥ 1.5 cm in the greatest transverse diameter) that is biopsy-proven SLL Venetoclax + JCAR017 combination cohorts must have diagnosis of:
  • CLL or SLL with an indication for treatment based on the Investigator’s opinion and measurable disease (any of the following: measurable lymph nodes ≥ 1.5 cm in the greatest transverse diameter and/or hepatomegaly or splenomegaly), and demonstration of CLL cells in the peripheral blood by flow cytometry.
• Subjects (other than those in the ibrutinib + JCAR017 combination therapy cohort) must have received and failed BTKi treatment or have been deemed ineligible for BTKi therapy due to requirement for full dose anticoagulation or history of arrhythmia. Failure to BTKi is defined as having stable disease or progressive disease (PD) as best response, or progression after previous response, or discontinuation due to intolerance. Intolerance is defined as failure to tolerate treatment due to unmanageable toxicity.
• Subjects in the JCAR017 monotherapy cohorts must have received previous treatment as follows:
  • Subjects with CLL or SLL and high-risk features, defined as having complex cytogenetic abnormalities (3 or more chromosomal abnormalities), 17p deletion, TP53 mutation, or unmutated immunoglobulin heavy chain variable region (IGHV), must have failed at least 2 lines of prior therapy;
  • Subjects with CLL or SLL and standard-risk features must have failed at least 3 lines of prior therapy.
• Subjects in the ibrutinib + JCAR017 combination cohorts must either:
  • be receiving ibrutinib, or other BTKi, and progressing at the time of study enrollment; or
  • be receiving ibrutinib, or other BTKi, for at least 6 months with a response less than CR and have high-risk features, as defined in inclusion criterion 5a; or
  • have BTK or phospholipase C gamma 2 (PLCγ2) mutations per local laboratory assessment, with or without progression on ibrutinib; or
  • have previously received ibrutinib, or other BTKi, and have no contraindications to initiate or reinitiate ibrutinib (i.e., ibrutinib was not discontinued due to intolerability and subject has no medical contraindications such as arrhythmia or need for anticoagulation) Subjects in the ibrutinib + JCAR017 combination therapy cohorts enrolled under at least amendment 5, must also meet the below criteria:
  • have progressed on a BTKi and f. have received prior therapy with venetoclax which is considered if they meet one of the following criteria:
    • the subject continued on venetoclax due to disease progression or intolerability and if the subject’s disease met indications for further therapy per iwCLL 2018 criteria; or
    • the subject failed to achieve an objective response within 3 months of initiating therapy. Subjects in the venetoclax + JCAR017 combination cohorts must:
  • Have failed at least 1 prior line of therapy, including having failed BTKi therapy or have been deemed ineligible to receive BTKi, as defined in Inclusion Criterion #4;
  • Be venetoclax naïve (required for dose expansion cohort); or
    • If prior venetoclax, (only for dose escalation cohort) (1) have no contraindications to reinitiation of venetoclax based on prior intolerance and (2) have had at least 6 months elapsed since the last dose of venetoclax, if either of the following criteria are met:
    • the best response was stable disease; or
    • the subject experienced disease progression on venetoclax within 6 months of venetoclax discontinuation.
• Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1.
• Assessed by the Investigator to have adequate bone marrow function to receive lymphodepleting chemotherapy.
• Adequate organ function, defined as:
  • Serum creatinine ≤ 1.5 × age-adjusted upper limit of normal (ULN) OR calculated creatinine clearance (Cockcroft and Gault) > 30 mL/min;
  • Alanine aminotransferase (ALT) ≤ 5 × ULN and total bilirubin < 2.0 mg/dL (or < 3.0 mg/dL for subjects with Gilbert’s syndrome or leukemic infiltration of the liver);
  • Adequate pulmonary function, defined as ≤ Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 dyspnea and saturated oxygen (SaO2) ≥ 92% on room air;
  • Adequate cardiac function, defined as left ventricular ejection fraction (LVEF) ≥ 40% as assessed by echocardiogram (ECHO) or multiple uptake gated acquisition (MUGA) scan performed within 30 days prior to determination of eligibility Subjects in the venetoclax + JCAR017 combination dose escalation and expansion cohorts must have:
    • Hemoglobin ≥ 9 g/dL, absolute neutrophil count (ANC) ≥ 500/mm^3 , and platelets ≥ 75,000/mm^3 , unless cytopenias judged by the Investigator to be due to CLL infiltration of the bone marrow.
• Subject either currently has central vascular access or is a candidate to receive central vascular access or peripheral vascular access for leukapheresis procedure.
• If prior CD19-targeted therapy has been administered, subject must have CD19-positive disease confirmed by immunohistochemistry or flow cytometry since completing the prior CD19-targeted therapy.
• Females of childbearing potential must either commit to true abstinence from heterosexual contact or agree to use one highly effective method of contraception from screening until at least 1 year after receiving lymphodepleting chemotherapy.
• Females of childbearing potential must have a negative serum beta human chorionic gonadotropin (ß-hCG) pregnancy test result at screening and within 48 hours prior to the first dose of lymphodepleting therapy.
• Males who have partners of childbearing potential must practice true abstinence or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential for at least 1 year after receiving lymphodepleting chemotherapy even if he has undergone a successful vasectomy.

• Subjects with known active central nervous system (CNS) involvement by malignancy. Subjects with prior CNS disease that has been effectively treated will be eligible if treatment was completed at least 3 months prior to enrollment with no evidence of symptomatic disease and stable abnormalities on repeat imaging.
• History of another primary malignancy that has not been in remission for at least 2 years. (The following are exempt from the 2-year limit: nonmelanoma skin cancer, completely resected stage 1 solid tumor with low risk for recurrence, curatively treated localized prostate cancer, cervical carcinoma in situ on biopsy or a squamous intraepithelial lesion on Pap smear, and in situ breast cancer that has been completely resected.).
• Subjects with Richter’s transformation.
• Prior treatment with any gene therapy product.
• Active hepatitis B, or active hepatitis C (Subjects with a negative polymerase chain reaction (PCR) assay for viral load for hepatitis B or C are permitted; subjects positive for hepatitis B surface antigen and/or anti-hepatitis B core antibody with negative viral load are eligible and should be considered for prophylactic antiviral therapy), or history of or active human immunodeficiency virus (HIV) infection.
• Systemic fungal, bacterial, viral, or other infection that is not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment).
• Presence of acute or extensive chronic graft versus host disease (GVHD).
• History of any one of the following cardiovascular conditions within the past 6 months: Class III or IV heart failure as defined by the New York Heart Association (NYHA), cardiac angioplasty or stenting, myocardial infarction, unstable angina, or other clinically significant cardiac disease.
• History or presence of clinically relevant CNS pathology such as epilepsy, generalized seizure disorder, aphasia, stroke with current neurologic sequelae, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, cerebral edema, or psychosis.
• Pregnant or nursing (lactating) women.
• Use of any of the following medications or treatments within the noted time prior to leukapheresis:
  • Alemtuzumab within 6 months prior to leukapheresis;
  • Allogeneic hematopoietic stem cell transplant within 100 days prior to leukapheresis;
  • Cladribine within 3 months prior to leukapheresis;
  • Donor lymphocyte infusions (DLI) within 2 months prior to leukapheresis;
  • Radiation including large bone marrow fields such as sternum or pelvis within 6 weeks prior to leukapheresis;
  • Fludarabine within 4 weeks prior to leukapheresis;
  • GVHD therapies such as calcineurin inhibitors, methotrexate or other chemotherapeutics, mycophenolate mofetil, rapamycin, or immunosuppressive antibodies (such as anti-tumor necrosis factor-α [TNFα], anti-interleukin-6 [IL-6], or anti-interleukin-6 receptor [IL-6R]) within 4 weeks prior to leukapheresis;
  • Cyclophosphamide, ifosfamide, bendamustine, chlorambucil, or melphalan within 2 weeks prior to leukapheresis;
  • Therapeutic doses of corticosteroids (defined as > 20 mg/day prednisone or equivalent) within 7 days prior to leukapheresis;
  • Anti-CD20 monoclonal antibodies within 7 days prior to leukapheresis;
  • Venetoclax within 4 days prior to leukapheresis;
  • Idelalisib or duvelisib within 2 days prior to leukapheresis;
  • Lenalidomide or acalabrutinib within 1 day prior to leukapheresis;
  • Experimental agents, including off-label use of approved drugs, within 4 weeks prior to leukapheresis unless progression is documented on the experimental therapy and at least 3 halflives have elapsed prior to leukapheresis.
• Uncontrolled medical, psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol, as judged by the Investigator; or subject unwillingness or inability to follow the procedures required in the protocol.
• Progressive vascular tumor invasion, thrombosis, or embolism.
• Venous thrombosis or embolism requiring treatment but not managed on a stable regimen of anticoagulation.
• For subjects in the venetoclax + JCAR017 combination cohorts only, concomitant treatment with CYP3A moderate/strong inducers or moderate/strong inhibitors which cannot be discontinued.

• Patients with hypophosphatemia or suspected tumor induced osteomalacia (TIO) or suspected or confirmed X-linked hypophosphatemia (XLH).

• Patients with iron deficiency and chronic kidney disease as these patients might have elevations of FGF23.

• Age 18-55 years old.
• BMI 21.0 – 32.0 kg/m^2.

• BMI > 32.0 kg/m^2.
• For the 20 participants who are involved in training - participation in structured exercise (>2 times per week for 30 minutes or longer).
• For the 10 participants in the aerobic arm
  •do not participate in structured exercise > 5 times per week.
• For all participants
  •cardiovascular, metabolic (type 2 diabetes, fasting plasma glucose at or above 110 mg/dL and untreated hypo- or hyperthyroidism) or renal disease, orthopedic problems that would keep them from being able to perform leg extensions; medications that are known to have an impact on mitochondrial function: 
  • Corticosteroids, opiates, benzodiazepines, tricyclic antidepressants, beta blockers, sulfonylureas, insulin, anticoagulants, barbiturates, insulin sensitizers, fibrates (PPAR gamma agonist), smoking, pregnancy. 
  •  

• Age greater than 18 years or older.

• Age < 18 years.
• Having received any investigational drug or device within 30 days prior to entry into the study.
• Clinically unstable patients (e.g. systolic blood pressure < 90 mmHg, ongoing requirement for vasopressors or mechanical circulatory support, or mechanical ventilation).
• Hospitalization within three months prior to study for hemodialysis or an ongoing requirement for hemodialysis or ultrafiltration.
• Prior organ transplantation or being on a waiting list for organ transplantation.
• Presence of cardiac conditions such as clinically significant cardiac valve stenosis, hypertrophic cardiomyopathy, restrictive cardiomyopathy, constrictive pericarditis, or primary arterial pulmonary hypertension (Group 1 PAH).
• History of blood pressure > 190/115 mmHg or unexplained syncope within the past 3 months.
• Symptomatic carotid artery disease, known critical carotid stenosis, or stroke within the past 3 months.
• Clinically significant intrinsic renal disease (eGFR <15 ml/min/1.72m2), renal artery stenosis, or history of fibromuscular dysplasia of the renal arteries.
• Baseline hemoglobin < 8.5 g/dl, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) that is five times or more the upper limit of normal or bilirubin three times or more the upper limit of normal.
• History of alcohol abuse within the past 6 months.
• Women who are pregnant, or breast-feeding.

• Adults, aged 18 and over.
• Confirmed C. difficile infection based on positive C. difficile toxin PCR testing and clinical evidence of diarrhea.

• Known pregnancy.
• Prior diagnosis of C. difficile infection within 2 months prior to this diagnosis.
• Other known active gastrointestinal infectious process.
• Known diagnosis of inflammatory bowel disease, microscopic colitis, celiac disease or other inflammatory conditions.
• Vulnerable adults.
• Any other disease(s), condition(s) or habit(s) that would interfere with completion of study, or in the judgment of the investigator would potentially interfere with compliance to this study or would adversely affect study outcomes.

Eligibility last updated 9/29/21. Questions regarding updates should be directed to the study team contact.

​​​​​​

• Ability to understand and willingness to provide informed consent.
• Stated willingness to comply with all study procedures and availability for the duration of the study.
• Male or female, aged ≥ 18 years.
• Diagnosed with Stage IV metastatic melanoma, or inoperable Stage III equivalent.
• FDG-PET/CT scan available to serve as baseline; the archived scan date must be within 30 days prior to date of enrollment (date initial ICF signed); images from external facilities are allowed. If no archived FDG-PET/CT scan in window, the baseline scan must be obtained at Screening.
• Complete blood count with differential, within 14 calendar days prior to enrollment, demonstrating the following:
  • White blood cells (WBC) > 2500/mm^3;
  • Hemoglobin (Hgb) > 9.0 g/dL;
  • Platelets > 60,000/mm^3;
  • Absolute Neutrophil Count (ANC) > 1,250/mm^3
    • If no differential is available in the SOC results for enrollment, a subject may be enrolled without the ANC level. Following enrollment, however, this criterion must be met to proceed in the study.
• Comprehensive metabolic panel, within 14 calendar days prior to enrollment, demonstrating values within the site’s upper limit of normal (ULN), with the following exceptions:
  • Alanine aminotransferase (ALT) ≤ 3 x ULN;
  • Aspartate aminotransferase (AST) ≤ 3 x ULN;
  • Alkaline phosphatase (ALP) ≤ 2.5 x ULN.
• Ability to lie flat and still for a minimum of two hours for the SPECT scan.
• For females of reproductive potential: use of highly effective contraception for at least one month prior to screening, and agreement to use such a method during study participation and for an additional four weeks after the end of last investigational imaging agent administration.
• For males of reproductive potential: use of condoms or other methods to ensure effective contraception with partner during study participation and for an additional four weeks after the end of last investigational imaging agent administration.
• Agreement to adhere to Lifestyle Considerations throughout study duration.
• Documented life expectancy of at least 3 months.
• Access to most recent biopsy is requested (if tissue is available) at screen or if it is obtained through SOC during an expanded window of acceptability; i.e., throughout entire conduct of study at this site. (An updated consent will be obtained.) If a biopsy is completed as part of routine clinical care prior to IRB closure, the study may request access to this sample for tissue MC1R staining and analysis.

• Active secondary malignancy.
• Prior treatment (for any reason) with radioactive nuclides; imaging tracers are acceptable.
• Pregnancy.
• Lactation.
• Febrile illness within 48 hours of scheduled imaging procedure.
• Uncontrolled infection.
• Treatment with another investigational drug within 30 days prior to enrollment date.
• Subjects initiating BRAFi drugs between baseline FDG scan and enrollment. Subjects receiving consistent, stable therapy with BRAFi for ≥ 3 months prior to enrollment and who have persistent FDG positive malignant lesions on PET imaging are eligible.
• eGFR < 50 mL/min/1.73m^2.
• BMI > 50 kg/m^2.
• Previous medical history of a condition resulting in anaphylaxis or angioedema.
• Planned treatment while on study with concomitant investigative agents that do not have disclosed safety profiles in the melanoma population (peer-reviewed publications and investigator’s brochures for phase 2 or 3 trials will be accepted as disclosed safety profiles).

Eligibility last updated 11/10/21. Questions regarding updates should be directed to the study team contact.

PREREGISTRATION (STEP 0)

• Age ≥ 18 years.
• Patient has pathologically-confirmed chronic phase-CML one of the following the following criteria:
  • Patient has been in MMR (i.e. MR3) with detectable BCR/ABL transcript by a standard RQ-PCR assay for at least 12 months from the first documentation of the MMR;
  • Has been in MMR (i.e. MR3) but still has detectable BCR/ABL transcript by a standard RQ-PCR assay for at least 12 months from the first documentation of the MMR;
  • Up to two values above MMR (0.1%) are allowed in the last 12 months long as there was no change in the type or dose of TKI in last 6 months, none of the lab values were higher than CCR (1% or more) in the last 12 months, and all values in the last 6 months were at MMR or deeper;
  • Patient has not maintained MR4.5 (CMR) within the time of initiation of TKI therapy and pre-registration. Patient can have intermittent values of CMR (at or below MR4.5). However the patient has to have detectable disease (i.e. cannot be in CMR) in the last 2 assessments before pre-registration; AND 
  • Patient must have a diagnosis of chronic phase-CML has been confirmed by a bone marrow aspirate and/or biopsy with ≤ 10 % myeloid blasts (i.e., no accelerated or blast phase) within 21after consenting and pre -registration to step 0 and MMR status and BCR/ABL results meets the criteria outlined above.
    • NOTE: Please be aware of the required timeframe restrictions. Patients are required to enroll on Step 1 within 21 days from the date of consenting (step 0, pre-registration)
• Patients with diagnoses of accelerated or blast phase CML are not eligible.
• Patient has been on TKI therapy (first and/or second line) for at least 2 years (starting from when first TKI was initiated) prior to pre-registration:
  • Allowed TKIs include:
    • • Dasatinib: 50 – 180 mg per day;
    • • Imatinib: 200 – 800 mg per day;
    • • Nilotinib: 200 – 400 mg every 12-24 hours.
• Patients must have been on a stable dose of the current TKI for the last 3 months prior to pre-registration. For patients with two values of above MMR (0.1%) within the last 12 months, patient must have been on stable dose of the current TKI for the last 6 months prior to pre-registration.
• For patients who are on second line TKI, patient has been on second line TKI for at least a year from start date of second line TKI.
• Patient must not have received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
• Patients must not have received a prior allogeneic transplant.

REGISTRATION TO TREATMENT (STEP 1)

• Institution has received central BCR-ABL test results confirming MRD positive status and bone marrow aspirate and/or biopsy has confirmed chronic phase CML (i.e. no accelerated or blast phase CML) Bone marrow showing morphologic remission is acceptable.
• Patients have an ECOG Performance Status of 0-2.
• Diagnosis of chronic phase-CML must had been confirmed by a bone marrow aspirate and/or biopsy with ≤ 10 % myeloid blasts (i.e., no accelerated or blast phase) within 21 days prior to registration to step 1. Bone marrow aspirate and/or biopsy showing morphologic remission is acceptable. MMR and BCR/ABL status meets the criteria defined above.
• No active hemolytic anemia requiring immunosuppressive therapy or other pharmacologic treatment. Patients who have a positive Coombs test but no evidence of hemolysis are NOT excluded from participation
• No current use of corticosteroids from time of consent to registration.
  • EXCEPTION: Low doses of steroids (< 10 mg of prednisone or equivalent dose of other steroid) used for treatment of non-hematologic medical condition (e.g., chronic adrenal insufficiency) is permitted.
• No other active primary malignancy (other than non-melanomatous skin cancer or carcinoma in situ of the cervix) requiring treatment or limiting expected survival to ≤ 2 years.
  • NOTE: If there is a history of prior malignancy, they must not be receiving other specific treatment (other than hormonal therapy for their cancer).
• Women must not be pregnant or breastfeeding due to the potential for congenital abnormalities and of harm to nursing infants due to the treatment regimens used. Patients must also not expect to conceive or father children from the time of registration, while on study treatment, and continue for 120 days after the last dose of study treatment
  • All females of childbearing potential must have a negative urine or serum pregnancy test conducted within 14 days prior to registration to rule out pregnancy. A urine or serum pregnancy test must be repeated within 72 hours prior to receiving the first dose of pembrolizumab if the test done for eligibility/registration to step 1 is done outside of this 72 hour window. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required;
  • A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point; 2)has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential)for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).
  • Female of child bearing potential? ______ (Yes or No)
    • Date of urine/serum study: ___________
• Women of childbearing potential and sexually active males must use accepted and effective method(s) of contraception or to abstain from sex from time of registration, while on study treatment, and continue for 120 days after the last dose of study treatment. 
• Patient may not be currently participating and receiving study therapy or have participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of registration.
• Patient must not have a diagnosis of immunodeficiency or be receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of treatment.
• Patient must not have a known history of active TB (Bacillus Tuberculosis).
• Patient must not have a history of hypersensitivity to pembrolizumab or any of its excipients.
• Patient must not have received a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to registration or have not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
• Patient must not have had prior chemotherapy, targeted small molecule therapy (aside from imatinib, dasatinib, or nilotinib), or radiation therapy within 2 weeks prior to registration to Step 1. Patients also must have recovered from all adverse events due to a previously administered agent.
  • NOTE: Patients with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.
  • NOTE: Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤ 2 weeks of radiotherapy) to non-CNS disease).
• Patients who have received major surgery must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
• Patient must not have a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
• Patient must not have known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of protocol treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to protocol treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
• Patient must not have active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 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
• Patient must not have known history of, or any evidence of active, non-infectious pneumonitis.
• Patient must not have an active infection requiring systemic therapy.
• Patient must not have a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
• Patient must not have known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• Patients who are Human Immunodeficiency Virus (HIV) positive are eligible if they have undetectable HIV viral load and CD4+ T-cell count ≥ 250/mm^3.
• Patients with a known positive test for Hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection may be be enrolled if the viral load by PCR is undetectable with/without active treatment.
• Patients must not have a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive).
• Patient must not have received a live vaccine within 30 days of registration.
  • NOTE: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.
• Patients must meet the following criteria with all screening labs performed within 14 days prior to registration:
  • Absolute neutrophil count (ANC) ≥ 1,500 /mcL
    • ANC: _________ Date of Test: _________
  • Platelet count ≥ 100,000 /mcL
    • Platelet:_______ Date of Test: _________
  • Hgb ≥ 9.0 g/dL OR ≥ 5.6 mmol/L without transfusion of EPO dependency
    • Hgb:__________ Date of Test:__________
  • Serum creatinine ≤ 1.5 X upper limit of normal (ULN) OR Creatinine clearance (per institutional standards) ≥ 60 mL/min for patient with creatinine levels > 1.5 X ULN
    • Serum creatinine ______________Date of Test: ________
  • or
    • Creatinine clearance: __________ Date of Test: ________
  • Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 X ULN
    • Bilirubin: __________ Institutional ULN: _________ Date of Test: __________
  • AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases
    • ALT: _______ Institutional ULN: _________ Date of Test: _______
    • AST:_______  Institutional ULN:_________ Date of Test: _______
• Patients should not be receiving concomitant strong CYP3A4 inducers or inhibitors ≤ 7 days prior to registration due to their potential to effect the activity or pharmacokinetics of study agents and/or QT interval prolongation toxicity. Should treatment with any of these agents be required, consult with study chair and reference Section 5.5 for TKI dose modifications related to concomitant drugs.
• Patients who received prior allogeneic transplant are not eligible.

REGISTRATION TO TREATMENT (STEP 2)

• Institution has received central BCR-ABL test results confirming MRD positive status at Cycle 16 or 17 or 18 following Step 1 treatment (MMR or deeper but not in CMR in the last two central lab checks before Step 2).
• Patients have an ECOG Performance Status of 0-2.
• No active hemolytic anemia requiring immunosuppressive therapy or other pharmacologic treatment. Patients who have a positive Coombs test but no evidence of hemolysis are NOT excluded from participation.
• No current use of corticosteroids. EXCEPTION: Low doses of steroids (< 10 mg of prednisone or equivalent dose of other steroid) used for treatment of non-hematologic medical condition (e.g., chronic adrenal insufficiency) is permitted.
• No other active primary malignancy (other than non-melanomatous skin cancer or carcinoma in situ of the cervix) requiring treatment or limiting expected survival to ≤ 2 years.
  • NOTE: If there is a history of prior malignancy, they must not be receiving other specific treatment (other than hormonal therapy for their cancer).
• Patient must not have a diagnosis of immunodeficiency or be receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of treatment.
• Patient must not have a known history of active TB (Bacillus Tuberculosis).
• Patient must not have a history of hypersensitivity to pembrolizumab or any of its excipients.
• Women must not be pregnant or breastfeeding due to the potential for congenital abnormalities and of harm to nursing infants due to the treatment regimens used. Patients must also not expect to conceive or father children from the time of registration, while on study treatment, and continue for 120 days after the last dose of study treatment
• All females of childbearing potential must have a negative urine or serum pregnancy within 14 days prior to registration on step 2 to rule out a pregnancy. A urine or serum pregnancy test must be repeated within 72 hours prior to receiving the first dose of pembrolizumab on step 2 if the test done for eligibility/registration to step 2 is done outside of this 72 hour window. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2)has not undergone a hysterectomy or bilateral oophorectomy; or3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).
• Female of child bearing potential? ______ (Yes or No)
  • Date of urine/serum study: ___________
• Women of childbearing potential and sexually active males must use accepted and effective method(s)of contraception or to abstain from sex from time of registration, while on study treatment, and continue for 120 days after the last dose of study treatment. (Refer to Section 5.6.2 for detailed information on contraception requirements while on this study).
• Patient must not have known history of, or any evidence of active, non-infectious pneumonitis.
• Patient must not have an active infection requiring systemic therapy.
• Patient must not have a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
• Patients who are Human Immunodeficiency Virus (HIV) positive are eligible if they have undetectable HIV viral load and CD4+ T-cell count ≥ 250/mm^3.
• Patient with a known positive test for Hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection might be enrolled if the viral load by PCR is undetectable with/without active treatment.
• Patients must not have a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive).
• Patient must not have received a live vaccine within 30 days of planned start of study therapy.
  • NOTE: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.
• Patients must meet the following criteria with all screening labs performed within 14 days prior to registration:
• Absolute neutrophil count (ANC) ≥ 1,500 /mcL
  • ANC:__________ Date of Test:__________
• Platelet count ≥ 100,000 /mcL
  • Platelet:__________ Date of Test:__________
• Hgb ≥ 9.0 g/dL OR ≥ 5.6 mmol/L without transfusion of EPO dependency
  • Hgb:__________ Date of Test:__________
• Serum creatinine ≤ 1.5 X upper limit of normal (ULN) OR Creatinine clearance (per institutional standards) ≥ 60 mL/min for patient with creatinine levels > 1.5 X ULN
  • Serum creatinine ______________Date of Test:________
• or
  • Creatinine clearance:__________ Date of Test:_________
• Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 X ULN
  • Bilirubin:__________ Institutional ULN:_________ Date of Test:__________
• AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases
  • ALT: _______ Institutional ULN:_________ Date of Test: _______
  • AST: _______ Institutional ULN:_________ Date of Test: _______
• Patients should not be receiving concomitant strong CYP3A4 inducers or inhibitors ≤ 7 days prior to registration due to their potential to effect the activity or pharmacokinetics of study agents and/or QT interval prolongation toxicity. Should treatment with any of these agents be required, consult with study chair and reference Section 5.5 for TKI dose modifications related to concomitant drugs.

• Participant must be at least 18 years of age or of the country's legal age of majority if the legal age is >18 years old at the time of signing the informed consent. 
• Participant has given voluntary written informed consent. 
• Participant has been previousy diagnosed with multiple myeloma based on standard criteria. 
• Part A:
  • Participant has received at least 3 prior lines of therapy for multiple myeloma, or at least 2 prior lines of therapy if at least 1 of those lines consisted of 2 or more multi-agent regimens (eg, multi-agent induction regimen with autologous stem cell transplantation, followed by maintenance regimen). 
  • Prior therapy for multiple myeloma has included at least 1 proteasome inhibitor (bortezomib, carfilzomib, ixazomib), at least 1 immunomodulatory agent (lenalidomide, thalidomide, pomalidomide), at least 1 anti-CD38 monoclonal antibody and at least 1 steroid. 
  • Participant had at least a minimal response (MR) to the anti-CD38 antibody containing regimen and had last dose of anti-CD38 monoclonal antibody at least 9 months prior to study entry, except the last cohort(s) of Part A who are anti CD38 naïve. 
• Part B and the last cohort(s) of Part A:
  • Participant has received at least 3 prior lines of therapy for multiple myeloma, or at least 2 prior line of therapy if at least 1 of those lines consisted of 2 or more multi-agent regimens (eg, multi-agent induction regimen with autologous stem cell transplantation, followed by maintenance regimen).
  • Prior therapy for multiple myeloma has included at least 1 proteasome inhibitor (bortezomib, carfilzomib, ixazomib), at least 1 immunomodulatory agent (lenalidomide, thalidomide, pomalidomide) and at least 1 steroid.
  • Prior therapy has not included an anti-CD38 monoclonal antibody. 
• Participant has myeloma disease progression on or after last therapy. 
• Participant must have measurable disease as defined as at least one of the following: 
  • Serum M protein ≥0.5 g/dL (≥5 g/L);
  • Urine M protein ≥200 mg/24 hours;
  • Serum FLC assay: Involved FLC assay ≥10 mg/dL (≥100 mg/L) and an abnormal serum;
  • FLC ratio (<0.26 or >1.65). 
• A male participant must agree to use contraception during the intervention period and for at least 150 days after the last dose of study drug and refrain from donating sperm during this period.
• 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);
  • A WOCBP who agrees to follow the contraceptive guidance during the intervention period and for at least 150 days after the last dose of study intervention.

• Participant is diagnosed or treated for another malignancy within 3 years prior to enrollment, with the exception of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, superficial bladder carcinoma or low risk prostate cancer. 
• Participant has an Eastern Cooperative Oncology Group (ECOG) performance status score > 2.
• Participant has a history of Chronic obstructive pulmonary disease (COPD) or asthma. 
• Participant has not recovered from adverse reactions to prior myeloma treatment or procedures (chemotherapy, immunotherapy, radiation therapy) to NCI CTCAE Grade ≤1 or baseline (exception: alopecia).
• Participant has congestive heart failure (New York Heart Association) Grade ≥ II; cardiac myopathy, active ischemia, or any other uncontrolled cardiac condition such as angina pectoris, clinically significant arrhythmia requiring therapy including anticoagulants, or clinically significant uncontrolled hypertension, QT interval corrected by the Fridericia method > 480 msec (Grade ≥ 2). 
• Participant has had acute myocardial infarction within 6 months before first dose of study medication. 
• Participant has ongoing sensory or motor neuropathy of National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade ≥ 3. 
• Participant has active autoimmune disease including autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, inflammatory bowel syndrome, pneumonitis or any chronic condition requiring a higher corticosteroid systemic equivalent than prednisone 10 mg daily.
• Known acquired immunodeficiency syndrome (AIDS) or related illnesses or human immunodeficiency virus (HIV) disease requiring antiretroviral treatment, or to have active hepatitis A, B (defined as a known positive hepatitis B surface antigen (HBsAg) result or positive HepB DNA), or C (defined as a known quantitative hepatitis C [HCV] ribonucleic acid RNA results greater than the lower limits of detection of the assay or positive HCV antigen) infection.
• Participant has positive Coombs test at baseline. The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

• Age ≥ 18 years old.
• Metastatic CRC patients with synchronous or metachronous peritoneal metastasis.
• Patients who plan to undergo either diagnostic laparoscopy with tissue biopsy of the peritoneal metastases or cytoreductive surgery of the peritoneal metastases as part of routine clinical care.
• Patients willing to consent for biopsy.

• Patients who will not have tissue biopsy from diagnostic laparoscopy or tumor resection from cytoreductive surgery as part of routine clinical care.
• Women known to be pregnant.
• Non-English speaking, students, prisoners.