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Testing Pembrolizumab with Existing Cancer Therapy in Patients with Evidence of Residual Chronic Myelogenous Leukemia

This phase II trial studies how well pembrolizumab and dasatinib, imatinib mesylate, nilotinib, or bosutinib work in treating patients with chronic myeloid leukemia and persistent detection of minimal residual disease, defined as the levels of a gene product called bcr-abl in the blood. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the bodys immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Dasatinib, imatinib mesylate, nilotinib, and bosutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving pembrolizumab and dasatinib, imatinib mesylate, nilotinib, or bosutinib may work better in treating patients with chronic myeloid leukemia compared to dasatinib, imatinib mesylate, nilotinib, or bosutinib alone.
Leukemia
Phase II
Adults
Mol. targeted/Immunotherapy/Biologics
AMN107, Bosutinib, Dasatinib (BMS-354825), Imatinib, MK-3475, Nilotinib, Pembrolizumab (MK-3475)
Mohan, Sanjay
International
Vanderbilt University
11-08-2021
Treatment
ECOGHEMEA9171
NCT03516279

Eligibility

18 Years
BOTH
NO
Inclusion Criteria:

PREREGISTRATION (STEP 0): NOTE: Following consent and preregistration to Step 0, peripheral blood must be collected for submission to Fred Hutchinson Cancer Research Center for central assessment of the establishment of BCR/ABL status to confirm patients eligibility for registration to Step 1; Fred Hutchinson will typically forward results within 1-2 business days of receipt of the peripheral blood to the submitting institution

Patient must have pathologically-confirmed chronic phase-CML by one of the following the following criteria: * Patient has been in MMR (i.e. MR^3) with detectable BCR/ABL transcript by a standard real-time quantitative polymerase chain reaction (RQ-PCR) assay for at least 12 months from the first documentation of the MMR * Patient has been in MMR (i.e. MR^3) 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 MR^4.5 (CMR) after initiation of last line TKI therapy; patient can have intermittent values of CMR (at or below MR^4.5); however the patient has to have detectable disease (i.e. cannot be in CMR) in the last one assessment before pre-registration to Step 0 AND Patient must have a diagnosis of chronic phase-CML which has been confirmed by a bone marrow aspirate and/or biopsy with =
PREREGISTRATION (STEP 0): Patients with diagnoses of accelerated or blast phase CML are not eligible

PREREGISTRATION (STEP 0): Patient has been on TKI therapy (first, second, and third line line) for at least 2 years (starting from when first TKI was initiated) prior to step 0 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 ** Bosutinib: 200 500 mg per day * Patients must have been on a stable dose of the current TKI for at least 3 months prior to start of EA9171 study therapy; 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 start of EA9171 study therapy * For patients who are on second line or third line TKI, patient has been on the last line TKI for at least 6 months

PREREGISTRATION (STEP 0): Patient must not have received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent

PREREGISTRATION (STEP 0): Patients must not have received a prior allogeneic transplant

REGISTRATION TO TREATMENT (STEP 1): Institution must have 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

REGISTRATION TO TREATMENT (STEP 1): Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

REGISTRATION TO TREATMENT (STEP 1): A diagnosis of chronic phase-CML must had been confirmed by a bone marrow aspirate and/or biopsy with =
REGISTRATION TO TREATMENT (STEP 1): Patient must not have any 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

REGISTRATION TO TREATMENT (STEP 1): Patient must not receive any corticosteroids from the time of consent to step 1 registration * EXCEPTION: Low doses of steroids (
REGISTRATION TO TREATMENT (STEP 1): 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; all females of childbearing potential must have a negative urine or serum pregnancy test within 14 days prior to Step 1 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 defined as 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)

REGISTRATION TO TREATMENT (STEP 1): Women of childbearing potential and sexually active males must not expect to conceive or father children by using accepted and effective method(s) of contraception or by abstaining from sex from the time of step 1 registration, while on study treatment, and continue for 120 days after the last dose of study treatment

REGISTRATION TO TREATMENT (STEP 1): 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 step 1 registration

REGISTRATION TO TREATMENT (STEP 1): 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

REGISTRATION TO TREATMENT (STEP 1): Patient must not have a known history of active TB (Bacillus tuberculosis)

REGISTRATION TO TREATMENT (STEP 1): Patient must not have a history of hypersensitivity to pembrolizumab or any of its excipients

REGISTRATION TO TREATMENT (STEP 1): Patient must not have received a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to step 1 registration or have not recovered (i.e., =
REGISTRATION TO TREATMENT (STEP 1): Patient must not have had prior chemotherapy, targeted small molecule therapy (aside from imatinib, dasatinib, bosutinib 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 =
REGISTRATION TO TREATMENT (STEP 1): Patients who have received major surgery must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy

REGISTRATION TO TREATMENT (STEP 1): Patient must not have a known primary or additional malignancy that is progressing or requires active treatment or limiting expected survival to =
REGISTRATION TO TREATMENT (STEP 1): 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

REGISTRATION TO TREATMENT (STEP 1): 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

REGISTRATION TO TREATMENT (STEP 1): Patient must not have known history of, or any evidence of active, non-infectious pneumonitis

REGISTRATION TO TREATMENT (STEP 1): Patient must not have an active infection requiring systemic therapy

REGISTRATION TO TREATMENT (STEP 1): 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 subjects 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

REGISTRATION TO TREATMENT (STEP 1): Patient must not have known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study

REGISTRATION TO TREATMENT (STEP 1): 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

REGISTRATION TO TREATMENT (STEP 1): Patients with a known positive test for hepatitis C virus ribonucleic acid (hepatitis C virus [HCV] antibody) indicating acute or chronic infection may be enrolled if the viral load by polymerase chain reaction (PCR) is undetectable with/without active treatment

REGISTRATION TO TREATMENT (STEP 1): Patient must not have a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive)

REGISTRATION TO TREATMENT (STEP 1): Patient must not have received a live vaccine within 30 days of step 1 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

REGISTRATION TO TREATMENT (STEP 1): Absolute neutrophil count (ANC) >= 1,500 /mcL (within 14 days prior registration)

REGISTRATION TO TREATMENT (STEP 1): Platelet count >= 100,000 /mcL (within 14 days prior to registration)

REGISTRATION TO TREATMENT (STEP 1): Hemoglobin (Hgb) >= 9.0 g/dL OR >= 5.6 mmol/L without transfusion of erythropoietin (EPO) dependency (within 14 days prior to registration)

REGISTRATION TO TREATMENT (STEP 1): Serum creatinine == 60 mL/min for patient with creatinine levels > 1.5 X ULN (within 14 days prior to registration)

REGISTRATION TO TREATMENT (STEP 1): Serum total bilirubin = 1.5 X ULN (within 14 days prior to registration)

REGISTRATION TO TREATMENT (STEP 1): Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =
REGISTRATION TO TREATMENT (STEP 1): Patients should not be receiving concomitant strong CYP3A4 inducers or inhibitors =
REGISTRATION TO TREATMENT (STEP 1): Patients who received prior allogeneic transplant are not eligible

REGISTRATION TO TREATMENT (STEP 2): Institution must have 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)

REGISTRATION TO TREATMENT (STEP 2): Patients must have an ECOG performance status of 0-2

REGISTRATION TO TREATMENT (STEP 2): Patient must have 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

REGISTRATION TO TREATMENT (STEP 2): No current use of corticosteroids; EXCEPTION: Low doses of steroids (
REGISTRATION TO TREATMENT (STEP 2): Patient must not have any other active primary malignancy (other than non-melanomatous skin cancer or carcinoma in situ of the cervix) requiring treatment or limiting expected survival to =
REGISTRATION TO TREATMENT (STEP 2): 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

REGISTRATION TO TREATMENT (STEP 2): Patient must not have a known history of active TB (Bacillus tuberculosis)

REGISTRATION TO TREATMENT (STEP 2): Patient must not have a history of hypersensitivity to pembrolizumab or any of its excipients

REGISTRATION TO TREATMENT (STEP 2): 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; 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 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 defined as 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)

REGISTRATION TO TREATMENT (STEP 2): Women of childbearing potential and sexually active males must not expect to conceive or father children by using accepted and effective method(s) of contraception or by abstaining from sex from the time of step 2 registration, while on study treatment, and continue for 120 days after the last dose of study treatment

REGISTRATION TO TREATMENT (STEP 2): Patient must not have known history of, or any evidence of active, non-infectious pneumonitis

REGISTRATION TO TREATMENT (STEP 2): Patient must not have an active infection requiring systemic therapy

REGISTRATION TO TREATMENT (STEP 2): Patient must not have a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the patientss participation for the full duration of the study, or is not in the best interest of the patient to participate, in the opinion of the treating investigator

REGISTRATION TO TREATMENT (STEP 2): 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

REGISTRATION TO TREATMENT (STEP 2): 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

REGISTRATION TO TREATMENT (STEP 2): Patients must not have a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive)

REGISTRATION TO TREATMENT (STEP 2): 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

REGISTRATION TO TREATMENT (STEP 2): Absolute neutrophil count (ANC) >= 1,500 /mcL (within 14 days prior to registration)

REGISTRATION TO TREATMENT (STEP 2): Platelet count >= 100,000 /mcL (within 14 days prior to registration)

REGISTRATION TO TREATMENT (STEP 2): Hgb >= 9.0 g/dL OR >= 5.6 mmol/L without transfusion of EPO dependency (within 14 days prior to registration)

REGISTRATION TO TREATMENT (STEP 2): Serum creatinine == 60 mL/min for patient with creatinine levels > 1.5 X ULN (within 14 days prior to registration)

REGISTRATION TO TREATMENT (STEP 2): Serum total bilirubin = 1.5 X ULN (within 14 days prior to registration)

REGISTRATION TO TREATMENT (STEP 2): AST (SGOT) and ALT (SGPT) =
REGISTRATION TO TREATMENT (STEP 2): Patients should not be receiving concomitant strong CYP3A4 inducers or inhibitors =

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