Clinical Trials /

Pembrolizumab and Dasatinib, Imatinib Mesylate, or Nilotinib in Treating Patients With Chronic Myeloid Leukemia and Persistently Detectable Minimal Residual Disease

NCT03516279

Description:

This phase II trial studies how well pembrolizumab and dasatinib, imatinib mesylate, or nilotinib 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. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of cancer cells to grow and spread. Dasatinib, imatinib mesylate, and nilotinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving pembrolizumab and dasatinib, imatinib mesylate, or nilotinib may work better in treating patients with chronic myeloid leukemia.

Related Conditions:
  • Chronic Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pembrolizumab and Dasatinib, Imatinib Mesylate, or Nilotinib in Treating Patients With Chronic Myeloid Leukemia and Persistently Detectable Minimal Residual Disease
  • Official Title: Phase II Study of Adding the Anti-PD-1 Pembrolizumab to Tyrosine Kinase Inhibitors in Patients With Chronic Myeloid Leukemia and Persistently Detectable Minimal Residual Disease

Clinical Trial IDs

  • ORG STUDY ID: EA9171
  • SECONDARY ID: NCI-2017-02161
  • SECONDARY ID: EA9171
  • SECONDARY ID: EA9171
  • SECONDARY ID: U10CA180820
  • NCT ID: NCT03516279

Conditions

  • Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive
  • Minimal Residual Disease

Interventions

DrugSynonymsArms
DasatinibBMS-354825, SprycelTreatment (pembrolizumab, dasatinib, imatinib, nilotinib)
Imatinib MesylateCGP 57148, CGP57148B, Gleevec, Glivec, STI 571, STI-571, STI571Treatment (pembrolizumab, dasatinib, imatinib, nilotinib)
NilotinibAMN 107, TasignaTreatment (pembrolizumab, dasatinib, imatinib, nilotinib)
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Treatment (pembrolizumab, dasatinib, imatinib, nilotinib)

Purpose

This phase II trial studies how well pembrolizumab and dasatinib, imatinib mesylate, or nilotinib 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. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of cancer cells to grow and spread. Dasatinib, imatinib mesylate, and nilotinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving pembrolizumab and dasatinib, imatinib mesylate, or nilotinib may work better in treating patients with chronic myeloid leukemia.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Assess the proportion of chronic myelogenous leukemia (CML) patients on stable-dose
      tyrosine kinase inhibitor (TKI) who convert to undetectable minimal residual disease (UMRD)
      (molecular response [MR]^4.5) during or within 2 years of initiating pembrolizumab therapy.

      SECONDARY OBJECTIVES:

      I. Among patients who have converted to UMRD (MR^4.5), assess the proportion of CML patients
      who maintain UMRD for 6 months and 12 months.

      II. Among patients who have converted to UMRD (MR^4.5), assess the proportion of CML patients
      who discontinue their TKI.

      III. Among patients who have converted to UMRD (MR^4.5), assess the proportion of CML
      patients who are UMRD and TKI-free at 2 years from first determined UMRD.

      IV. Assess the proportion of CML patients who develop grade 3 or 4 immune related adverse
      events related to pembrolizumab treatment during the first 2 years after registration (not
      including grade 3 events that respond to corticosteroids and improve to grade 1 or less
      within 4 weeks).

      OUTLINE:

      Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1 and dasatinib,
      imatinib mesylate, or nilotinib orally (PO) as clinically indicated per the treating
      physician. Treatment repeats every 21 days for up to 18 courses in the absence of disease
      progression or unacceptable toxicity. Patients with detectable MRD after course 18 continue
      pembrolizumab and dasatinib, imatinib mesylate, or nilotinib every 21 days for up to an
      additional 18 courses in the absence of disease progression or unacceptable toxicity.
      Patients with UMRD at any time before course 18 discontinue pembrolizumab after course 18 and
      continue dasatinib, imatinib mesylate, or nilotinib every 21 days for up to an additional 18
      courses in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 6 months for 6 years from
      the date of registration.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (pembrolizumab, dasatinib, imatinib, nilotinib)ExperimentalPatients receive pembrolizumab IV over 30 minutes on day 1 and dasatinib, imatinib mesylate, or nilotinib PO as clinically indicated per the treating physician. Treatment repeats every 21 days for up to 18 courses in the absence of disease progression or unacceptable toxicity. Patients with detectable MRD after course 18 continue pembrolizumab and dasatinib, imatinib mesylate, or nilotinib every 21 days for up to an additional 18 courses in the absence of disease progression or unacceptable toxicity. Patients with UMRD at any time before course 18 discontinue pembrolizumab after course 18 and continue dasatinib, imatinib mesylate, or nilotinib every 21 days for up to an additional 18 courses in the absence of disease progression or unacceptable toxicity.
  • Dasatinib
  • Imatinib Mesylate
  • Nilotinib
  • Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

          -  PREREGISTRATION (STEP 0): Patient has pathologically-confirmed chronic phase-CML on a
             first line TKI and must meet the following criteria:

               -  The patient has to be on first-line TKI therapy (the same TKI) for at least 2
                  years prior to pre-registration

               -  Has been in MMR (i.e. MR^3) but still have detectable BCR-ABL transcript by a
                  standard real-time quantitative polymerase chain reaction (RQ-PCR) assay with a
                  limit of detection (sensitivity) of 4.5 for at least 12 months from the first
                  documentation of the MMR

               -  Patient has not achieved MR^4.5 (complete molecular remission [CMR]) within the
                  time of initiation of TKI therapy and pre-registration

          -  PREREGISTRATION (STEP 0): Patient must be scheduled to undergo a standard of care bone
             marrow biopsy within 7 days of step 0 registration

          -  PREREGISTRATION (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 patient?s eligibility for registration to Step 1; Fred
             Hutchinson will forward results within 1-2 business days of receipt of the peripheral
             blood to the submitting institution

          -  REGISTRATION TO TREATMENT (STEP 1): Institution has received central BCR-ABL test
             results confirming MRD positive status

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

          -  REGISTRATION TO TREATMENT (STEP 1): 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 1): 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

          -  REGISTRATION TO TREATMENT (STEP 1): 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)

          -  REGISTRATION TO TREATMENT (STEP 1): Women must not be pregnant or breastfeeding;
             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 72 hours prior to receiving the first dose of pembrolizumab;
             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 not undergone a hysterectomy or bilateral oophorectomy; or
             2) has not been naturally postmenopausal 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 use an accepted and effective method of contraception or to abstain
             from sexual from time of registration, while on study treatment, and continue for 120
             days after the last dose of study treatment

          -  REGISTRATION TO TREATMENT (STEP 1): Patients must have been on a stable dose of the
             TKI for the last 3 months prior to pre-registration

          -  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 the
             first dose of treatment

          -  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 study registration or have not
             recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents
             administered more than 4 weeks earlier

          -  REGISTRATION TO TREATMENT (STEP 1): 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 study registration; 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

          -  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 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

          -  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 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

          -  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 trial

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

          -  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/mm3.

          -  REGISTRATION TO TREATMENT (STEP 1): Patients 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 1): Patients must not have 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 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 1): Absolute neutrophil count (ANC) >= 1,500 /mcL,
             within 14 days prior to first dose of pembrolizumab

          -  REGISTRATION TO TREATMENT (STEP 1): Platelet count >= 100,000 /mcL, within 14 days
             prior to first dose of pembrolizumab

          -  REGISTRATION TO TREATMENT (STEP 1): Hemoglobin (Hgb) >= 9 g/dL OR >= 5.6 mmol/L
             without transfusion of erythropoietin (EPO) dependency, within 14 days prior to first
             dose of pembrolizumab

          -  REGISTRATION TO TREATMENT (STEP 1): 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, within 14 days prior to first dose of
             pembrolizumab

          -  REGISTRATION TO TREATMENT (STEP 1): Serum total bilirubin =< 1.5 X ULN OR direct
             bilirubin

             =< ULN for subjects with total bilirubin levels > 1.5 X ULN, within 14 days prior to
             first dose of pembrolizumab

          -  REGISTRATION TO TREATMENT (STEP 1): Aspartate aminotransferase (AST) (serum glutamic
             oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic
             pyruvic transaminase [SGPT]) =< 2.5 X ULN OR =< 5 X ULN for subjects with liver
             metastases, within 14 days prior to first dose of pembrolizumab

          -  REGISTRATION TO TREATMENT (STEP 1): 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.

          -  REGISTRATION TO TREATMENT (STEP 1): Patients should not have received prior allogeneic
             transplant.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Proportion of patients on tyrosine kinase inhibitor (TKI) who convert to undetectable minimal residual disease (UMRD)
Time Frame:Up to 2 years of initiating pembrolizumab
Safety Issue:
Description:Will be reported with exact confidence intervals. The binomial test will be used to test the null hypothesis that this proportion is 0.2 with the alternative hypothesis being that this proportion is greater than 0.2.

Secondary Outcome Measures

Measure:Proportion of patients who maintain UMRD for 6 months
Time Frame:Up to 6 years
Safety Issue:
Description:Will be assessed among patients who achieve UMRD within two years of initiating pembrolizumab. The proportions will be reported with exact confidence intervals.
Measure:Proportion of patients who maintain UMRD for 6 and 12 months
Time Frame:Up to 6 years
Safety Issue:
Description:Will be assessed among patients who achieve UMRD within two years of initiating pembrolizumab. The proportions will be reported with exact confidence intervals.
Measure:Proportion of patients who meet the criteria for discontinuing TKI
Time Frame:Up to 6 years
Safety Issue:
Description:Will be assessed among patients who achieve and maintain UMRD within two years of initiating pembrolizumab. The proportions will be reported with exact confidence intervals.
Measure:Proportion of patients who maintain UMRD for 2 years after first achieving UMRD
Time Frame:Up to 6 years
Safety Issue:
Description:Will be assessed among patients who have converted to UMRD (molecular response [MR]^4.5) and discontinued TKI. The proportions will be reported with exact confidence intervals.
Measure:Proportion of patients who develop grade 3 or 4 immune related adverse events (not including grade 3 events that respond to corticosteroids and improve to grade 1 or less within 4 weeks)
Time Frame:Up to 6 years
Safety Issue:
Description:Will be tabulated based on grade Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:ECOG-ACRIN Cancer Research Group

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