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

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ClinicalTrials.gov Identifier: NCT03516279
Recruitment Status : Recruiting
First Posted : May 4, 2018
Last Update Posted : January 1, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Eastern Cooperative Oncology Group ( ECOG-ACRIN Cancer Research Group )

Tracking Information
First Submitted Date  ICMJE April 24, 2018
First Posted Date  ICMJE May 4, 2018
Last Update Posted Date January 1, 2019
Actual Study Start Date  ICMJE October 3, 2018
Estimated Primary Completion Date August 31, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 24, 2018)
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 ]
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03516279 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: April 24, 2018)
  • Proportion of patients who maintain UMRD for 6 months [ Time Frame: Up to 6 years ]
    Will be assessed among patients who achieve UMRD within two years of initiating pembrolizumab. The proportions will be reported with exact confidence intervals.
  • Proportion of patients who maintain UMRD for 6 and 12 months [ Time Frame: Up to 6 years ]
    Will be assessed among patients who achieve UMRD within two years of initiating pembrolizumab. The proportions will be reported with exact confidence intervals.
  • Proportion of patients who meet the criteria for discontinuing TKI [ Time Frame: Up to 6 years ]
    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.
  • Proportion of patients who maintain UMRD for 2 years after first achieving UMRD [ Time Frame: Up to 6 years ]
    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.
  • 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 ]
    Will be tabulated based on grade Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Pembrolizumab and Dasatinib, Imatinib Mesylate, or Nilotinib in Treating Patients With Chronic Myeloid Leukemia and Persistently Detectable Minimal Residual Disease
Official Title  ICMJE 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
Brief Summary 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive
  • Minimal Residual Disease
Intervention  ICMJE
  • Drug: Dasatinib
    Given PO
    Other Names:
    • BMS-354825
    • Sprycel
  • Drug: Imatinib Mesylate
    Given PO
    Other Names:
    • CGP 57148
    • CGP57148B
    • Gleevec
    • Glivec
    • STI 571
    • STI-571
    • STI571
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Drug: Nilotinib
    Given PO
    Other Names:
    • AMN 107
    • Tasigna
  • Biological: Pembrolizumab
    Given IV
    Other Names:
    • Keytruda
    • Lambrolizumab
    • MK-3475
    • SCH 900475
Study Arms  ICMJE Experimental: Treatment (pembrolizumab, dasatinib, imatinib, nilotinib)
Patients 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.
Interventions:
  • Drug: Dasatinib
  • Drug: Imatinib Mesylate
  • Other: Laboratory Biomarker Analysis
  • Drug: Nilotinib
  • Biological: Pembrolizumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 24, 2018)
40
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE August 31, 2031
Estimated Primary Completion Date August 31, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03516279
Other Study ID Numbers  ICMJE EA9171
NCI-2017-02161 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
EA9171 ( Other Identifier: ECOG-ACRIN Cancer Research Group )
EA9171 ( Other Identifier: CTEP )
U10CA180820 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Eastern Cooperative Oncology Group ( ECOG-ACRIN Cancer Research Group )
Study Sponsor  ICMJE ECOG-ACRIN Cancer Research Group
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Amer Zeidan ECOG-ACRIN Cancer Research Group
PRS Account Eastern Cooperative Oncology Group
Verification Date December 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP