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A Phase 1B Study to Investigate the Safety and Preliminary Efficacy for the Combination of Dasatinib Plus Nivolumab in Patients With Chronic Myeloid Leukemia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02011945
Recruitment Status : Completed
First Posted : December 16, 2013
Results First Posted : February 17, 2020
Last Update Posted : March 18, 2020
Sponsor:
Information provided by (Responsible Party):
Bristol-Myers Squibb

Brief Summary:
The purpose of this study is to find a dose of Nivolumab that can be safely added to Dasatinib in patients with Chronic Myeloid Leukemia.

Condition or disease Intervention/treatment Phase
Chronic Myeloid Leukemia Drug: Dasatinib Drug: Nivolumab Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 35 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1B Dose Escalation Study to Investigate the Safety, Tolerability and Preliminary Efficacy for the Combination Dasatinib (BMS-354825) Plus Nivolumab (BMS-936558) in Patients Chronic Myeloid Leukemia (CML)
Actual Study Start Date : February 7, 2014
Actual Primary Completion Date : December 26, 2018
Actual Study Completion Date : December 26, 2018


Arm Intervention/treatment
Experimental: dasatinib Only
dasatinib 100 mg QD(CP) or 140 mg QD (AP)
Drug: Dasatinib
Other Name: BMS-354825

Experimental: Dose Level 1
Nivolumab 1 mg/kg q 2 weeks + dasatinib 100 mg QD (CP) or 140 mg QD (AP)
Drug: Dasatinib
Other Name: BMS-354825

Drug: Nivolumab
Other Name: BMS-936558

Experimental: Dose Level 2
Nivolumab 3 mg/kg q 2 weeks + dasatinib 100 mg QD (CP) or 140 mg QD (AP)
Drug: Dasatinib
Other Name: BMS-354825

Drug: Nivolumab
Other Name: BMS-936558




Primary Outcome Measures :
  1. Incidence of Dose Limiting Toxicities (DLT) [ Time Frame: Week 3 to week 6 ]

    DLT will be determined based on the incidence and intensity of drug related adverse events (AEs). The following drug-related AEs (whether related to one or both agents) occurring during the first 6 weeks of combined treatment with both dasatinib plus nivolumab (ie, Weeks 3 to 8, inclusive) would be considered DLTs:

    • Grade 4 hematologic AE lasting > 7 days despite appropriate medical intervention, except as noted below;
    • Grade 3 or Grade 4 nonhematologic AE irrespective of duration;
    • Grade 2 nonhematologic AE lasting > 7 days despite appropriate medical intervention (exception: asymptomatic laboratory values of Grade 2 which do not require medical intervention);
    • Any toxicity managed by discontinuation of nivolumab;
    • Grade ≥ 2 AE not controlled by medical intervention and requiring dasatinib treatment interruption for > 28 consecutive days;
    • Grade ≥ 2 AE not controlled by medical intervention and requiring missing 2 consecutive doses of nivolumab.

  2. Incidence of Adverse Events (AEs) [ Time Frame: Initiation of study drug to discontinuation of nivolumab stop date + 100 days or discontinuation of dasatinib + 30 days ]
    Any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation subject administered an investigational (medicinal) product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of investigational product, whether or not considered related to the investigational product.

  3. Incidence of Serious Adverse Events (SAEs) [ Time Frame: Initiation of study drug to within 100 days of discontinuation of nivolumab dosing and 30 days of dasatinib dosing ]
    Any untoward medical occurrence that at any dose: results in death, is life threatening, requires in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is a important medical event.Requires inpatient hospitalization or causes prolongation of existing hospitalization, results.

  4. Incidence of Change From Baseline in Clinical Laboratory Tests: Hematology [ Time Frame: Up to 40 Months ]
    The number of participants with a shift in laboratory test results from baseline to Grade 3-4 in hematology

  5. Incidence of Abnormalities in Clinical Laboratory Tests: Liver Tests [ Time Frame: Up to 40 Months ]

    The number of participants with an abnormal Liver function test.

    Aspartate aminotransferase (AST) Alanine aminotransferase (ALT) Upper Limit of Normal (ULN)


  6. Incidence of Laboratory Abnormalities in Specific Thyroid Tests [ Time Frame: Up to 40 Months ]
    Free T3 (FT3) Free T4 (FT4) Lower Limit of Normal (LLN)


Secondary Outcome Measures :
  1. Rate of Major Molecular Response (MMR) : Chronic Myelogenous Leukemia - Chronic Phase (CML-CP), No Prior Dasatinib Participants [ Time Frame: upto 36 Months ]

    Molecular response was assessed using BCR-ABL transcript levels measurement by real-time quantitative polymerase chain reaction (RQ-PCR).

    MMR is defined as ≥ 3-log reduction in BCR-ABL transcripts or a ratio of ≤ 0.1% on the International Scale (IS).


  2. Rate of Major Molecular Response (MMR) : Chronic Myelogenous Leukemia - Chronic Phase (CML-CP), Prior Dasatinib Participants [ Time Frame: upto 36 Months ]

    Molecular response was assessed using BCR-ABL transcript levels measurement by real-time quantitative polymerase chain reaction (RQ-PCR).

    MMR is defined as ≥ 3-log reduction in BCR-ABL transcripts or a ratio of ≤ 0.1% on the International Scale (IS).


  3. Rate of Major Molecular Response (MMR) : Chronic Myelogenous Leukemia - Advanced Phase (CML-AP) Participants [ Time Frame: upto 36 Months ]

    Molecular response was assessed using BCR-ABL transcript levels measurement by real-time quantitative polymerase chain reaction (RQ-PCR).

    MMR is defined as ≥ 3-log reduction in BCR-ABL transcripts or a ratio of ≤ 0.1% on the International Scale (IS).


  4. Rate of Molecular Response 4.5 (MR4.5) : Chronic Myelogenous Leukemia - Chronic Phase (CML-CP), No Prior Dasatinib Participants [ Time Frame: upto 36 Months ]

    Molecular response was assessed using BCR-ABL transcript levels measurement by real-time quantitative polymerase chain reaction (RQ-PCR).

    A molecular response 4.5 (MR4.5) was defined as ≥ 4.5-log reduction in BCR-ABL transcripts or a ratio of ≤ 0.00316% on the International Scale (IS).


  5. Rate of Molecular Response 4.5 (MR4.5) : Chronic Myelogenous Leukemia - Chronic Phase (CML-CP), Prior Dasatinib Participants [ Time Frame: upto 36 Months ]

    Molecular response was assessed using BCR-ABL transcript levels measurement by real-time quantitative polymerase chain reaction (RQ-PCR).

    A molecular response 4.5 (MR4.5) was defined as ≥ 4.5-log reduction in BCR-ABL transcripts or a ratio of ≤ 0.00316% on the International Scale (IS).


  6. Rate of Molecular Response 4.5 (MR4.5) : Chronic Myelogenous Leukemia - Advanced Phase (CML-AP) Participants [ Time Frame: upto 36 Months ]

    Molecular response was assessed using BCR-ABL transcript levels measurement by real-time quantitative polymerase chain reaction (RQ-PCR).

    A molecular response 4.5 (MR4.5) was defined as ≥ 4.5-log reduction in BCR-ABL transcripts or a ratio of ≤ 0.00316% on the International Scale (IS).


  7. Time to Major Molecular Response (MMR) - CML-CP No Prior Dasatinib Participants [ Time Frame: Up to 36 Months ]
    measured from the date of first dosing until measurement criteria are first met for MMR. The participants who do not respond will be censored on the date of their last molecular assessment. It is defined for all treated participants.

  8. Time to Major Molecular Response (MMR) - CML-CP Prior Dasatinib Participants [ Time Frame: Up to 36 Months ]
    measured from the date of first dosing until measurement criteria are first met for MMR. The participants who do not respond will be censored on the date of their last molecular assessment. It is defined for all treated participants.

  9. Time to Major Molecular Response (MMR) - CML-AP Participants [ Time Frame: Up to 36 Months ]
    measured from the date of first dosing until measurement criteria are first met for MMR. The participants who do not respond will be censored on the date of their last molecular assessment. It is defined for all treated participants.

  10. Duration of Major Molecular Response (MMR) - CML-CP No Prior Dasatinib Participants [ Time Frame: Up to 36 Months ]
    will be computed for participants who have achieved MMR. It will be defined as the time from the first assessment in which MMR, is documented until the first assessment at which disease progression (or confirmed loss of MMR) is documented. Participants who neither progress nor die will be censored on the date of their last molecular assessment

  11. Duration of Major Molecular Response (MMR) - CML-CP Prior Dasatinib Participants [ Time Frame: Up to 36 Months ]
    will be computed for participants who have achieved MMR. It will be defined as the time from the first assessment in which MMR, is documented until the first assessment at which disease progression (or confirmed loss of MMR) is documented. Participants who neither progress nor die will be censored on the date of their last molecular assessment

  12. Duration of Major Molecular Response (MMR) - CML-AP Participants [ Time Frame: Up to 36 Months ]
    will be computed for participants who have achieved MMR. It will be defined as the time from the first assessment in which MMR, is documented until the first assessment at which disease progression (or confirmed loss of MMR) is documented. Participants who neither progress nor die will be censored on the date of their last molecular assessment

  13. Time to Molecular Response 4.5(MR4.5) - CML-CP No Prior Dasatinib Participants [ Time Frame: Up to 36 Months ]
    measured from the date of first dosing until measurement criteria are first met for MR4.5. The participants who do not respond will be censored on the date of their last molecular assessment. It is defined for all treated participants.

  14. Time to Molecular Response 4.5(MR4.5) - CML-CP Prior Dasatinib Participants [ Time Frame: Up to 36 Months ]
    measured from the date of first dosing until measurement criteria are first met for MR4.5. The participants who do not respond will be censored on the date of their last molecular assessment. It is defined for all treated participants.

  15. Time to Molecular Response 4.5(MR4.5) - CML-AP Participants [ Time Frame: Up to 36 Months ]
    measured from the date of first dosing until measurement criteria are first met for MR4.5. The participants who do not respond will be censored on the date of their last molecular assessment. It is defined for all treated participants.

  16. Duration of Molecular Response 4.5 (MR4.5) - CML-CP No Prior Dasatinib Participants [ Time Frame: Up to 36 Months ]
    will be computed for participants who have achieved MR4.5. It will be defined as the time from the first assessment in which MR4.5, is documented until the first assessment at which disease progression (or confirmed loss of MR4.5 documented. Participants who neither progress nor die will be censored on the date of their last molecular assessment

  17. Duration of Molecular Response 4.5 (MR4.5) - CML-CP Prior Dasatinib Participants [ Time Frame: Up to 36 Months ]
    will be computed for participants who have achieved MR4.5. It will be defined as the time from the first assessment in which MR4.5, is documented until the first assessment at which disease progression (or confirmed loss of MR4.5 documented. Participants who neither progress nor die will be censored on the date of their last molecular assessment

  18. Duration of Molecular Response 4.5 (MR4.5) - CML-AP Participants [ Time Frame: Up to 36 Months ]
    will be computed for participants who have achieved MR4.5. It will be defined as the time from the first assessment in which MR4.5, is documented until the first assessment at which disease progression (or confirmed loss of MR4.5 documented. Participants who neither progress nor die will be censored on the date of their last molecular assessment



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com.

Inclusion Criteria:

  • Confirmed diagnosis of Chronic Myeloid Leukemia in Chronic Phase or Accelerated Phase :

    • With historically documented Ph+ cells
    • ≥2 prior Tyrosine Kinase Inhibitors (TKI) therapies for CML
    • Currently progressing, resistance to or with a suboptimal response to their most recent therapy
  • Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Score 0 - 1

Exclusion Criteria:

  • Blast phase CML
  • Known Abl-kinase mutation resistant to Dasatinib (e.g. T315I or T315A)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02011945


Locations
Show Show 21 study locations
Sponsors and Collaborators
Bristol-Myers Squibb
Investigators
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Study Director: Bristol-Myers Squibb Bristol-Myers Squibb
  Study Documents (Full-Text)

Documents provided by Bristol-Myers Squibb:
Statistical Analysis Plan  [PDF] June 30, 2015
Study Protocol  [PDF] October 13, 2016


Additional Information:
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Responsible Party: Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT02011945    
Other Study ID Numbers: CA180-373
2013-002156-33 ( EudraCT Number )
First Posted: December 16, 2013    Key Record Dates
Results First Posted: February 17, 2020
Last Update Posted: March 18, 2020
Last Verified: February 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Neoplasms by Histologic Type
Neoplasms
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Nivolumab
Dasatinib
Antineoplastic Agents, Immunological
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action