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

Study Overview
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Brief Summary
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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.

Official Title
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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)

Conditions
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Chronic Myeloid Leukemia

Intervention / Treatment
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* Drug: Dasatinib
* Drug: Nivolumab


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: dasatinib Only<br>dasatinib 100 mg QD(CP) or 140 mg QD (AP) | Drug: Dasatinib<br> <br> * Other names: BMS-354825;|
| Experimental: Dose Level 1<br>Nivolumab 1 mg/kg q 2 weeks + dasatinib 100 mg QD (CP) or 140 mg QD (AP) | Drug: Dasatinib<br> <br> * Other names: BMS-354825;Drug: Nivolumab<br> <br> * Other names: BMS-936558;|
| Experimental: Dose Level 2<br>Nivolumab 3 mg/kg q 2 weeks + dasatinib 100 mg QD (CP) or 140 mg QD (AP) | Drug: Dasatinib<br> <br> * Other names: BMS-354825;Drug: Nivolumab<br> <br> * Other names: BMS-936558;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Dose Limiting Toxicities (DLT) | 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. | Week 3 to week 6 | 
| Incidence of Adverse Events (AEs) | 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. | Initiation of study drug to discontinuation of nivolumab stop date + 100 days or discontinuation of dasatinib + 30 days | 
| Incidence of Serious Adverse Events (SAEs) | 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. | Initiation of study drug to within 100 days of discontinuation of nivolumab dosing and 30 days of dasatinib dosing | 
| Incidence of Change From Baseline in Clinical Laboratory Tests: Hematology | The number of participants with a shift in laboratory test results from baseline to Grade 3-4 in hematology | Up to 40 Months | 
| Incidence of Abnormalities in Clinical Laboratory Tests: Liver Tests | The number of participants with an abnormal Liver function test. Aspartate aminotransferase (AST) Alanine aminotransferase (ALT) Upper Limit of Normal (ULN) | Up to 40 Months | 
| Incidence of Laboratory Abnormalities in Specific Thyroid Tests | Free T3 (FT3) Free T4 (FT4) Lower Limit of Normal (LLN) | Up to 40 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Major Molecular Response (MMR) : Chronic Myelogenous Leukemia - Chronic Phase (CML-CP), No Prior Dasatinib Participants | 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). | upto 36 Months | 
| Rate of Major Molecular Response (MMR) : Chronic Myelogenous Leukemia - Chronic Phase (CML-CP), Prior Dasatinib Participants | 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). | upto 36 Months | 
| Rate of Major Molecular Response (MMR) : Chronic Myelogenous Leukemia - Advanced Phase (CML-AP) Participants | 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). | upto 36 Months | 
| Rate of Molecular Response 4.5 (MR4.5) : Chronic Myelogenous Leukemia - Chronic Phase (CML-CP), No Prior Dasatinib Participants | 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). | upto 36 Months | 
| Rate of Molecular Response 4.5 (MR4.5) : Chronic Myelogenous Leukemia - Chronic Phase (CML-CP), Prior Dasatinib Participants | 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). | upto 36 Months | 
| Rate of Molecular Response 4.5 (MR4.5) : Chronic Myelogenous Leukemia - Advanced Phase (CML-AP) Participants | 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). | upto 36 Months | 
| Time to Major Molecular Response (MMR) - CML-CP No Prior Dasatinib Participants | 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. | Up to 36 Months | 
| Time to Major Molecular Response (MMR) - CML-CP Prior Dasatinib Participants | 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. | Up to 36 Months | 
| Time to Major Molecular Response (MMR) - CML-AP Participants | 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. | Up to 36 Months | 
| Duration of Major Molecular Response (MMR) - CML-CP No Prior Dasatinib Participants | 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 | Up to 36 Months | 
| Duration of Major Molecular Response (MMR) - CML-CP Prior Dasatinib Participants | 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 | Up to 36 Months | 
| Duration of Major Molecular Response (MMR) - CML-AP Participants | 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 | Up to 36 Months | 
| Time to Molecular Response 4.5(MR4.5) - CML-CP No Prior Dasatinib Participants | 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. | Up to 36 Months | 
| Time to Molecular Response 4.5(MR4.5) - CML-CP Prior Dasatinib Participants | 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. | Up to 36 Months | 
| Time to Molecular Response 4.5(MR4.5) - CML-AP Participants | 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. | Up to 36 Months | 
| Duration of Molecular Response 4.5 (MR4.5) - CML-CP No Prior Dasatinib Participants | 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 | Up to 36 Months | 
| Duration of Molecular Response 4.5 (MR4.5) - CML-CP Prior Dasatinib Participants | 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 | Up to 36 Months | 
| Duration of Molecular Response 4.5 (MR4.5) - CML-AP Participants | 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 | Up to 36 Months |