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

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)

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.

Study Overview

• Status: Completed
• Conditions: Chronic Myeloid Leukemia
• Intervention / Treatment: Drug: Dasatinib; Drug: Nivolumab

• Study Type: Interventional
• Enrollment (Actual): 35
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • St Leonards, New South Wales, Australia, 2065
      • Local Institution
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Local Institution
  • Victoria
    • Parkville, Victoria, Australia, 3050
      • Local Institution
• Canada
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 2Y9
      • QEII Health Sciences Centre-VG Site
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret Cancer Centre
  • Quebec
    • Montreal, Quebec, Canada, H1T 2M4
      • Hôpital Maisonneuve-Rosemont
• France
  • Bordeaux, France, 33000
    • Local Institution
• Germany
  • Berlin, Germany, 13353
    • Campus Virchow Klinikum Der Charite
  • Bonn, Germany, 53127
    • Universitaetsklinikum Bonn
  • Dresden, Germany, 01307
    • Universitaetsklinikum Carl Gustav Carus
  • Frankfurt am Main, Germany, 60590
    • Universitaetsklinik Frankfurt
• Italy
  • Napoli, Italy, 80131
    • Local Institution
  • Orbassano, Italy, 10043
    • Local Institution
  • Roma, Italy, 00161
    • Local Institution
• Spain
  • Madrid, Spain, 28047
    • Local Institution
  • Valencia, Spain, 46010
    • Local Institution
• United States
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Winship Cancer Institute
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute.
  • Texas
    • Dallas, Texas, United States, 75390
      • UT Southwestern Medical Center at Dallas
    • Houston, Texas, United States, 77030
      • The University of Texas MD Anderson Cancer Center
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Froedtert Hospital & Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: dasatinib Only; dasatinib 100 mg QD(CP) or 140 mg QD (AP)	Drug: Dasatinib; Other Names: 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 Names: BMS-354825; Drug: Nivolumab; Other Names: 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 Names: BMS-354825; Drug: Nivolumab; Other Names: BMS-936558

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb

Publications and helpful links

Helpful Links

• BMS Clinical Trial Information
• BMS Clinical Trial Patient Recruiting
• FDA Safety Alerts and Recalls

Study record dates

Study Major Dates

• Study Start (ACTUAL): February 7, 2014
• Primary Completion (ACTUAL): December 26, 2018
• Study Completion (ACTUAL): December 26, 2018

Study Registration Dates

• First Submitted: November 21, 2013
• First Submitted That Met QC Criteria: December 10, 2013
• First Posted (ESTIMATE): December 16, 2013

Study Record Updates

• Last Update Posted (ACTUAL): March 18, 2020
• Last Update Submitted That Met QC Criteria: March 4, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Immunological; Protein Kinase Inhibitors; Immune Checkpoint Inhibitors; Nivolumab; Dasatinib
• Other Study ID Numbers: CA180-373; 2013-002156-33 (EUDRACT_NUMBER)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No