First in Human Study to Determine the Safety, Tolerability and Preliminary Efficacy of an Anti-CXCR4 Antibody in Subjects With Acute Myelogenous Leukemia and Selected B-cell Cancers

Phase 1

Completed

• Conditions: Chronic Lymphocytic Leukemia; Follicular Lymphoma; Acute Myelogenous Leukemia; Diffuse Large B-Cell Leukemia
• Interventions: Drug: BMS-936564 (Anti-CXCR4)

• Registration Number: NCT01120457
• Lead Sponsor: Bristol-Myers Squibb

Brief Summary

The purpose of this study is to assess the safety and tolerability of BMS-936564 (MDX-1338) in relapsed Acute myelogenous leukemia (AML) and other selected B-cell cancers and to determine the maximum tolerated dose (MTD) of the drug alone in relapsed/refractory AML

Detailed Description

Not available

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2010-05-07
• Study First Submitted QC: 2010-05-10
• Study First Posted: 2010-05-11
• Study Start: 2010-08
• Primary Completion: 2014-11
• Study Completion: 2014-11
• Status Verified: 2015-01
• Last Update Submitted: 2015-03-05
• Last Update Posted: 2015-03-06

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 96

Inclusion Criteria

A. Common to All Indications:

• Life expectancy at least 12 weeks
• ECOG Performance Status of 0-2

B. For Acute myelogenous leukemia (AML) Subjects:

• First Relapse and primary induction failure in AML (M3 excluded)
• Secondary AML subjects from myelodysplastic syndrome (MDS) or prior chemotherapy are eligible. MDS-only subjects are not eligible

C. For Follicular Lymphoma (FL), Diffuse Large B-Cell Lymphoma (DLBCL) Subjects:

• Must be at least 4 weeks (for FL) or 2 weeks (for DLBCL) since prior cytotoxic, biologic, monoclonal antibody, or investigational therapy
• Ability to undergo tumor biopsy pre-treatment and at end of monotherapy period (though not mandatory for all subjects)
• Subjects must have a histologically confirmed diagnosis of relapsed or refractory disease

D. For Chronic lymphocytic leukemia (CLL) Subjects:

• Subjects must have a histologically confirmed diagnosis of relapsed or refractory disease
• Must be at least 4 weeks since prior cytotoxic, biologic, monoclonal antibody, or investigational therapy, including corticosteroids

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Exclusion Criteria

A. Common to All indications:

• Prior anti-CXCR4 therapy including BMS-936564 (MDX-1338)
• Less than 3 months from prior hematopoietic stem cell transplant
• Presence of active graft versus host disease

B. For AML Subjects:

• Acute promyelocytic leukemia (M3)
• Left ventricular ejection fraction < institutional limits of normal

C. For FL, DLBCL Subjects:

• (For DLBCL): Inadequate renal function defined as creatinine clearance (by Cockcroft-Gault formula) < 60 mL/min
• Major surgery, not related to debulking procedures, within 21 days of first dose
• Myocardial infarction within 6 months prior to screening or Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia
• Myelodysplastic syndrome (MDS)

D. For CLL Subjects:

• No progression to more aggressive B-cell cancers, such as Richter's syndrome
• Major surgery within 21 days of Cycle 1, Day 1. Patients undergoing debulking procedures and minor surgery are allowed after a recovery period, in the judgment of the Investigator
• Myocardial infarction within 6 months prior to screening Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm 4: Dose Expansion cohort (FL Patient)	BMS-936564 (Anti-CXCR4)	BMS-936564 MTD based on Arm 1, weekly 60 minute infusion in cycle 1 (up to 56 days) and with chemotherapy for subsequent cycles (28 days/cycle)
Arm 3: Dose Expansion cohort (CLL Patient)	BMS-936564 (Anti-CXCR4)	BMS-936564 MTD based on Arm 1, weekly 60 minute infusion in cycle 1 (up to 56 days) and with chemotherapy for subsequent cycles (28 days/cycle)
Arm 1: Dose Escalation and Expansion cohort (AML Patients)	BMS-936564 (Anti-CXCR4)	Dose Escalation: BMS-936564 0.3-10 mg/kg solution, Intravenous, Single 60 minute infusion as monotherapy 7 days/cycle 1 and with chemotherapy for subsequent cycles (28 days/cycle) Dose Expansion: BMS-936564 maximum tolerated dose (MTD) based on dose escalation, solution, Intravenous, Single 60 minute infusion as monotherapy 7 days/cycle 1 and with chemotherapy for subsequent cycles (28 days/cycle)
Arm 2: Dose Expansion cohort (DLBCL Patient)	BMS-936564 (Anti-CXCR4)	BMS-936564 MTD based on Arm 1, weekly 60 minute infusion in cycle 1 (up to 56 days) and with chemotherapy for subsequent cycles (28 days/cycle)

Primary Outcome Measures

Name	Time	Method
Safety and tolerability as monotherapy	Within 28 days for the selected B-cell malignancies	Safety and tolerability measured by incidence of adverse events (AEs), AEs leading to discontinuation, Serious Adverse Events (SAEs), deaths, and laboratory abnormalities

Secondary Outcome Measures

Name	Time	Method
Trough observed serum concentration (Cmin) of BMS-936564 (MDX-1338) will be derived from serum concentration versus actual time	For a maximum of thirteen 28-day cycles for the AML cohort and for a maximum of six 28-day cycles for the B-cell malignancies
Area under the concentration-time curve from time zero extrapolated to infinite time [AUC(INF)] of BMS-936564 (MDX-1338) will be derived from serum concentration versus actual time	For a maximum of thirteen 28-day cycles for the AML cohort and for a maximum of six 28-day cycles for the B-cell malignancies
Safety, as measured by vital signs, clinical laboratory tests,ECOG performance status, physical exams, 12 lead ECGs incidence and severity of adverse events	For a maximum of thirteen 28-day cycles for the AML cohort and for a maximum of six 28-day cycles for the B-cell malignancies	ECOG - Eastern Cooperative Oncology Group ECG - Electrocardiograms
Efficacy- including best overall response (BOR) derived from changes in tumor burden and metabolic response based on FDG-PET (for DLBCL)	For a maximum of thirteen 28-day cycles for the AML cohort and for a maximum of six 28-day cycles for the B-cell malignancies	FDG-PET - fluoro-2-deoxyglucose positron emission tomography DLBCL - Diffuse Large B-Cell Lymphoma
Area under the concentration-time curve from time zero to the time of the last quantifiable concentration [AUC(0-T)] of BMS-936564 (MDX-1338) will be derived from serum concentration versus actual time	For a maximum of thirteen 28-day cycles for the AML cohort and for a maximum of six 28-day cycles for the B-cell malignancies
Maximum observed serum concentration (Cmax) of BMS-936564 (MDX-1338) will be derived from serum concentration versus actual time	For a maximum of thirteen 28-day cycles for the AML cohort and for a maximum of six 28-day cycles for the B-cell malignancies
Time of maximum observed concentration (Tmax) of BMS-936564 (MDX-1338) will be derived from serum concentration versus actual time	For a maximum of thirteen 28-day cycles for the AML cohort and for a maximum of six 28-day cycles for the B-cell malignancies
Biomarker- characterizing the pharmacodynamic (PD) profiles of BMS-936564 (MDX-1338). The main PD biomarkers are cell trafficking	For a maximum of thirteen 28-day cycles for the AML cohort and for a maximum of six 28-day cycles for the B-cell malignancies
Immunogenicity measurement for human anti human antibodies (HAHA) -characterizing the immunogenicity of BMS-936564	For a maximum of thirteen 28-day cycles for the AML cohort and for a maximum of six 28-day cycles for the B-cell malignancies	Subjects will be called as immunogenicity positive/negative to antibodies against BMS-936564 (MDX-1338) using immunogenicity assay, and will be classified as negative, positive baseline, or negative baseline with at least one positive post-treatment. The number and percentage of subjects in each classification will be reported for each dose level.
Area under the concentration-time curve in one dosing interval [AUC(TAU)] of BMS-936564 (MDX-1338) will be derived from serum concentration versus actual time	For a maximum of thirteen 28-day cycles for the AML cohort and for a maximum of six 28-day cycles for the B-cell malignancies
Half life (T-HALF) of BMS-936564 (MDX-1338) will be derived from serum concentration versus actual time	For a maximum of thirteen 28-day cycles for the AML cohort and for a maximum of six 28-day cycles for the B-cell malignancies
Exploratory Biomarkers- are detection of apoptosis, cytokine analyses, CXCR4 expression, ZAP-70 and CD38 expression	For a maximum of thirteen 28-day cycles for the AML cohort and for a maximum of six 28-day cycles for the B-cell malignancies
Total body clearance(CLT) of BMS-936564 (MDX-1338) will be derived from serum concentration versus actual time	For a maximum of thirteen 28-day cycles for the AML cohort and for a maximum of six 28-day cycles for the B-cell malignancies
Volume of distribution at steady-state (Vss) of BMS-936564 (MDX-1338) will be derived from serum concentration versus actual time	For a maximum of thirteen 28-day cycles for the AML cohort and for a maximum of six 28-day cycles for the B-cell malignancies

Trial Locations

Locations (11)

Ucla-Division Of Hematology/Oncology; 🇺🇸 Los Angeles, California, United States

The University Of Texas Md Anderson Cancer Center; 🇺🇸 Houston, Texas, United States

Uc San Diego Moores Cancer Center; 🇺🇸 La Jolla, California, United States

University Of Washington School Of Medicine; 🇺🇸 Seattle, Washington, United States

University Of Kansas Cancer Center And Medical Pavillion; 🇺🇸 Westwood, Kansas, United States

Uab Comprehensive Cancer Center; 🇺🇸 Birmingham, Alabama, United States

Usc - Norris Comprehensive Cancer Center And Hospital; 🇺🇸 Los Angeles, California, United States

Mayo Clinic; 🇺🇸 Jacksonville, Florida, United States

Northwestern University Feinberg School Of Medicine; 🇺🇸 Chicago, Illinois, United States

Dana-Farber Cancer Inst; 🇺🇸 Boston, Massachusetts, United States

B. Douglas Smith, M.D.; 🇺🇸 Baltimore, Maryland, United States