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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

Primary Purpose

Acute Myelogenous Leukemia, Diffuse Large B-Cell Leukemia, Chronic Lymphocytic Leukemia

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

BMS-936564 (Anti-CXCR4)

About this trial

This is an interventional treatment trial for Acute Myelogenous Leukemia

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

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

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

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Arm Label

Arm 1: Dose Escalation and Expansion cohort (AML Patients)

Arm 2: Dose Expansion cohort (DLBCL Patient)

Arm 3: Dose Expansion cohort (CLL Patient)

Arm 4: Dose Expansion cohort (FL Patient)

Arm Description

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)

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)

Outcomes

Primary Outcome Measures

Safety and tolerability as monotherapy

Safety and tolerability measured by incidence of adverse events (AEs), AEs leading to discontinuation, Serious Adverse Events (SAEs), deaths, and laboratory abnormalities

Safety and tolerability as monotherapy

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

Safety, as measured by vital signs, clinical laboratory tests,ECOG performance status, physical exams, 12 lead ECGs incidence and severity of adverse events

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)

FDG-PET - fluoro-2-deoxyglucose positron emission tomography DLBCL - Diffuse Large B-Cell Lymphoma

Immunogenicity measurement for human anti human antibodies (HAHA) -characterizing the immunogenicity of BMS-936564

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.

Maximum observed serum concentration (Cmax) of BMS-936564 (MDX-1338) will be derived from serum concentration versus actual time

Trough observed serum concentration (Cmin) of BMS-936564 (MDX-1338) will be derived from serum concentration versus actual time

Time of maximum observed concentration (Tmax) of BMS-936564 (MDX-1338) will be derived from serum concentration versus actual time

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

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

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

Half life (T-HALF) of BMS-936564 (MDX-1338) will be derived from serum concentration versus actual time

Total body clearance(CLT) of BMS-936564 (MDX-1338) will be derived from serum concentration versus actual time

Volume of distribution at steady-state (Vss) of BMS-936564 (MDX-1338) will be derived from serum concentration versus actual time

Biomarker- characterizing the pharmacodynamic (PD) profiles of BMS-936564 (MDX-1338). The main PD biomarkers are cell trafficking

Exploratory Biomarkers- are detection of apoptosis, cytokine analyses, CXCR4 expression, ZAP-70 and CD38 expression

Full Information

NCT ID

NCT01120457

First Posted

May 7, 2010

Last Updated

March 5, 2015

Sponsor

Bristol-Myers Squibb

1. Study Identification

Unique Protocol Identification Number

NCT01120457

Brief Title

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

Official Title

A Phase 1, Open-label, Multicenter Study of BMS-936564 (MDX-1338) in Subjects With Relapsed Acute Myelogenous Leukemia and Selected B-cell Malignancies

Study Type

Interventional

2. Study Status

Record Verification Date

January 2015

Overall Recruitment Status

Completed

Study Start Date

August 2010 (undefined)

Primary Completion Date

November 2014 (Actual)

Study Completion Date

November 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Bristol-Myers Squibb

4. Oversight

Data Monitoring Committee

5. Study Description

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Acute Myelogenous Leukemia, Diffuse Large B-Cell Leukemia, Chronic Lymphocytic Leukemia, Follicular Lymphoma

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

96 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Arm 1: Dose Escalation and Expansion cohort (AML Patients)

Arm Type

Experimental

Arm Description

Arm Title

Arm 2: Dose Expansion cohort (DLBCL Patient)

Arm Type

Experimental

Arm Description

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 Title

Arm 3: Dose Expansion cohort (CLL Patient)

Arm Type

Experimental

Arm Description

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 Title

Arm 4: Dose Expansion cohort (FL Patient)

Arm Type

Experimental

Arm Description

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)

Intervention Type

Drug

Intervention Name(s)

BMS-936564 (Anti-CXCR4)

Other Intervention Name(s)

MDX-1338

Primary Outcome Measure Information:

Title

Safety and tolerability as monotherapy

Description

Safety and tolerability measured by incidence of adverse events (AEs), AEs leading to discontinuation, Serious Adverse Events (SAEs), deaths, and laboratory abnormalities

Time Frame

Within the first 7 days for AML

Title

Safety and tolerability as monotherapy

Description

Safety and tolerability measured by incidence of adverse events (AEs), AEs leading to discontinuation, Serious Adverse Events (SAEs), deaths, and laboratory abnormalities

Time Frame

Within 28 days for the selected B-cell malignancies

Secondary Outcome Measure Information:

Title

Safety, as measured by vital signs, clinical laboratory tests,ECOG performance status, physical exams, 12 lead ECGs incidence and severity of adverse events

Description

ECOG - Eastern Cooperative Oncology Group ECG - Electrocardiograms

Time Frame