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

Sponsor

Bristol-Myers Squibb (Industry)

Overall Status

Completed

CT.gov ID

NCT01120457

Collaborator

(none)

Enrollment

Locations

Arms

Duration (Months)

8.7

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

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

Condition or Disease	Intervention/Treatment	Phase
Acute Myelogenous Leukemia Diffuse Large B-Cell Leukemia Chronic Lymphocytic Leukemia Follicular Lymphoma	Drug: BMS-936564 (Anti-CXCR4)	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

96 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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 Start Date :

Aug 1, 2010

Actual Primary Completion Date :

Nov 1, 2014

Actual Study Completion Date :

Nov 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm 1: Dose Escalation and Expansion cohort (AML Patients) 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)	Drug: BMS-936564 (Anti-CXCR4) Other Names: MDX-1338
Experimental: Arm 2: Dose Expansion cohort (DLBCL Patient) 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)	Drug: BMS-936564 (Anti-CXCR4) Other Names: MDX-1338
Experimental: Arm 3: Dose Expansion cohort (CLL Patient) 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)	Drug: BMS-936564 (Anti-CXCR4) Other Names: MDX-1338
Experimental: Arm 4: Dose Expansion cohort (FL Patient) 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)	Drug: BMS-936564 (Anti-CXCR4) Other Names: MDX-1338

Outcome Measures

Primary Outcome Measures

Safety and tolerability as monotherapy [Within the first 7 days for AML]
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 [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

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
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.
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]
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]
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]
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]
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]
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]
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]
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]
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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Uab Comprehensive Cancer Center	Birmingham	Alabama	United States	35294
2	Uc San Diego Moores Cancer Center	La Jolla	California	United States	92093
3	Usc - Norris Comprehensive Cancer Center And Hospital	Los Angeles	California	United States	90033
4	Ucla-Division Of Hematology/Oncology	Los Angeles	California	United States	90095
5	Mayo Clinic	Jacksonville	Florida	United States	32224
6	Northwestern University Feinberg School Of Medicine	Chicago	Illinois	United States	60611
7	University Of Kansas Cancer Center And Medical Pavillion	Westwood	Kansas	United States	66205
8	B. Douglas Smith, M.D.	Baltimore	Maryland	United States	21287
9	Dana-Farber Cancer Inst	Boston	Massachusetts	United States	02215
10	The University Of Texas Md Anderson Cancer Center	Houston	Texas	United States	77030
11	University Of Washington School Of Medicine	Seattle	Washington	United States	98109