Acute Myelogenous Leukemia, Chronic Lymphocytic Leukemia, Diffuse Large B-Cell Leukemia, Follicular Lymphoma
Conditions
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
Interventions
DRUGBMS-936564 (Anti-CXCR4)
Sponsors
Bristol-Myers Squibb
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | — |
| 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 |
| 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 | — |
| 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 | — |
Countries
United States
Outcome results
None listed