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

• Safety and tolerability as monotherapy [ Time Frame: Within the first 7 days for AML ] [ Designated as safety issue: Yes ]
  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 [ Time Frame: Within 28 days for the selected B-cell malignancies ] [ Designated as safety issue: Yes ]
  Safety and tolerability measured by incidence of adverse events (AEs), AEs leading to discontinuation, Serious Adverse Events (SAEs), deaths, and laboratory abnormalities

• Safety, as measured by vital signs, clinical laboratory tests,ECOG performance status, physical exams, 12 lead ECGs incidence and severity of adverse events [ Time Frame: 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 ] [ Designated as safety issue: Yes ]
  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) [ Time Frame: 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 ] [ Designated as safety issue: No ]
  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 [ Time Frame: 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 ] [ Designated as safety issue: No ]
  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 [ Time Frame: 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 ] [ Designated as safety issue: No ]
• Trough observed serum concentration (Cmin) of BMS-936564 (MDX-1338) will be derived from serum concentration versus actual time [ Time Frame: 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 ] [ Designated as safety issue: No ]
• Time of maximum observed concentration (Tmax) of BMS-936564 (MDX-1338) will be derived from serum concentration versus actual time [ Time Frame: 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 ] [ Designated as safety issue: No ]
• 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 [ Time Frame: 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 ] [ Designated as safety issue: No ]
• 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 [ Time Frame: 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 ] [ Designated as safety issue: No ]
• 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 [ Time Frame: 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 ] [ Designated as safety issue: No ]
• Half life (T-HALF) of BMS-936564 (MDX-1338) will be derived from serum concentration versus actual time [ Time Frame: 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 ] [ Designated as safety issue: No ]
• Total body clearance(CLT) of BMS-936564 (MDX-1338) will be derived from serum concentration versus actual time [ Time Frame: 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 ] [ Designated as safety issue: No ]
• Volume of distribution at steady-state (Vss) of BMS-936564 (MDX-1338) will be derived from serum concentration versus actual time [ Time Frame: 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 ] [ Designated as safety issue: No ]
• Biomarker- characterizing the pharmacodynamic (PD) profiles of BMS-936564 (MDX-1338). The main PD biomarkers are cell trafficking [ Time Frame: 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 ] [ Designated as safety issue: No ]
• Exploratory Biomarkers- are detection of apoptosis, cytokine analyses, CXCR4 expression, ZAP-70 and CD38 expression [ Time Frame: 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 ] [ Designated as safety issue: No ]

• Safety, as measured by vital signs, clinical laboratory tests, bone marrow tests, immunogenicity, ECOG performance status, physical exams, 12 lead ECGs incidence and severity of adverse events, and concomitant medications [ Time Frame: Up to 28 days from each treatment cycle ] [ Designated as safety issue: Yes ]
• Evaluate preliminary efficacy by Objective Response in subjects treated with MDX1338/BMS-936564 as monotherapy & in combination of chemotherapy. Leukemia response evaluated at the end of each cycle using AML International Working Group (IWG) 2003 [ Time Frame: Up to 28 days from each treatment cycle ] [ Designated as safety issue: Yes ]

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

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

• 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)

  Intervention: Drug: BMS-936564 (Anti-CXCR4)
• 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)
  Intervention: Drug: BMS-936564 (Anti-CXCR4)
• 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)
  Intervention: Drug: BMS-936564 (Anti-CXCR4)
• 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)
  Intervention: Drug: BMS-936564 (Anti-CXCR4)

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