Safety Study of Anti-Programmed Death-Ligand 1 in Hematologic Malignancy

A Phase I Dose Escalation Study to Investigate the Safety, Pharmacokinetics, Immunoregulatory Activity, and Preliminary Antitumor Activity of Anti-Programmed-Death-Ligand 1 (PD-L1) Antibody (BMS-936559) in Subjects With Relapsed or Refractory Hematologic Malignancy

The purpose of this study is to determine the side effects of treatment with the monoclonal antibody anti-PD-L1 (BMS-936559) in subjects with compromised bone marrow function and the dose that should be recommended for use in future studies.

Study Overview

• Status: Withdrawn
• Conditions: Multiple Myeloma; Hodgkin Lymphoma; Non-Hodgkin's Lymphoma; Chronic Myelogenous Leukemia
• Intervention / Treatment: Biological: BMS-936559 (Anti PD-L1)

• Study Type: Interventional
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Eastern Cooperative Oncology Group (ECOG) Performance of 0 or 1
• Subjects must have histological confirmation of relapsed or refractory hematologic malignancy
• Subjects with non-Hodgkin's lymphoma or Hodgkin lymphoma must have at least one measureable lesion as defined by lymphoma response criteria. Tumor sites that are considered measureable must not have received prior radiation therapy
• Subjects with multiple myeloma (MM) must have detectable disease as measured by presence of monoclonal immunoglobulin protein in a serum electrophoresis: IgG, IgA, IgM, (M-protein ≥ 0.5 g/dl or serum IgD M-protein ≥ 0.05 g/dl) or serum free-light chain or 24 hour urine with free light chain. Excluded are subjects with only plasmacytomas, plasma cell leukemia, or non-secretory myeloma
• Subjects with chronic myelogenous leukemia (CML) must have evidence of the Philadelphia chromosome by polymerase chain reaction (PCR) or chromosome analysis
• Life expectancy of at least 3 months
• For subjects with lymphoma, either a formalin fixed tissue block or 7 to 15 slides of tumor sample (archival or fresh) must be available for performance of correlative studies
• Subjects must have received at least one prior chemotherapy regimen. Subjects must be off therapy for at least 4 weeks ( 2 weeks for oral agents) prior to Day 1
• Prior palliative radiation must have been completed at least 2 weeks prior to study Day 1
• Toxicities related to prior therapy must have returned to Grade 1 or less, except for alopecia. Peripheral neuropathy must be Grade 2 or less

• Adequate bone marrow function defined as:

  1. Absolute neutrophil count ≥ 1000/μl (stable off any growth factor within 1 week of study drug administration)
  2. Hemoglobin ≥ 9 g/dL (transfusion to achieve this level is permitted)
  3. Platelet count ≥ 50 X 103/ μl (transfusion to achieve this level is not permitted)
• Adequate renal parameters defined as Creatinine clearance (CrCl) > 40 ml/min (Cockcroft-Gault formula)

• Adequate hepatic parameters defined as:

  1. Aspartate aminotransferase (AST) ≤ 3 x ULN
  2. Alanine aminotransferase (ALT) ≤ 3 x ULN
  3. Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert's Syndrome, who must have total bilirubin < 3.0 mg/dL and direct bilirubin < 0.5 mg/dL)
• Women of child bearing potential (WOCBP) and for at least 70 days after the last dose of investigational product
• Men and women ≥ 18 years of age

Exclusion Criteria:

• Subjects with acute leukemias, blast phase CML, T cell lymphoblastic or Burkitt lymphoma
• Subjects with a history of central nervous system involvement by hematologic malignancy or symptoms suggestive of central nervous system involvement
• Subjects with concomitant second malignancies (except adequately treated nonmelanomatous skin cancers, ductal carcinoma in situ, treated superficial bladder cancer or prostate cancer or in situ cervical cancers) are excluded unless a complete remission was achieved at least 3 years prior to study entry and no additional therapy is required or anticipated to be required during the study period
• Subjects with any active autoimmune disease or a history of known or suspected autoimmune disease, or history of syndrome that requires systemic corticosteroids or immunosuppressive medications, except for subjects with vitiligo or resolved childhood asthma/atopy
• A serious uncontrolled medical disorder or active infection which would impair the ability of the subject to receive protocol therapy or whose control may be jeopardized by the complications of this therapy
• Prior therapy with an anti programmed death-1 (anti-PD-1), anti Programmed death ligand 1 (anti-PD-L1), anti Programmed death ligand 2 (anti-PD-L2), anti-CD137 or anti Cytotoxic T lymphocyte-associated antigen 4 (anti-CTLA-4) antibody (or any other antibody or drug specifically targeting T-cell costimulation or checkpoint pathways)
• Non-oncology vaccine therapies for prevention of infectious diseases (eg seasonal flu vaccine, Human Papilloma Virus (HPV) vaccine) within 4 weeks of study drug administration Vaccination while on study is also prohibited except for administration of the inactivated influenza vaccine
• Prior organ allograft or allogeneic bone marrow transplantation
• Positive for human immunodeficiency virus (HIV 1/2) or known acquired immunodeficiency syndrome (AIDS)
• Positive tests for hepatitis B virus surface antigen (HBsAg), or antibody to hepatitis B core Ag or hepatitis C virus antibody (confirmed by Western Blot) or hepatitis C ribonucleic acid (RNA) in serum
• Ejection fraction less than 45% in subjects with prior anthracycline exposure
• History of Grade 4 anaphylactic reaction to monoclonal antibody therapy
• Women who are pregnant or breastfeeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1: BMS-936559	Biological: BMS-936559 (Anti PD-L1); Injection for infusion, Intravenous (IV), 1, 3 or 10 mg/kg, Every 2 weeks, 48-96 weeks depending on response

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Safety and tolerability of BMS-936559 as measured by the incidence of adverse events (AEs), serious AEs, dose-limiting toxicities, laboratory test abnormalities, and changes in vital signs	Weeks 1
Safety and tolerability of BMS-936559 as measured by the incidence of adverse events (AEs), serious AEs, dose-limiting toxicities, laboratory test abnormalities, and changes in vital signs	Weeks 2
Safety and tolerability of BMS-936559 as measured by the incidence of adverse events (AEs), serious AEs, dose-limiting toxicities, laboratory test abnormalities, and changes in vital signs	Weeks 3
Safety and tolerability of BMS-936559 as measured by the incidence of adverse events (AEs), serious AEs, dose-limiting toxicities, laboratory test abnormalities, and changes in vital signs	Weeks 6
Safety and tolerability of BMS-936559 as measured by the incidence of adverse events (AEs), serious AEs, dose-limiting toxicities, laboratory test abnormalities, and changes in vital signs	Every 2 weeks until 70 days after last treatment

Secondary Outcome Measures

Outcome Measure	Time Frame
Pharmacokinetics of BMS-936559 as measured by maximum observed serum concentration (Cmax)	Within the first 22 weeks, weeks 34, weeks 46, and at follow-up (35 ± 7 days after last treatment and 70-90 days since last treatment)
Pharmacokinetics of BMS-936559 as measured by time of maximum observed serum concentration (Tmax)	Within the first 22 weeks, weeks 34, weeks 46, and at follow-up (35 ± 7 days after last treatment and 70-90 days since last treatment)
Pharmacokinetics of BMS-936559 as measured by area under the serum concentration time curve in the dosing interval [AUC(TAU)]	Within the first 22 weeks, weeks 34, weeks 46, and at follow-up (35 ± 7 days after last treatment and 70-90 days since last treatment)
Pharmacokinetics of BMS-936559 as measured by accumulation index (AI) calculated ar ratio of the AUC(TAU) at steady state and first dose	Within the first 22 weeks, weeks 34, weeks 46, and at follow-up (35 ± 7 days after last treatment and 70-90 days since last treatment)
Pharmacokinetics of BMS-936559 as measured by serum concentration achieved at the end of dosing interval (trough concentration) (Cmin)	Within the first 22 weeks, weeks 34, weeks 46, and at follow-up (35 ± 7 days after last treatment and 70-90 days since last treatment)
Pharmacokinetics of BMS-936559 as measured by serum concentration achieved at the end of the infusion (Ceoinf)	Within the first 22 weeks, weeks 34, weeks 46, and at follow-up (35 ± 7 days after last treatment and 70-90 days since last treatment)
Antitumor activity of BMS-936559 as measured by the objective response rate, duration of response, and progression free survival	Week 4, week 12, week 20, and every 16 weeks until confirmed disease progression assessed up to Week 214
Immunogenicity of BMS-936559 as measured by the frequency of subjects with an increase in anti-drug antibody levels from baseline	Baseline, weeks 3, weeks 12, weeks 20, weeks 34, weeks 46, and at follow-up (35 ± 7 days after last treatment and 70-90 days since last treatment)
Programmed death ligand 1 (PD-L1) receptor occupancy levels as measured by changes from baseline	Baseline and within the first 3 weeks

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb

Study record dates

Study Major Dates

• Study Start: November 1, 2011
• Primary Completion (Anticipated): November 1, 2014
• Study Completion (Anticipated): November 1, 2014

Study Registration Dates

• First Submitted: October 4, 2011
• First Submitted That Met QC Criteria: October 11, 2011
• First Posted (Estimate): October 14, 2011

Study Record Updates

• Last Update Posted (Estimate): February 23, 2012
• Last Update Submitted That Met QC Criteria: February 22, 2012
• Last Verified: February 1, 2012

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Neoplasms by Site; Bone Marrow Diseases; Hematologic Diseases; Hemorrhagic Disorders; Myeloproliferative Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Neoplasms, Plasma Cell; Leukemia; Lymphoma; Hematologic Neoplasms; Multiple Myeloma; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Antineoplastic Agents; Antineoplastic Agents, Immunological; BMS-936559
• Other Study ID Numbers: CA210-003