Safety Study of Nivolumab and Ipilimumab in Hematologic Malignancy

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2014 by Bristol-Myers Squibb
Sponsor:
Information provided by (Responsible Party):
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT01592370
First received: May 3, 2012
Last updated: July 9, 2014
Last verified: April 2014
  Purpose

The purpose of this study is to determine the side effects of treatment with Nivolumab alone and in combination with Ipilimumab in subjects with hematological malignancies and the dose that should be recommended for use in future studies.


Condition Intervention Phase
Non-Hodgkin's Lymphoma
Hodgkin Lymphoma
Multiple Myeloma
Biological: Nivolumab
Biological: Ipilimumab
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Dose Escalation Study to Investigate the Safety, Pharmacokinetics, Immunoregulatory Activity, and Preliminary Antitumor Activity of Anti-Programmed-Death 1 (PD-1) Antibody (Nivolumab, BMS 936558) and the Combination of Nivolumab and Ipilimumab in Subjects With Relapsed or Refractory Hematologic Malignancy

Resource links provided by NLM:


Further study details as provided by Bristol-Myers Squibb:

Primary Outcome Measures:
  • Safety and tolerability of Nivolumab alone and in combination with Ipilimumab as measured by the incidence of drug related adverse events (AEs), serious drug related AEs, dose-limiting toxicities, and laboratory test abnormalities [ Time Frame: Up to 100 days after the last dose of study (expected to be no more than 225 weeks) ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Maximum observed serum concentration (Cmax) of Nivolumab and Ipilimumab [ Time Frame: 7 time points up to 20 weeks ] [ Designated as safety issue: No ]
  • Serum concentration achieved at the end of dosing interval (trough concentration, all subjects) [Cmin] of Nivolumab and Ipilimumab [ Time Frame: 7 time points up to 20 weeks ] [ Designated as safety issue: No ]
  • Time of maximum observed serum concentration (Tmax) of Nivolumab and Ipilimumab [ Time Frame: 7 time points up to 20 weeks ] [ Designated as safety issue: No ]
  • Area under the plasma concentration-time curve from time zero to the last time of the last quantifiable concentration [AUC(0-T)] of Nivolumab and Ipilimumab [ Time Frame: 7 time points up to 20 weeks ] [ Designated as safety issue: No ]
  • Area under the concentration-time curve in one dosing interval [AUC(TAU)] of Nivolumab and Ipilimumab [ Time Frame: 7 time points up to 20 weeks ] [ Designated as safety issue: No ]
  • Serum concentration achieved at the end of study drug infusion (Ceoinf) of Nivolumab and Ipilimumab [ Time Frame: 7 time points up to 20 weeks ] [ Designated as safety issue: No ]
  • Antitumor Activity of Nivolumab and Ipilimumab as measured by Best Overall Response (BOR) [ Time Frame: Baseline (within 28 days of treatment), Week 4, Week 8, Week 16, Week 24, and every 16 weeks thereafter until confirmed disease progression assessed up to Week 156 ] [ Designated as safety issue: No ]
    BOR is defined as the best response designation over the study as a whole, recorded between the date of first dose and the last tumor assessment prior to subsequent therapy

  • Antitumor Activity of Nivolumab and Ipilimumab as measured by Objective Response Rate (ORR) [ Time Frame: Baseline (within 28 days of treatment), Week 4, Week 8, Week 16, Week 24, and every 16 weeks thereafter until confirmed disease progression assessed up to Week 156 ] [ Designated as safety issue: No ]
    ORR is defined as the proportion of subjects whose BOR is either partial response (PR) or complete response (CR) divided by the number of treated subjects (or response-evaluable subjects)

  • Antitumor Activity of Nivolumab and Ipilimumab as measured by duration of Objective Response [ Time Frame: Baseline (within 28 days of treatment), Week 4, Week 8, Week 16, Week 24, and every 16 weeks thereafter until confirmed disease progression assessed up to Week 156 ] [ Designated as safety issue: No ]
    The duration of response is defined as the time when the measurement criteria are first met for PR or CR (whichever is reported first) until the date of documented disease progression or death. For subjects who neither progress nor die, the duration of response will be censored at the date of their last disease assessment

  • Antitumor Activity of Nivolumab and Ipilimumab as measured by Progression Free Survival Rate (PFSR) [ Time Frame: Baseline (within 28 days of treatment), Week 4, Week 8, Week 16, Week 24, and every 16 weeks thereafter until confirmed disease progression assessed up to Week 156 ] [ Designated as safety issue: No ]
    The PFSR is defined as the proportion of subjects remaining progression free or surviving to time t, where t = 8, 16 and 24 weeks for patients receiving monotherapy Nivolumab, and t = 7, 13, 21 and 29 weeks for patients receiving the combination of Nivolumab and Ipilimumab. Progression free survival (PFS) is defined as the time between date of first dose of study therapy and date of progression or death, whichever occurs first

  • Modified Severity Weighted Assessment Tool (mSWAT) [ Time Frame: Baseline (within 28 days of treatment), Week 4, Week 8, Week 16, Week 24, and every 16 weeks thereafter until confirmed disease progression assessed up to Week 156 ] [ Designated as safety issue: No ]
  • Immunogenicity of Nivolumab and Ipilimumab as measured by the anti-drug antibody status both at the sample level and at the subject level [ Time Frame: Baseline (within 28 days of treatment), week 4, week 6, week 12, week 20, and at follow-up (35 ± 7 days after last treatment and 90-120 days since last treatment) ] [ Designated as safety issue: Yes ]
  • PD-L1 expression levels [ Time Frame: Baseline (within 28 days of treatment) ] [ Designated as safety issue: No ]

Estimated Enrollment: 180
Study Start Date: June 2012
Estimated Study Completion Date: March 2018
Estimated Primary Completion Date: February 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm 1: Cohort 1- Nivolumab monotherapy (Dose Escalation)

Nivolumab 1 or 3 mg/kg solution intravenously (IV) every 2-3 weeks up to 48-96 weeks depending on response

Enrollment is closed for Arm 1

Biological: Nivolumab
Other Name: BMS-936558
Experimental: Arm 2: Cohort 1- Nivolumab and Ipilimumab combination therapy
Nivolumab 3 mg/kg and Ipilimumab 1 or 3 mg/kg solution intravenously (IV) every 2-3 weeks for 48 - 96 weeks depending on response
Biological: Nivolumab
Other Name: BMS-936558
Biological: Ipilimumab

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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

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 > 1.5 cm 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 an archived Formalin fixed tissue block, or 7 to 15 slides of tumor sample for performance of correlative studies
  • Subjects must have received at least one prior chemotherapy regimen. Subjects must be off therapy for at least 3 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:

    • Absolute neutrophil count ≥ 1000/μl (stable off any growth factor within 1 week of study drug administration)
    • Hemoglobin ≥ 9 g/dL (transfusion to achieve this level is permitted)
    • Platelet count ≥ 50 X 1000/ 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:

    • Aspartate aminotransferase (AST) ≤ 3 x Upper limit of normal (ULN)
    • Alanine aminotransferase (ALT) ≤ 3 x ULN
    • 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) must use highly effective methods of birth control for up to 18 weeks after the last dose of investigational product
  • Men and women ≥ 18 years of age

Exclusion Criteria:

  • Subjects with myelodysplasia, polycythemia vera, idiopathic thrombocythemia, myelofibrosis, acute leukemias, CML, T cell lymphoblastic or Burkitt lymphoma acute leukemias
  • 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, carcinoma in situ of the breast, 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, resolved childhood asthma/atopy or autoimmune thyroid disorders
  • 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 human papilloma virus (HPV) vaccine) within 4 weeks of study drug administration. The inactivated seasonal influenza vaccine can be given to subjects before treatment and while on therapy without restriction. Influenza vaccines containing live virus or other clinically indicated vaccinations for infectious diseases (ie, pneumovax, varicella, etc.] may be permitted; but must be discussed with the Sponsor's Medical Monitor and may require a study drug washout period prior to and after administration of 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 Antigen 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
  • WOCBP who are unwilling or unable to use an acceptable method to minimize the risk of pregnancy for the entire study period and for at least 18 weeks after the last dose of investigational product
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01592370

Contacts
Contact: Recruiting sites have contact information. Please contact the sites directly. If there is no contact information, please email: Clinical.Trials@bms.com
Contact: First line of the email MUST contain NCT# and Site #.

Locations
United States, California
Division Of Hematology & Oncology Ctr. For Health Sciences Active, not recruiting
Los Angeles, California, United States, 90095
United States, Connecticut
Yale University School Of Medicine Active, not recruiting
New Haven, Connecticut, United States, 06520
United States, Florida
Holy Cross Hospital-Bienes Cancer Center Active, not recruiting
Fort Lauderdale, Florida, United States, 33308
United States, Maryland
The Sidney Kimmel Comprehensive Cancer Center Recruiting
Baltimore, Maryland, United States, 21231
Contact: Ivan Borrello, Site 003    410-614-4838      
United States, Massachusetts
Dana-Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Philippe Armand, Site 009    617-582-8437      
Dana Farber Cancer Institute Active, not recruiting
Boston, Massachusetts, United States, 02215
United States, Michigan
University Of Michigan Health System Completed
Ann Arbor, Michigan, United States, 48109
United States, Minnesota
Mayo Clinic Recruiting
Rochester, Minnesota, United States, 55905
Contact: Stephen Ansell, Site 002    507-293-1933      
United States, New Jersey
John Theurer Cancer Center Active, not recruiting
Hackensack, New Jersey, United States, 07601
United States, New York
Memorial Sloan Kettering Cancer Ctr Recruiting
New York, New York, United States, 10065
Contact: Alexander M Lesokhin, Site 001    646-888-3359      
United States, Oregon
Or Hsu Ctrforhema Malignancies Active, not recruiting
Portland, Oregon, United States, 97239
United States, Pennsylvania
Fox Chase Cancer Center Active, not recruiting
Philadelphia, Pennsylvania, United States, 19111
Abramson Cancer Center Of The University Of Pennsylvania Active, not recruiting
Philadelphia, Pennsylvania, United States, 19104
United States, Utah
Huntsman Cancer Institute At The Univ. Of Utah Active, not recruiting
Salt Lake City, Utah, United States, 84112
Sponsors and Collaborators
Bristol-Myers Squibb
Investigators
Study Director: Bristol-Myers Squibb Bristol-Myers Squibb
  More Information

Additional Information:
No publications provided

Responsible Party: Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT01592370     History of Changes
Other Study ID Numbers: CA209-039
Study First Received: May 3, 2012
Last Updated: July 9, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Hodgkin Disease
Lymphoma
Lymphoma, Non-Hodgkin
Multiple Myeloma
Neoplasms, Plasma Cell
Hematologic Neoplasms
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Neoplasms by Site

ClinicalTrials.gov processed this record on July 28, 2014