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: September 22, 2014
Last verified: April 2014

May 3, 2012
September 22, 2014
June 2012
February 2017   (final data collection date for primary outcome measure)
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 ]
Safety and tolerability of BMS-936558 as measured by the occurrence of AEs, SAEs, deaths, hematologic laboratory abnormalities, serum chemistry laboratory abnormalities, and changes in blood pressure and heart rate measurements [ Time Frame: Up to 100 days after the last treatment (expected to be no more than 225 weeks) ] [ Designated as safety issue: Yes ]
  • AEs = adverse events
  • SAEs = serious adverse events
Complete list of historical versions of study NCT01592370 on ClinicalTrials.gov Archive Site
  • 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 ]
  • Maximum observed serum concentration (Cmax) of BMS-936558 [ 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) [Cmin] of BMS-936558 [ Time Frame: 7 time points up to 20 weeks ] [ Designated as safety issue: No ]
  • Time of maximum observed serum concentration (Tmax) of BMS-936558 [ 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 BMS-936558 [ Time Frame: 7 time points up to 20 weeks ] [ Designated as safety issue: No ]
  • Antitumor Activity of BMS-936558 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 BMS-936558 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 BMS-936558 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 BMS-936558 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 probability of a subject remaining progression free or surviving to time t, where t = 8, 16 and 24 weeks. 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
  • Immunogenicity of BMS-936558 as measured by the frequency of subjects with an increase in anti-drug antibody levels from baseline [ 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 ]
Not Provided
Not Provided
 
Safety Study of Nivolumab and Ipilimumab in Hematologic Malignancy
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

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.

Not Provided
Interventional
Phase 1
Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Non-Hodgkin's Lymphoma
  • Hodgkin Lymphoma
  • Multiple Myeloma
  • Biological: Nivolumab
    Other Name: BMS-936558
  • Biological: Ipilimumab
  • 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

    Intervention: Biological: Nivolumab
  • 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
    Interventions:
    • Biological: Nivolumab
    • Biological: Ipilimumab
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
180
March 2018
February 2017   (final data collection date for primary outcome measure)

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
Both
18 Years and older
No
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 #.
United States
 
NCT01592370
CA209-039
No
Bristol-Myers Squibb
Bristol-Myers Squibb
Not Provided
Study Director: Bristol-Myers Squibb Bristol-Myers Squibb
Bristol-Myers Squibb
April 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP