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Ipilimumab or Nivolumab in Treating Patients With Relapsed Hematologic Malignancies After Donor Stem Cell Transplant

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01822509
Recruitment Status : Active, not recruiting
First Posted : April 2, 2013
Last Update Posted : December 28, 2020
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE April 1, 2013
First Posted Date  ICMJE April 2, 2013
Last Update Posted Date December 28, 2020
Actual Study Start Date  ICMJE May 16, 2013
Actual Primary Completion Date December 31, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 31, 2019)
  • Maximum tolerated dose (MTD) of ipilimumab according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (Phase I) [ Time Frame: At 12 weeks ]
    Dose-limiting toxic (DLT) effects were defined as grade III or IV acute graft versus host disease (GVHD), grade 4 hematologic toxic effects unrelated to the underlying disease, or grade 3 nonhematologic toxic effects that did not improve to grade 1 with a 3-week dose delay. Immune-related adverse events that resolved to grade 1 or lower with the use of glucocorticoids were not considered to be dose-limiting toxic effects. We designated the observation period for toxic effects to be 12 weeks to capture delayed immunologic toxic effects.
  • Maximum tolerated dose (MTD) of nivolumab according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (Phase I) [ Time Frame: At 12 weeks ]
    Dose-limiting toxic (DLT) effects are defined as grade III or IV acute GVHD, grade 4 hematologic toxic effects unrelated to the underlying disease, or grade 3 nonhematologic toxic effects that did not improve to grade 1 with a 3-week dose delay. Immune-related adverse events that resolved to grade 1 or lower with the use of glucocorticoids were not considered to be dose-limiting toxic effects. We designated the observation period for toxic effects to be 12 weeks to capture delayed immunologic toxic effects.
  • Incidence of adverse events as assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (Phase Ib) [ Time Frame: Up to 1 year after completion of study treatment ]
    A serious adverse event (SAE) is any adverse event, occurring at any dose and regardless of causality that 1) Results in death, 2) Is life-threatening, 3) Requires or prolongs inpatient hospitalization, 4) Results in persistent or significant disability/incapacity, 5) Is an important medical event when, based upon appropriate medical judgment, it may jeopardize the participant and require medical or surgical intervention to prevent one of the outcomes listed above.
Original Primary Outcome Measures  ICMJE
 (submitted: April 1, 2013)
  • MTD of ipilimumab according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (Phase I) [ Time Frame: At 12 weeks ]
  • Incidence of adverse events as assessed by NCI CTCAE version 4.0 (Phase Ib) [ Time Frame: Up to 1 year after completion of study treatment ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 2, 2018)
  • Clinical response [ Time Frame: Up to 1 year ]
    Summarized by simple descriptive summary statistics delineating complete, partial, and best overall response, stable and progressive disease.
  • Progression-free survival (PFS) [ Time Frame: From start of treatment to time of objective disease progression, assessed up to 1 year ]
    Using the Kaplan-Meier method. Will be analyzed and reported both for the entire cohort and within each disease group if feasible.
  • Overall survival (OS) [ Time Frame: From the start of treatment to time of death, assessed up to 1 year ]
    Using the Kaplan-Meier method. Will be analyzed and reported both for the entire cohort and within each disease group if feasible.
Original Secondary Outcome Measures  ICMJE
 (submitted: April 1, 2013)
  • Clinical response [ Time Frame: Up to 1 year ]
    Summarized by simple descriptive summary statistics delineating complete, partial, and best overall response, stable and progressive disease.
  • Progression-free survival [ Time Frame: From start of treatment to time of objective disease progression, assessed up to 1 year ]
    Using the Kaplan-Meier method.
  • Overall survival [ Time Frame: From the start of treatment to time of death, assessed up to 1 year. ]
    Using the Kaplan-Meier method.
Current Other Pre-specified Outcome Measures
 (submitted: March 2, 2018)
  • Change in immune cell numbers [ Time Frame: Baseline to up to 1 year ]
    Laboratory studies will be performed to characterize the effects of ipilimumab and nivolumab in the post allogeneic stem cell transplantation (alloSCT) setting on B cells, NK, cells, or dendritic cells, both in terms of pre and post alloSCT changes in cell numbers.
  • Change in cytokine production [ Time Frame: Baseline to up to 1 year ]
    Laboratory studies will be performed to characterize the effects of ipilimumab and nivolumab in the post alloSCT setting on B cells, NK, cells, or dendritic cells, both in terms of pre and post alloSCT changes in cell numbers.
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Ipilimumab or Nivolumab in Treating Patients With Relapsed Hematologic Malignancies After Donor Stem Cell Transplant
Official Title  ICMJE A Phase I/IB Study of Ipilimumab or Nivolumab in Patients With Relapsed Hematologic Malignancies After Allogeneic Hematopoietic Cell Transplantation
Brief Summary This phase I/Ib trial studies the side effects and best dose of ipilimumab or nivolumab in treating patients with cancers of the blood and blood-forming tissues (hematologic cancers) that have returned after a period of improvement (relapsed) after donor stem cell transplant. Immunotherapy with monoclonal antibodies, such as ipilimumab and nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.
Detailed Description

PRIMARY OBJECTIVES:

I. To determine the maximum-tolerated dose (MTD) of ipilimumab or nivolumab administered to patients with relapsed hematologic malignancies following allogeneic stem cell transplantation. (Phase I) II. To characterize the toxicity of ipilimumab or nivolumab administered at the MTD in this patient population. (Phase Ib)

SECONDARY OBJECTIVES:

I. To assess response rate. II. To assess progression free and overall survival.

EXPLORATORY OBJECTIVE:

I. To assess the phenotypic and functional effects of ipilimumab or nivolumab on immune cells.

OUTLINE: This is a dose-escalation study.

INDUCTION PHASE: Patients receive ipilimumab intravenously (IV) over 90 minutes on day 1. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive nivolumab IV over 30 minutes on day 1. Treatment repeats every 14 days for 8 cycles in the absence of disease progression or unacceptable toxicity.

MAINTENANCE PHASE: Patients receive ipilimumab IV over 90 minutes. Treatment repeats every 12 weeks beginning at cycle 5 (24 weeks after the first dose of ipilimumab) for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients achieving clinical benefit will have the option to continue with ongoing maintenance dosing every 12 weeks in the absence of disease progression or unacceptable toxicity. Patients also receive nivolumab IV over 30 minutes every 2 weeks in the absence of disease progression or unacceptable toxicity. Treatment repeats every 14 days for up to a total of 60 weeks (including Induction) in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 1 year.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Allogeneic Hematopoietic Stem Cell Transplant Recipient
  • Myeloproliferative Neoplasm
  • Recurrent Acute Lymphoblastic Leukemia
  • Recurrent Acute Myeloid Leukemia
  • Recurrent Chronic Lymphocytic Leukemia
  • Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive
  • Recurrent Hematologic Malignancy
  • Recurrent Hodgkin Lymphoma
  • Recurrent Myelodysplastic Syndrome
  • Recurrent Non-Hodgkin Lymphoma
  • Recurrent Plasma Cell Myeloma
Intervention  ICMJE
  • Biological: Ipilimumab
    Given IV
    Other Names:
    • Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody
    • BMS-734016
    • MDX-010
    • MDX-CTLA4
    • Yervoy
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Biological: Nivolumab
    Given IV
    Other Names:
    • BMS-936558
    • MDX-1106
    • NIVO
    • ONO-4538
    • Opdivo
Study Arms  ICMJE Experimental: Treatment (ipilimumab, nivolumab)
See Detailed Description.
Interventions:
  • Biological: Ipilimumab
  • Other: Laboratory Biomarker Analysis
  • Biological: Nivolumab
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: June 16, 2020)
71
Original Estimated Enrollment  ICMJE
 (submitted: April 1, 2013)
40
Estimated Study Completion Date  ICMJE April 1, 2022
Actual Primary Completion Date December 31, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Histologically or cytologically confirmed hematologic malignancy
  • The following malignancies will be considered eligible if progressive or persistent:

    • Chronic lymphocytic leukemia (CLL)
    • Non-Hodgkin lymphoma (NHL)
    • Hodgkin lymphoma (HL)
    • Multiple myeloma (MM)
    • Acute leukemia (acute myeloid leukemia [AML], acute lymphoblastic leukemia [ALL])
    • Myelodysplastic syndrome (MDS)
    • Myeloproliferative neoplasms (MPN)
    • Chronic myeloid leukemia (CML)
  • Life expectancy of greater than 3 months
  • Must have undergone allogeneic hematopoietic stem cell transplantation (HSCT) (regardless of stem cell source)
  • Must have baseline donor T cell chimerism of >= 20%
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2
  • Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (unless due to Gilbert's disease or disease-related hemolysis, then =< 3.0 x ULN)
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional ULN
  • Creatinine =< 1.5 x institutional ULN
  • Prednisone dose =< 5 mg/day and off all other systemic immunosuppressive medications for at least 4 weeks prior to study entry
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

  • Participants who have had anti-tumor therapy or other investigational agents within 4 weeks prior to registration (6 weeks for nitrosoureas or mitomycin C), or those who have not recovered from adverse events due to agents administered more than 4 weeks prior to registration
  • Patients with prior history of or active severe (grade 3 or 4) acute graft-versus-host disease (GVHD)
  • Patients with a history of prior treatment with ipilimumab, anti-programmed cell death protein 1 (PD 1) antibody, or cluster of differentiation (CD)137 agonist therapy are ineligible for the ipilimumab arm, but are eligible for the nivolumab arm
  • Patients who have had donor lymphocyte infusion (DLI) within 8 weeks prior to registration
  • Autoimmune disease: Patients with a history of inflammatory bowel disease, including ulcerative colitis and Crohn's disease, are excluded from this study, as are patients with a history of symptomatic disease (e.g., rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [e.g., Wegener's granulomatosis]) and motor neuropathy considered of autoimmune origin (e.g. Guillain-Barre syndrome and myasthenia gravis); patients with Hashimoto's thyroiditis are eligible to go on study
  • Patients with known chronic human immunodeficiency virus (HIV), hepatitis B or hepatitis C infections should be excluded
  • Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Pregnant women are excluded from this study because ipilimumab and nivolumab are immunomodulatory agents with the potential for teratogenic or abortifacient effects; the effects of ipilimumab and nivolumab on the developing human fetus are unknown; for this reason and because immunomodulatory agents are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study or within 23 weeks after the last dose of study drug, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and for at least 31 weeks after completion of ipilimumab or nivolumab administration
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01822509
Other Study ID Numbers  ICMJE NCI-2013-00739
NCI-2013-00739 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
12-537
9204 ( Other Identifier: Dana-Farber Cancer Institute )
9204 ( Other Identifier: CTEP )
P30CA006516 ( U.S. NIH Grant/Contract )
R01CA183559 ( U.S. NIH Grant/Contract )
U01CA062490 ( U.S. NIH Grant/Contract )
UM1CA186709 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Matthew S Davids Dana-Farber Cancer Institute
PRS Account National Cancer Institute (NCI)
Verification Date December 2020

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