Ipilimumab and Rituximab in Treating Patients With Relapsed or Refractory B-cell Lymphoma

A Phase I Study of Ipilimumab in Combination With Rituximab in Patients With Relapsed/Refractory CD20+ B-Cell Lymphoma

This partially randomized phase I trial studies the side effects and best dose of ipilimumab when given together with rituximab in treating patients with B-cell lymphoma that has returned or has not responded to treatment. Monoclonal antibodies, such as ipilimumab and rituximab, may interfere with the ability of cancer cells to grow and spread.

Study Overview

• Status: Completed
• Conditions: Refractory B-Cell Non-Hodgkin Lymphoma; Recurrent B-Cell Non-Hodgkin Lymphoma; CD20 Positive
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Biological: Ipilimumab; Biological: Rituximab

Detailed Description

PRIMARY OBJECTIVES:

I. To determine a recommended phase II dose for ipilimumab in combination with rituximab.

SECONDARY OBJECTIVES:

I. To obtain preliminary information on the effect of adding ipilimumab to rituximab in regard to: immune response; clinical anti-tumor response/overall remission rate (ORR) (complete remission + partial remission); progression free survival (PFS).

OUTLINE: This is a dose-escalation study of ipilimumab followed by a randomized study.

PART I:

INDUCTION: Patients receive ipilimumab intravenously (IV) over 90 minutes once every 3 weeks for 12 weeks and rituximab IV over 2-6 hours once weekly for 4 weeks.

MAINTENANCE: Patients receive ipilimumab IV over 90 minutes and rituximab IV over 2-6 hours once every 12 weeks for up to 1 year.

PART II: Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients receive rituximab IV over 2-6 hours once weekly in weeks 1-4 and ipilimumab IV over 90 minutes once weekly in weeks 1, 4, 7, and 10. Patients then receive ipilimumab IV over 90 minutes and rituximab IV over 2-6 hours once every 12 weeks for up to 1 year in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive rituximab IV over 2-6 hours once weekly in weeks 1-4 and ipilimumab IV over 90 minutes once weekly in weeks 3, 6, 9, and 12. Patients then receive ipilimumab IV over 90 minutes and rituximab IV over 2-6 hours once every 12 weeks for up to 1 year in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 12 months.

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope Comprehensive Cancer Center
    • Los Angeles, California, United States, 90033
      • USC / Norris Comprehensive Cancer Center
    • Sacramento, California, United States, 95817
      • University of California Davis Comprehensive Cancer Center
    • South Pasadena, California, United States, 91030
      • City of Hope South Pasadena
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033-0850
      • Penn State Milton S Hershey Medical Center

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:

• Previously treated, histologically confirmed cluster of differentiation (CD)20+ B cell lymphoma; bone marrow biopsies as the sole means of diagnosis are not acceptable, but they may be submitted in conjunction with nodal biopsies or extra nodal biopsies; fine needle aspirates are not acceptable
• All patients must be informed of the investigative nature of the clinical trial and give written informed consent in accordance with institutional and federal guidelines
• Able to adhere to the study visit schedule and other protocol requirements
• Karnofsky >= 70%
• Life expectancy expected to be greater than 3 months
• Leukocytes >= 3,000/mcL
• Absolute neutrophil count >= 1,000/mcL
• Platelets >= 50,000/mcL
• Total bilirubin =< 2.0 x institutional upper limit of normal
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal
• Serum creatinine =< 2.0 x upper limit of normal OR calculated creatinine clearance >= 30 ml/min/1.73 M^2 by the modified Cockcroft and Gault formula OR creatinine clearance >= 30 mL/min obtained from a 24-hour urine collection
• At least one measurable lesion according to international workshop lymphoma response criteria; there must be measurable lymphadenopathy to follow with serial exam and/or imaging
• All previous cancer therapy, including radiation, hormonal therapy and surgery, must have been discontinued at least 4 weeks prior to treatment in this study
• Patients must have evidence of progression of disease during or after last treatment
• Submission of original biopsy for review and verification by participating center hematopathologist
• Disease free of prior malignancies for >= 3 years with exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix or breast

Exclusion Criteria:

• Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
• Patients with a history of prior treatment with ipilimumab
• Patients with a history of prior treatment with an anti-programmed cell death (PD) 1 antibody, CD137 agonist or other immune activating therapy such as anti-CD 40 antibody are excluded unless 5 half-lives of the agent (minimum of 8 weeks) have intervened since the therapy; patients who have received prior vaccine therapy are eligible
• Patients who are receiving any other investigational agents
• 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]); central nervous system (CNS) or motor neuropathy considered of autoimmune origin (e.g. Guillain-Barre syndrome and myasthenia gravis, multiple sclerosis)
• Patients with known immune impairment who may be unable to respond to anti-cytotoxic T-lymphocyte antigen 4 (CTLA 4) antibody
• Patients with known uncontrolled brain metastases are excluded; however, patients with stable brain disease (off corticosteroids) at least 2 weeks after completion of appropriate therapy for their brain metastases are eligible
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to rituximab
• Patients on systemic corticosteroids (except for patients on stable doses of hormone replacement therapy such as hydrocortisone), or other immunosuppressants (e.g., infliximab, mycophenolate mofetil) are 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
• Patients with chronic human immunodeficiency virus (HIV), hepatitis B or hepatitis C infections are excluded
• Pregnant women are excluded from this study
• HIV-positive patients on combination antiretroviral therapy are ineligible
• Rituximab within six weeks

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A (ipilimumab and rituximab); Patients receive rituximab IV over 2-6 hours once weekly in weeks 1-4 and ipilimumab IV over 90 minutes once weekly in weeks 1, 4, 7, and 10. Patients then receive ipilimumab IV over 90 minutes and rituximab IV over 2-6 hours once every 12 weeks for up to 1 year in the absence of disease progression or unacceptable toxicity.	Other: Laboratory Biomarker Analysis; Correlative studies; Biological: Ipilimumab; Given IV; Other Names: Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody; BMS-734016; MDX-010; MDX-CTLA4; Yervoy; Biological: Rituximab; Given IV; Other Names: Rituxan; MabThera; ABP 798; BI 695500; C2B8 Monoclonal Antibody; Chimeric Anti-CD20 Antibody; CT-P10; IDEC-102; IDEC-C2B8; IDEC-C2B8 Monoclonal Antibody; Monoclonal Antibody IDEC-C2B8; PF-05280586; Rituximab Biosimilar ABP 798; Rituximab Biosimilar BI 695500; Rituximab Biosimilar CT-P10; Rituximab Biosimilar GB241; Rituximab Biosimilar IBI301; Rituximab Biosimilar PF-05280586; Rituximab Biosimilar RTXM83; Rituximab Biosimilar SAIT101; RTXM83
Experimental: Arm B (ipilimumab and rituximab); Patients receive rituximab IV over 2-6 hours once weekly in weeks 1-4 and ipilimumab IV over 90 minutes once weekly in weeks 3, 6, 9, and 12. Patients then receive ipilimumab IV over 90 minutes and rituximab IV over 2-6 hours once every 12 weeks for up to 1 year in the absence of disease progression or unacceptable toxicity.	Other: Laboratory Biomarker Analysis; Correlative studies; Biological: Ipilimumab; Given IV; Other Names: Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody; BMS-734016; MDX-010; MDX-CTLA4; Yervoy; Biological: Rituximab; Given IV; Other Names: Rituxan; MabThera; ABP 798; BI 695500; C2B8 Monoclonal Antibody; Chimeric Anti-CD20 Antibody; CT-P10; IDEC-102; IDEC-C2B8; IDEC-C2B8 Monoclonal Antibody; Monoclonal Antibody IDEC-C2B8; PF-05280586; Rituximab Biosimilar ABP 798; Rituximab Biosimilar BI 695500; Rituximab Biosimilar CT-P10; Rituximab Biosimilar GB241; Rituximab Biosimilar IBI301; Rituximab Biosimilar PF-05280586; Rituximab Biosimilar RTXM83; Rituximab Biosimilar SAIT101; RTXM83

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of toxicities according to the Common Terminology Criteria for Adverse Events version 4	Tables will be created to summarize the toxicities and side effects by dose, course, organ and severity.	Up to 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Immune response as measured by the frequency of activated T-cells, absolute lymphocyte count, antibody dependent cell-mediated cytotoxicity, and kinetics and magnitude of B-cell depletion	Regression methods (adapted for repeated measures) will be used to describe the changes over time. In addition to summarizing the changes over time within each arm, these regression models will contain contrasts to compare the two arms in terms of changes.	Up to 14 weeks
Clinical anti-tumor response (complete response and partial response as per international workshop lymphoma response criteria [Cheson 2007])		Up to 12 months
Progression-free survival	Progression-free survival will be summarized using Kaplan-Meier plots.	From when the patient started treatment to the time the patient is first recorded as having disease relapse/progression, or to the date of death if the patient dies due to causes other than disease progression, assessed up to 12 months

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Joseph Tuscano, City of Hope Comprehensive Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): November 19, 2012
• Primary Completion (Actual): March 30, 2018
• Study Completion (Actual): March 30, 2018

Study Registration Dates

• First Submitted: November 14, 2012
• First Submitted That Met QC Criteria: November 14, 2012
• First Posted (Estimate): November 20, 2012

Study Record Updates

• Last Update Posted (Actual): April 11, 2018
• Last Update Submitted That Met QC Criteria: April 10, 2018
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma; Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Immune Checkpoint Inhibitors; Antibodies; Immunoglobulins; Rituximab; Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Ipilimumab
• Other Study ID Numbers: NCI-2012-02213 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); P30CA033572 (U.S. NIH Grant/Contract); UM1CA186704 (U.S. NIH Grant/Contract); U01CA062505 (U.S. NIH Grant/Contract); UM1CA186717 (U.S. NIH Grant/Contract); PHI-69; CDR0000743246; NCI# 9197; 9197 (Other Identifier: CTEP)