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Ipilimumab, Ibrutinib, and Nivolumab for the Treatment of Chronic Lymphocytic Leukemia and Richter Transformation

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ClinicalTrials.gov Identifier: NCT04781855
Recruitment Status : Recruiting
First Posted : March 4, 2021
Last Update Posted : October 14, 2022
Sponsor:
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:
This phase I/Ib trial evaluates the best dose and side effects of ipilimumab in combination with either ibrutinib alone or with ibrutinib and nivolumab in treating patients with chronic lymphocytic leukemia (CLL) and Richter transformation (RT). 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 cancer cells to grow and spread. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving ipilimumab with either ibrutinib alone or with ibrutinib and nivolumab may help control CLL and RT.

Condition or disease Intervention/treatment Phase
Hematopoietic and Lymphoid Cell Neoplasm Recurrent Chronic Lymphocytic Leukemia Recurrent Small Lymphocytic Lymphoma Refractory Chronic Lymphocytic Leukemia Refractory Small Lymphocytic Lymphoma Richter Syndrome Drug: Ibrutinib Biological: Ipilimumab Biological: Nivolumab Phase 1

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of ipilimumab in combination with ibrutinib in patients with CLL/small lymphocytic lymphoma (SLL)/RT. (Part A) II. To determine the MTD and DLT of ipilimumab in combination with nivolumab and ibrutinib in patients with CLL/SLL/RT. (Part B)

SECONDARY OBJECTIVES:

I. To determine the efficacy (response rate, defined as complete response [CR] + complete response with incomplete marrow recovery [CRi] + partial response [PR]) of the combination therapy.

II. To determine the progression-free survival and overall survival of the combination therapy.

EXPLORATORY OBJECTIVE:

I. To study immunological and molecular changes in peripheral blood, lymph node, and bone marrow in response to the combination therapy.

OUTLINE: This is a dose-escalation study of ipilimumab followed by a dose-expansion study. Patients are assigned to 1 of 2 parts.

PART A: Patients receive ipilimumab intravenously (IV) over 90 minutes on day 1. Treatment repeats every 3 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Beginning day 1 of cycle 1, patients also receive ibrutinib orally (PO) once daily (QD) in the absence of disease progression or unacceptable toxicity. Patients who complete 4 doses of ipilimumab and are deriving benefit from it, without severe toxicities, may continue to receive ipilimumab every 12 weeks for up to a total of 2 years.

PART B: Patients receive ipilimumab IV over 90 minutes and nivolumab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Beginning day 7 of cycle 1, patients also receive ibrutinib PO QD in the absence of disease progression or unacceptable toxicity. Patients who complete 4 doses of ipilimumab and nivolumab, and are deriving benefit from it, without severe toxicities, may continue to receive ipilimumab every 12 weeks and nivolumab every 4 weeks for up to a total of 2 years.

After completion of study treatment, patients are followed up at 30 days, and then every 3 months thereafter.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Ipilimumab Combined With Ibrutinib and Nivolumab for Patients With Chronic Lymphocytic Leukemia (CLL) and Richter Transformation (RT)
Actual Study Start Date : July 14, 2022
Estimated Primary Completion Date : December 31, 2024
Estimated Study Completion Date : December 31, 2024


Arm Intervention/treatment
Experimental: Part A (ipilimumab, ibrutinib)
Patients receive ipilimumab IV over 90 minutes on day 1. Treatment repeats every 3 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Beginning day 1 of cycle 1, patients also receive ibrutinib PO QD in the absence of disease progression or unacceptable toxicity. Patients who complete 4 doses of ipilimumab and are deriving benefit from it, without severe toxicities, may continue to receive ipilimumab every 12 weeks for up to a total of 2 years.
Drug: Ibrutinib
Given PO
Other Names:
  • BTK Inhibitor PCI-32765
  • CRA-032765
  • Imbruvica
  • PCI-32765

Biological: Ipilimumab
Given IV
Other Names:
  • Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody
  • BMS-734016
  • Ipilimumab Biosimilar CS1002
  • MDX-010
  • MDX-CTLA4
  • Yervoy

Experimental: Part B (ipilimumab, nivolumab, ibrutinib)
Patients receive ipilimumab IV over 90 minutes and nivolumab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Beginning day 7 of cycle 1, patients also receive ibrutinib PO QD in the absence of disease progression or unacceptable toxicity. Patients who complete 4 doses of ipilimumab and nivolumab, and are deriving benefit from it, without severe toxicities, may continue to receive ipilimumab every 12 weeks and nivolumab every 4 weeks for up to a total of 2 years.
Drug: Ibrutinib
Given PO
Other Names:
  • BTK Inhibitor PCI-32765
  • CRA-032765
  • Imbruvica
  • PCI-32765

Biological: Ipilimumab
Given IV
Other Names:
  • Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody
  • BMS-734016
  • Ipilimumab Biosimilar CS1002
  • MDX-010
  • MDX-CTLA4
  • Yervoy

Biological: Nivolumab
Given IV
Other Names:
  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo




Primary Outcome Measures :
  1. Maximum tolerated dose of ipilimumab [ Time Frame: Up to 2 years ]
  2. Dose limiting toxicities [ Time Frame: During first 21 days on study intervention ]
    DLT is defined as clinically significant non-hematologic adverse event or abnormal laboratory value assessed as unrelated to disease, intercurrent illness, or concomitant medications and occurring during the first 21 days.


Secondary Outcome Measures :
  1. Overall response rate [ Time Frame: Up to 2 years ]
    Defined as complete response (CR) + complete response with incomplete marrow recovery (CRi) + partial response (PR). Response will be assessed by the investigator, based on physical examinations, computed tomography scans, laboratory results, and bone marrow examinations, according to the modified 2008 International Workshop on Chronic Lymphocytic Leukemia response criteria for chronic lymphocytic leukemia. The overall response rate (i.e., CR/CRi/PR) will be estimated along with the exact 95% confidence interval.

  2. Progression-free survival [ Time Frame: From treatment start date until the date of disease progression date or death due to any cause, whichever occurred first, assessed up to 2 years ]
    Assessed using Kaplan-Meier method.

  3. Overall survival [ Time Frame: From treatment start date until the date of death due to any cause, assessed up to 2 years ]
    Assessed using Kaplan-Meier method.

  4. Incidence of adverse events [ Time Frame: Up to 2 years ]
    Will be summarized by treatment, category, severity and attribution.



Information from the National Library of Medicine

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, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Cohort 1: Patients with a diagnosis of CLL or SLL, refractory to and/or relapsed after at least one prior therapy (prior therapy could be a chemoimmunotherapy regimen, or a targeted therapy such as a BTK inhibitor, a BCL2 inhibitor, or a PI3 kinase inhibitor) or untreated with del(17p) by fluorescence in situ hybridization (FISH) (high-risk cytogenetics) and have an indication for treatment by International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria
  • Cohort 2: Patients with a diagnosis of CLL or SLL who have been on ibrutinib for at least 9 months with measurable persistent disease (absolute lymphocyte count [ALC] > 4K/uL, any lymph node > 1.5 cm by computed tomography [CT] scan, or > 30% lymphocytes on bone marrow aspirate differential)
  • Cohort 3: Patients with a diagnosis of RT
  • Age 18 years or older
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2
  • Total bilirubin =< 1.5 x upper limit of normal (ULN). For patients with Gilbert's disease, total bilirubin up to =< 3 x ULN is allowed provided normal direct bilirubin
  • Serum creatinine =< 1.5 x ULN
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN (unless deemed to be disease related)
  • Females of childbearing potential must have a negative serum or urine beta human chorionic gonadotrophin (beta-human chorionic gonadotropin [hCG]) pregnancy test result within 14 days prior to the first dose of treatment and must agree to use an effective contraception method during the study and for 23 weeks following the last dose of the study drugs. Females of non-childbearing potential are those who are postmenopausal greater than 1 year or who have had a bilateral tubal ligation or hysterectomy. Males who have partners of childbearing potential must agree to use an effective contraceptive method during the study and for 31 weeks following the last dose of study drugs
  • Patients or their legally authorized representative must provide written informed consent

Exclusion Criteria:

  • History of another primary invasive malignancy that has not been definitively treated or in remission for at least 2 years. Patients with non-melanoma skin cancers or with carcinomas in situ are eligible regardless of the time from diagnosis (including concomitant diagnoses). If patients have another malignancy that was treated within the last 2 years, such patients may be enrolled if the likelihood of requiring systemic therapy for this other malignancy within 2 years is less than 10%, as determined by an expert in that particular malignancy at MD Anderson Cancer Center and after consultation with the principal investigator
  • Any major surgery, radiotherapy, cytotoxic chemotherapy, biologic therapy, immunotherapy, immunomodulatory drugs, experimental therapy within 4 weeks prior to the first dose of the study drugs. Note: Prior therapy with anti CD20 monoclonal antibody, anti CD52 monoclonal antibody, and lenalidomide are allowed. For oral targeted therapies (such as idelalisib, venetoclax), a washout of 3 days is allowed. For patients who are on ibrutinib at study entry - may continue ibrutinib without interruption
  • Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 2 months of screening, or any class 3 or 4 cardiac disease as defined by the New York Heart Association Functional classification
  • History of stroke or cerebral hemorrhage within 2 month
  • Patients who have uncontrolled hypertension (defined as sustained systolic blood pressure >= 140 mmHg or diastolic >= 90 mmHg)
  • Known evidence of active cerebral/meningeal CLL. Patients may have history of central nervous system (CNS) leukemic involvement if definitively treated with prior therapy and no evidence of active disease at the time of registration
  • Active, uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia requiring steroid therapy
  • Patients with autoimmune diseases are excluded: Patients with a history of inflammatory bowel disease (including Crohn's disease and ulcerative colitis) are excluded from this study as are patients with a history of autoimmune disease (e.g., rheumatoid arthritis, systemic progressive sclerosis, systemic lupus erythematosus, Wegener's granulomatosis)
  • Patients with previous allogeneic stem cell transplant (SCT) within 6 months or with active acute or chronic graft-versus host disease are excluded. Patients must be off immunosuppression for graft versus host disease (GVHD) for at least 30 days before cycle 1 day 1
  • Patients with organ allografts (such as renal transplant) are excluded
  • History of interstitial lung disease or pneumonitis
  • Patients who are on high dose steroids (> 10 mg daily of prednisone or equivalent) or immune suppression medications. Note: Patients on high-dose steroids (doses > 10 mg/day of prednisone or equivalent) or immune suppression medications are eligible provided these drugs are discontinued at least 3 days prior to starting on the study drugs
  • Patients with uncontrolled active infection (viral, bacterial, and fungal) are not eligible
  • Current or chronic hepatitis B or C infection, or known seropositivity for human immunodeficiency virus (HIV)
  • Patient is pregnant or breast-feeding
  • Concurrent use of investigational therapeutic agent
  • Malabsorption syndrome or other condition that precludes enteral route of administration
  • Concomitant use of warfarin or other vitamin K antagonists
  • Requires treatment with a strong cytochrome P450 (CYP) 3A inhibitor
  • Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that in the opinion of the investigator may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and/or would make the patient inappropriate for enrollment into this study

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04781855


Contacts
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Contact: Nitin Jain, MD 713-745-6080 njain@mdanderson.org

Locations
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United States, Texas
M D Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Nitin Jain, MD    713-745-6080    njain@mdanderson.org   
Principal Investigator: Nitin Jain, MD         
Sponsors and Collaborators
M.D. Anderson Cancer Center
Investigators
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Principal Investigator: Nitin Jain, MD M.D. Anderson Cancer Center
Additional Information:
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Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT04781855    
Other Study ID Numbers: 2020-0571
NCI-2020-14161 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2020-0571 ( Other Identifier: M D Anderson Cancer Center )
First Posted: March 4, 2021    Key Record Dates
Last Update Posted: October 14, 2022
Last Verified: October 2022

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Lymphoma
Leukemia
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Recurrence
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Disease Attributes
Pathologic Processes
Leukemia, B-Cell
Nivolumab
Ipilimumab
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action