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

Primary Purpose

Hematopoietic and Lymphoid Cell Neoplasm, Recurrent Chronic Lymphocytic Leukemia, Recurrent Small Lymphocytic Lymphoma

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Ibrutinib
Ipilimumab
Nivolumab
Sponsored by
M.D. Anderson Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hematopoietic and Lymphoid Cell Neoplasm

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • M D Anderson Cancer CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Part A (ipilimumab, ibrutinib)

Part B (ipilimumab, nivolumab, ibrutinib)

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

Maximum tolerated dose of ipilimumab
Dose limiting toxicities
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

Overall response rate
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.
Progression-free survival
Assessed using Kaplan-Meier method.
Overall survival
Assessed using Kaplan-Meier method.
Incidence of adverse events
Will be summarized by treatment, category, severity and attribution.

Full Information

First Posted
February 24, 2021
Last Updated
August 22, 2023
Sponsor
M.D. Anderson Cancer Center
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1. Study Identification

Unique Protocol Identification Number
NCT04781855
Brief Title
Ipilimumab, Ibrutinib, and Nivolumab for the Treatment of Chronic Lymphocytic Leukemia and Richter Transformation
Official Title
Ipilimumab Combined With Ibrutinib and Nivolumab for Patients With Chronic Lymphocytic Leukemia (CLL) and Richter Transformation (RT)
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Recruiting
Study Start Date
July 14, 2022 (Actual)
Primary Completion Date
December 31, 2024 (Anticipated)
Study Completion Date
December 31, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
M.D. Anderson Cancer Center

4. Oversight

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
Data Monitoring Committee
Yes

5. Study Description

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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hematopoietic and Lymphoid Cell Neoplasm, Recurrent Chronic Lymphocytic Leukemia, Recurrent Small Lymphocytic Lymphoma, Refractory Chronic Lymphocytic Leukemia, Refractory Small Lymphocytic Lymphoma, Richter Syndrome

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
50 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Part A (ipilimumab, ibrutinib)
Arm Type
Experimental
Arm Description
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.
Arm Title
Part B (ipilimumab, nivolumab, ibrutinib)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Ibrutinib
Other Intervention Name(s)
BTK Inhibitor PCI-32765, CRA-032765, Imbruvica, PCI-32765
Intervention Description
Given PO
Intervention Type
Biological
Intervention Name(s)
Ipilimumab
Other Intervention Name(s)
Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS-734016, Ipilimumab Biosimilar CS1002, MDX-010, MDX-CTLA4, Yervoy
Intervention Description
Given IV
Intervention Type
Biological
Intervention Name(s)
Nivolumab
Other Intervention Name(s)
BMS-936558, MDX-1106, NIVO, ONO-4538, Opdivo
Intervention Description
Given IV
Primary Outcome Measure Information:
Title
Maximum tolerated dose of ipilimumab
Time Frame
Up to 2 years
Title
Dose limiting toxicities
Description
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.
Time Frame
During first 21 days on study intervention
Secondary Outcome Measure Information:
Title
Overall response rate
Description
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.
Time Frame
Up to 2 years
Title
Progression-free survival
Description
Assessed using Kaplan-Meier method.
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
Title
Overall survival
Description
Assessed using Kaplan-Meier method.
Time Frame
From treatment start date until the date of death due to any cause, assessed up to 2 years
Title
Incidence of adverse events
Description
Will be summarized by treatment, category, severity and attribution.
Time Frame
Up to 2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Nitin Jain, MD
Phone
713-745-6080
Email
njain@mdanderson.org
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Nitin Jain, MD
Organizational Affiliation
M.D. Anderson Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
M D Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Nitin Jain, MD
Phone
713-745-6080
Email
njain@mdanderson.org
First Name & Middle Initial & Last Name & Degree
Nitin Jain, MD

12. IPD Sharing Statement

Links:
URL
http://www.mdanderson.org
Description
M D Anderson Cancer Center

Learn more about this trial

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

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