Nivolumab and Ibrutinib in Treating Patients With Relapsed, Refractory, or High-Risk Untreated Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, or Richter Transformation

NCT02420912 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: 2014-0931NCI-2015-00844
• Study Type: interventional
• Target: 37
• Locations: 1 country
• Sites: 1

Brief Summary

This phase II trial studies how well nivolumab and ibrutinib work when given together in treating patients with chronic lymphocytic leukemia, small lymphocytic lymphoma, or Richter transformation that has come back after a period of improvement (relapsed), does not respond to treatment (refractory), or is at high risk of spreading and has not been treated. Immunotherapy with monoclonal antibodies, such as niolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving nivolumab together with ibrutinib may kill more cancer cells.

Conditions

Loss of Chromosome 17p; Recurrent Chronic Lymphocytic Leukemia; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Small Lymphocytic Lymphoma; Richter Syndrome

Outcome Measures

Primary Outcomes (2)

• Number of Participants With a Response for Cohorts 1 and 3

  Response is Complete Response (CR) + Partial Response (PR). CR = Peripheral blood Lymphocytes \<4000/uL, no lymphadenopathy, no hepatomegaly or splenomegaly by exam or scan, absence of symptoms, neutrophils \> 1,500/uL, Platelets \> 1000,000/uL, hemoglobin \> 11.0 g/dl (untransfused) and normocellular bone marrow \< 30% nucleated cells being lymphocytes, no lymphoid nodules. PR = 1 for \>/= 2 months: \>/= 50% decrease in peripheral lymphocyte count from baseline, \>/= 50% reduction in lymphadenopathy, \>/= 50% reduction in pretreatment enlargement of the spleen or liver by scan. Additionally for PR must have 1 of the following for \>/= 2 months: Neutrophils \> 1,500/uL, Platelets \> 100,000/uL or \>/= 50% improvement over baseline or Hemoglobin \> 11.0 g/dl (untransfused) or \>/= 50% improvement over baseline. Additionally if patients fufill CR but have one of the following, be considered a PR: bone marrow nodules or persistent anemia, thrombocytopenia, neutropenia unrelated to disease.

  Up to 12 months

• Number of Participants in Cohort 2 to Convert From a Partial Response (PR) to Complete Response (CR)

  Complete Response (CR) = Peripheral blood Lymphocytes \<4000/uL, no lymphadenopathy, no hepatomegaly or splenomegaly by exam or scan, absence of symptoms, neutrophils \> 1,500/uL, Platelets \> 1000,000/uL, hemoglobin \> 11.0 g/dl (untransfused) and normocellular bone marrow \< 30% nucleated cells being lymphocytes, no lymphoid nodules. Partial Response (PR) = 1 for \>/= 2 months: \>/= 50% decrease in peripheral lymphocyte count from baseline, \>/= 50% reduction in lymphadenopathy, \>/= 50% reduction in pretreatment enlargement of the spleen or liver by scan. Additionally for PR must have 1 of the following for \>/= 2 months: Neutrophils \> 1,500/uL, Platelets \> 100,000/uL or \>/= 50% improvement over baseline or Hemoglobin \> 11.0 g/dl (untransfused) or \>/= 50% improvement over baseline. Additionally if patients fufill CR but have one of the following, be considered a PR: bone marrow nodules or persistent anemia, thrombocytopenia, neutropenia unrelated to disease.

  Up to 12 months

Secondary Outcomes (2)

• Overall Survival (OS)

  Up to 6 years, 7 months

• Progression-free Survival (PFS)

  Up to 6 years, 7 months

Study Arms (3)

Cohort I (nivolumab, ibrutinib) Chronic Lymphocytic Leukemia (CLL)

EXPERIMENTAL

Patients receive nivolumab IV over 1 hour on days 1 and 15 and ibrutinib PO QD on days 1-28 of courses 2-24. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.

Drug: Ibrutinib; Other: Laboratory Biomarker Analysis; Biological: Nivolumab

Cohort II (nivolumab, previous ibrutinib) Chronic Lymphocytic Leukemia (CLL)

EXPERIMENTAL

Patients receive nivolumab as in Cohort I and continue previous ibrutinib treatment.

Drug: Ibrutinib; Other: Laboratory Biomarker Analysis; Biological: Nivolumab

Cohort III (nivolumab, ibrutinib) Richters Transformation (RT)

EXPERIMENTAL

Patients receive nivolumab and ibrutinib as in cohort I. Ibrutinib may be given earlier than course 2 in case of worsening disease after discussion with study principal investigator. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.

Drug: Ibrutinib; Other: Laboratory Biomarker Analysis; Biological: Nivolumab

Interventions

Ibrutinib DRUG

Given PO

Also known as: BTK Inhibitor PCI-32765, CRA-032765, Imbruvica, PCI-32765

Cohort I (nivolumab, ibrutinib) Chronic Lymphocytic Leukemia (CLL); Cohort II (nivolumab, previous ibrutinib) Chronic Lymphocytic Leukemia (CLL); Cohort III (nivolumab, ibrutinib) Richters Transformation (RT)

Laboratory Biomarker Analysis OTHER

Correlative studies

Cohort I (nivolumab, ibrutinib) Chronic Lymphocytic Leukemia (CLL); Cohort II (nivolumab, previous ibrutinib) Chronic Lymphocytic Leukemia (CLL); Cohort III (nivolumab, ibrutinib) Richters Transformation (RT)

Nivolumab BIOLOGICAL

Given IV

Also known as: BMS-936558, MDX-1106, NIVO, ONO-4538, Opdivo

Cohort I (nivolumab, ibrutinib) Chronic Lymphocytic Leukemia (CLL); Cohort II (nivolumab, previous ibrutinib) Chronic Lymphocytic Leukemia (CLL); Cohort III (nivolumab, ibrutinib) Richters Transformation (RT)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients will have a diagnosis of CLL or small lymphocytic lymphoma (SLL), refractory to or relapsed after at least one prior standard therapy or untreated with deletion (del)(17p) by fluorescence in-situ hybridization (FISH) (high-risk cytogenetics) and have an indication for treatment by IWCLL 2008 criteria (Cohort 1) OR have been on ibrutinib for at least 9 months with measurable persistent disease (absolute lymphocyte count \[ALC\] \> 4 K/muL, any lymph node \> 1.5 cm by computed tomography \[CT\] scan, or \> 30% lymphocytes on bone marrow aspirate differential) (Cohort 2), OR patients will have a diagnosis of RT, refractory to and/or relapsed after at least one prior standard therapy or untreated with del(17p) by FISH (high-risk cytogenetics) (Cohort 3)
• 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
• Females of childbearing potential must have a negative serum or urine beta human chorionic gonadotrophin (beta-hCG) pregnancy test result within 24 hours 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

You may not qualify if:

• 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 cluster of differentiation (CD)20 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
• 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 \>= 160 mmHg or diastolic \>= 100 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 steroid (\> 10 mg daily of prednisone or equivalent) or immune suppression medications; Note: patients on high-dose steroids (doses \> 10mg/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

Sponsors & Collaborators

• M.D. Anderson Cancer Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

M D Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Publications (1)

• Jain N, Senapati J, Thakral B, Ferrajoli A, Thompson P, Burger J, Basu S, Kadia T, Daver N, Borthakur G, Konopleva M, Pemmaraju N, Parry E, Wu CJ, Khoury J, Bueso-Ramos C, Garg N, Wang X, Lopez W, Ayala A, O'Brien S, Kantarjian H, Keating M, Allison J, Sharma P, Wierda W. A phase 2 study of nivolumab combined with ibrutinib in patients with diffuse large B-cell Richter transformation of CLL. Blood Adv. 2023 May 23;7(10):1958-1966. doi: 10.1182/bloodadvances.2022008790.

  PMID: 36287248 DERIVED

Related Links

• University of Texas MD Anderson Cancer Center Website

MeSH Terms

Conditions

Chromosome 17 deletion; Leukemia, Lymphocytic, Chronic, B-Cell

Interventions

ibrutinib; Nivolumab

Condition Hierarchy (Ancestors)

Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Nitin Jain, MD/Associate Professor
• Organization: The University of Texas MD Anderson Cancer Center

njain@mdanderson.org

713-745-6080

Study Officials

• Nitin Jain

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 15, 2015
• First Posted: April 20, 2015
• Study Start: June 19, 2015
• Primary Completion: February 14, 2022
• Study Completion: February 14, 2022
• Last Updated: March 20, 2024
• Results First Posted: March 20, 2024

Record last verified: 2024-02

Locations

US (1)