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Loss of Chromosome 17pPhase 2NCT02420912

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

A Phase 2 study testing Ibrutinib, Laboratory Biomarker Analysis and Nivolumab in people with Loss of Chromosome 17p and Recurrent Chronic Lymphocytic Leukemia, run by M.D. Anderson Cancer Center at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Ibrutinib, Laboratory Biomarker Analysis and Nivolumab
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
37 participants
Where
1 siteUnited States
Study dates
19 Jun 2015to 14 Feb 2022
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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

Who cannot join

  • 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
Show all 20Show fewer
  • 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
  • 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) family 3, subfamily A (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

Trial locations and contacts

1 site in 1 country.

United States1 site

  • M D Anderson Cancer Center

    Houston, Texas, 77030

Other trials in United States

About this study

Official title: Nivolumab Combined With Ibrutinib for Relapsed, Refractory or High-Risk Untreated Patients With Chronic Lymphocytic Leukemia (CLL)

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.

Read the detailed description

PRIMARY OBJECTIVES:

  1. To determine the efficacy (response rate) of nivolumab in combination with ibrutinib in patients with relapsed/refractory or high-risk untreated chronic lymphocytic leukemia (CLL).

II. Determine the response rate (complete response [CR]/complete response with incomplete marrow recovery [CRi]) by 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria. (Cohort I) III. Determine the conversion rate from partial response (PR) to CR/CRi by 2008 IWCLL criteria. (Cohort II) IV. Determine the response rate (CR/CRi). (Cohort III)

SECONDARY OBJECTIVES:

  1. To determine the safety of nivolumab in combination with ibrutinib in patients with relapsed, refractory or high-risk untreated CLL/Richter transformation (RT).

II. To determine the progression-free survival of patients with relapsed, refractory or high-risk untreated CLL/RT treated with nivolumab in combination with ibrutinib.

III. To determine the overall survival of patients with relapsed, refractory or high-risk untreated CLL/RT treated with nivolumab in combination with ibrutinib.

EXPLORATORY OBJECTIVES:

  1. To study immunological and molecular changes in peripheral blood, lymph node, and bone marrow in response to nivolumab and ibrutinib therapy.

OUTLINE: Patients are assigned to 1 of 3 treatment cohorts.

COHORT I (NO CURRENT IBRUTINIB TREATMENT): Patients receive nivolumab intravenously (IV) over 1 hour on days 1 and 15 and ibrutinib orally (PO) once daily (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.

COHORT II (IBRUTINIB TREATMENT > 9 MONTHS): Patients receive nivolumab as in Cohort I and continue previous ibrutinib treatment.

COHORT III (RICHTER TRANSFORMATION): 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

  • Note: After 3 cycles of treatment, nivolumab administration may be decreased to once every 4 weeks in all cohorts, in consultation with the study principal investigator.

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

Being tested
Ibrutinib, Laboratory Biomarker Analysis, Nivolumab
Medical subject headings
Chromosome 17 deletion, Leukemia, Lymphocytic, Chronic, B-Cell

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • IbrutinibDrug

    Also called BTK Inhibitor PCI-32765, CRA-032765, Imbruvica, PCI-32765

    Given PO

  • Laboratory Biomarker AnalysisOther

    Correlative studies

  • NivolumabBiological

    Also called BMS-936558, MDX-1106, NIVO, ONO-4538

    Given IV

Study groups in NCT02420912
Study groupRoleWhat they receive
Cohort I (nivolumab, ibrutinib) Chronic Lymphocytic Leukemia (CLL)ExperimentalPatients 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.
Receives: Drug: Ibrutinib; Other: Laboratory Biomarker Analysis; Biological: Nivolumab
Cohort II (nivolumab, previous ibrutinib) Chronic Lymphocytic Leukemia (CLL)ExperimentalPatients receive nivolumab as in Cohort I and continue previous ibrutinib treatment.
Receives: Drug: Ibrutinib; Other: Laboratory Biomarker Analysis; Biological: Nivolumab
Cohort III (nivolumab, ibrutinib) Richters Transformation (RT)ExperimentalPatients 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.
Receives: Drug: Ibrutinib; Other: Laboratory Biomarker Analysis; Biological: Nivolumab

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: Up to 12 months

  2. 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.

    Measured: Up to 12 months

Secondary outcomes (2)

  1. Overall Survival (OS)

    Time from date of treatment start until date of death due to any cause or last Follow-up. Survival will be presented by median survival, which is the time point at which the cumulative survival drops below 50%. If there is no median survival (not reached), it means the cumulative survival was more than 50%.

    Measured: Up to 6 years, 7 months

  2. Progression-free Survival (PFS)

    Time from date of treatment start until the date of first objective documentation of disease-relapse.

    Measured: Up to 6 years, 7 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted20 Apr 2015 (estimated)
  2. Study start19 Jun 2015
  3. Primary completion14 Feb 2022
  4. Study completion14 Feb 2022

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
37 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02420912
Sponsor's protocol ID
2014-0931
Other IDs
NCI-2015-00844, 2014-0931
Status last verified
Feb 2024
First submitted
15 Apr 2015
Last updated
20 Mar 2024
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No

Publications

  • 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.

    PubMed 36287248

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Ibrutinib, Laboratory Biomarker Analysis and Nivolumab in people with Loss of Chromosome 17p and Recurrent Chronic Lymphocytic Leukemia, run by M.D. Anderson Cancer Center at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 20 Mar 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 20 Mar 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of Participants With a Response for Cohorts 1 and 3 (time frame: Up to 12 months). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02420912, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Mar 2024.

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