Clinical Trials /

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

NCT02420912

Description:

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.

Related Conditions:
  • Chronic Lymphocytic Leukemia
  • Small Lymphocytic Lymphoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: 2014-0931
  • SECONDARY ID: NCI-2015-00844
  • NCT ID: NCT02420912

Conditions

  • Leukemia
  • Chronic Lymphocytic Leukemia

Interventions

DrugSynonymsArms
NivolumabBMS-936558, OpdivoCohort 1: Not Previously on Ibrutinib
IbrutinibPCI-32765, ImbruvicaCohort 1: Not Previously on Ibrutinib

Purpose

The goal of this clinical research study is to learn if nivolumab in combination with ibrutinib can help control CLL, NHL, or SLL. The safety of this drug combination will also be studied.

Detailed Description

Study Groups and Study Drug Administration:

If you are found to be eligible to take part in this study, you will be assigned to 1 of 2 study groups, depending on if you are already taking ibrutinib or not. If you are NOT already taking ibrutinib, you will be assigned to Group 1. If you are already taking ibrutinib, you will be assigned to Group 2.

All participants will receive nivolumab by vein over about 1 hour on Days 1 and 15 of Cycles 1-24.

If you are in Group 1, starting at Cycle 2, you will also begin to take ibrutinib by mouth 1 time each day at about the same time, about 2 hours after eating but 30 minutes before your next meal. You should take your dose of ibrutinib with a cup (about 8 ounces) of water. Do not open the capsules or dissolve them in water.

If you are in Group 2, you will continue to take the dose of ibrutinib that you are currently taking.

Study Visits:

On Day 1 of all cycles:

- You will have a physical exam, including a neurological exam.

- Blood (about 2 tablespoons) will be drawn for routine tests. If the doctor thinks it is needed, you may have this blood draw performed more often.

- During Cycles 2-4, urine will be collected for routine tests.

On Days 8, 15, and 22 of Cycles 1-6:

- Blood (about 2 tablespoon) will be drawn for routine tests.

- On Day 15 of Cycle 1 only, urine will be collected for routine tests.

- If the doctor thinks it is needed, you will have a physical exam, including a neurological exam. After Cycle 1, you will only have this physical exam on Day 15.

If you are in Group 1, on Day 28 of Cycle 1:

- You will have a bone marrow aspiration to check the status of the disease.

- You will have a CT or PET scan to check the status of the disease.

On Day 28 of Cycle 3 and then every 3 cycles after that for the first year (Cycles 6, 9, 12, and so on) and then every 6 cycles after that:

- You will have a bone marrow aspiration to check the status of the disease.

- If the doctor thinks it is needed, you will have a CT or PET scan to check the status of the disease.

On Day 1 of Cycles 7 and beyond:

- You will have a physical exam, including a neurological exam.

- Blood (about 2 tablespoons) will be drawn for routine tests and to check the status of the disease.

- Every 3 cycles (Cycles 7, 10, 13, and so on), urine will be collected for routine tests.

Every 6 weeks, if you can become pregnant, blood (about 1 tablespoon) or urine will be collected for a pregnancy test.

At any time that the doctor thinks it is needed, you may have blood draws, CT/PET scans, and/or bone marrow aspiration/biopsies to check the status of the disease, while you are on study.

Length of Study:

You may receive up to 24 cycles of nivolumab. You can continue to take ibrutinib as long as the doctor thinks it is in your best interest. You will no longer be able to take the study drug if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.

Your participation on the study will be over after the follow-up visits.

End-of-Study Visit:

Within 30 days after your last dose of study drugs:

- You will have a physical exam, including a neurological exam.

- Blood (about 2-3 tablespoons) will be drawn for routine tests and to check the status of the disease.

- If the doctor thinks it is needed, you will have a bone marrow aspirate to check the status of the disease.

- If the doctor thinks it is needed, you will have a CT or PET scan to check the status of the disease.

Long-Term Follow-Up:

About 1 month after your end-of-study visit, you will continue to have follow-up visits for up to 1 year.

- You will have a physical exam 1 time each month.

- Blood (about 2-3 tablespoons) will be drawn for routine tests 1 time each month.

- Blood (about 1 tablespoon) will be drawn for antibody testing 1 time every 3 months.

- If the doctor thinks it is needed, you will have a bone marrow aspirate to check the status of the disease every 3-6 months.

- If the doctor thinks it is needed, you will have a CT or PET scan to check the status of the disease every 3-6 months.

If you start a new type of anti-CLL/SLL treatment during the follow-up period, you will stop having these study visits.

This is an investigational study. Nivolumab is FDA approved and commercially available for use in melanoma patients. Its use in this study is investigational. Ibrutinib is FDA approved and commercially available for the treatment of patients with CLL/SLL. The use of these drugs in combination is considered investigational. The study doctor can explain how the drugs are designed to work.

Up to 72 participants will be enrolled in this study. All will take part at MD Anderson.

Trial Arms

NameTypeDescriptionInterventions
Cohort 1: Not Previously on IbrutinibExperimentalCohort 1: Determine the response rate (complete response (CR)/complete response with incomplete marrow recovery(CRi)) by 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria. Participants consists of those who were refractory to or relapsed after at least one prior standard therapy or untreated with del(17p) by FISH. Cohort 1: Participants receive Nivolumab 3 mg/kg by vein monotherapy for the first cycle to assess for monotherapy toxicities of Nivolumab. Nivolumab continues for up to 24 cycles (96 weeks; 48 infusions). Ibrutinib 420 mg given by mouth daily at the start of Course 2 on Days 1 and 15 of Cycles 1-24. Cycle of therapy is 28 days.
  • Nivolumab
  • Ibrutinib
Group 2: Currently on IbrutinibExperimentalCohort 2: Determine the conversion rate from PR to CR/CRi by 2008 IWCLL criteria. Cohort 2: Participants receive Nivolumab 3 mg/kg by vein monotherapy for the first cycle to assess for monotherapy toxicities of Nivolumab. Nivolumab continues for up to 24 cycles (96 weeks; 48 infusions). Participants to have been on Ibrutinib for >9 months. Ibrutinib given by mouth daily, at same dose currently receiving, on Days 1 and 15 of Cycles 1-24. Cycle of therapy is 28 days.
  • Nivolumab
  • Ibrutinib
Cohort 3: Not Previously on IbrutinibExperimentalCohort 3: Determine the response rate (CR/CRi). Determine the response rate (complete response (CR)/complete response with incomplete marrow recovery(CRi)) by 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria. Participants consists of those who who were refractory to or relapsed after at least one prior standard therapy or untreated with del(17p) by FISH. Cohort 3: Participants receive Nivolumab 3 mg/kg by vein monotherapy for the first cycle to assess for monotherapy toxicities of Nivolumab. Nivolumab continues for up to 24 cycles (96 weeks; 48 infusions). Ibrutinib 420 mg given by mouth daily at the start of Course 2 on Days 1 and 15 of Cycles 1-24. Cycle of therapy is 28 days.
  • Nivolumab
  • Ibrutinib

Eligibility Criteria

Inclusion Criteria:

1. Patients will have a diagnosis of CLL or SLL, refractory to or relapsed after at least one prior standard therapy or untreated with 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) > 4K/muL, any lymph node > 1.5 cm by 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).

2. Age 18 years or older.

3. Eastern Cooperative Oncology Group (ECOG) Performance Status </=2.

4. Patients must have adequate renal and hepatic function: -- 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.

5. 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.

6. Patients or their legally authorized representative must provide written informed consent.

Exclusion Criteria:

1. 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

2. 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.

3. 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.

4. History of stroke or cerebral hemorrhage within 2 month.

5. Patients who have uncontrolled hypertension (defined as sustained systolic blood pressure >/= 160 mmHg or diastolic >/= 100 mmHg).

6. 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.

7. Active, uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia requiring steroid therapy.

8. 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).

9. Patients with previous allogeneic stem cell transplant (SCT) ) within 6 months or with active acute or chronic graft-versus host disease are exclude. Patients must be off immunosuppression for GVHD for at least 30 days before cycle 1 day 1.

10. Patients with organ allografts (such as renal transplant) are excluded.

11. History of interstitial lung disease or pneumonitis.

12. Patients who are on high dose steroids (>10mg 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.

13. Patients with uncontrolled active infection (viral, bacterial, and fungal) are not eligible.

14. Current or chronic hepatitis B or C infection, or known seropositivity for Human Immunodeficiency Virus (HIV).

15. Patient is pregnant or breast-feeding.

16. Concurrent use of investigational therapeutic agent.

17. Malabsorption syndrome or other condition that precludes enteral route of administration.

18. Concomitant use of warfarin or other Vitamin K antagonists.

19. Requires treatment with a strong cytochrome P450 (CYP) 3A inhibitor.

20. 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.

Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Cohort 1 and 3: Response Rate of Nivolumab in Combination with Ibrutinib
Time Frame:12 months
Safety Issue:
Description:Best response (BR) defined as complete response (CR) or complete response with incomplete marrow recovery (CRi) that occurs during the first 12 months of treatment, as described by 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria.

Secondary Outcome Measures

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Trial Keywords

  • Leukemia
  • Chronic Lymphocytic Leukemia
  • CLL
  • Relapsed
  • Refractory
  • High-risk
  • Untreated
  • Nivolumab
  • BMS-936558
  • Opdivo
  • Ibrutinib
  • PCI-32765
  • Imbruvica

Last Updated

February 23, 2017