Testing The Addition of a New Anti-cancer Drug, Venetoclax, to the Usual Treatment (Ibrutinib and Obinutuzumab) in Untreated, Older Patients With Chronic Lymphocytic Leukemia

• ClinicalTrials.gov Identifier: NCT03737981
• Recruitment Status: Recruiting
• First Posted: November 12, 2018
• Last Update Posted: October 18, 2019
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Cancer Institute (NCI)

Study Description

Brief Summary:

This phase III trial compares adding a new anti-cancer drug (venetoclax) to the usual treatment (ibrutinib plus obinutuzumab) in older patients with chronic lymphocytic leukemia who have not received previous treatment. The addition of venetoclax to the usual treatment might prevent chronic lymphocytic leukemia from returning. This trial also will investigate whether patients who receive ibrutinib plus obinutuzumab plus venetoclax and have no detectable chronic lymphocytic leukemia after 1 year of treatment, can stop taking ibrutinib. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Immunotherapy with obinutuzumab may induce changes in body's immune system and may interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as venetoclax work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving ibrutinib and obinutuzumab with venetoclax may work better at treating chronic lymphocytic leukemia compared to ibrutinib and obinutuzumab.

Condition or disease	Intervention/treatment	Phase
Chronic Lymphocytic Leukemia	Drug: Ibrutinib; Biological: Obinutuzumab; Other: Observation; Drug: Venetoclax	Phase 3

Detailed Description:

PRIMARY OBJECTIVE:

I. To compare the progression-free survival (PFS) between control treatment and experimental treatment strategies: ibrutinib/obinutuzumab (IO) with ibrutinib maintenance (IM) versus ibrutinib/venetoclax/obinutuzumab (IVO) regardless of IM or observation.

SECONDARY OBJECTIVES:

I. To compare bone marrow (BM) minimal residual disease (MRD)- complete response (CR) rates and depth of response at cycle 15 day 1 between patients treated with IO versus IVO.

II. To compare overall survival (OS) between the control and experimental treatment strategies: IO with IM versus IVO regardless of IM or observation.

III. To compare the 5-year PFS and overall survival (OS) for the control and experimental treatment strategies: IO with IM versus IVO regardless of IM or observation.

IV. To describe the toxicity profile for each of the treatment strategies and by each treatment course.

CORRELATIVES SCIENCE OBJECTIVE:

I. To compare MRD status between blood and bone marrow at the end of induction treatment/cycle 15 day 1 to determine whether blood MRD can be used as a surrogate to bone marrow MRD with these treatment regimens.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive ibrutinib orally (PO) once daily (QD) on days 1-28. Patients also receive obinutuzumab intravenously (IV) on days 1, 2, 8, and 15 of cycle 1, and on day 1 of cycles 2-6. Treatment repeats every 28 days for up to 14 cycles in the absence of disease progression or unacceptable toxicity. Beginning cycle 15, patients receive ibrutinib PO QD every 28 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive ibrutinib PO QD on days 1-28. Patients also receive obinutuzumab IV on days 1, 2, 8, and 15 of cycle 1, and on day 1 of cycles 2-6. Beginning cycle 3, patients also receive venetoclax PO QD on days 1-28. Treatment repeats every 28 days for 14 cycles in the absence of disease progression or unacceptable toxicity. All patients will then receive a 15th cycle of ibrutinib. Beginning cycle 16, patients who do not achieve a BM MRD negative CR, receive ibrutinib PO QD every 28 days in the absence of disease progression or unacceptable toxicity. Patients who achieve a BM MRD negative CR undergo observation every 3 cycles for 6 years, then every 6 cycles thereafter.

After completion of study treatment, followed every 6 months until 10 years from registration.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 454 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Phase III Study of Ibrutinib Plus Obinutuzumab Versus Ibrutinib Plus Venetoclax and Obinutuzumab in Untreated Older Patients (>/= 70 Years of Age) With Chronic Lymphocytic Leukemia (CLL)
• Actual Study Start Date: January 4, 2019
• Estimated Primary Completion Date: June 1, 2027
• Estimated Study Completion Date: June 1, 2027

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Arm I (ibrutinib, obinutuzumab); Patients receive ibrutinib PO QD on days 1-28. Patients also receive obinutuzumab IV on days 1, 2, 8, and 15 of cycle 1, and on day 1 of cycles 2-6. Treatment repeats every 28 days for up to 14 cycles in the absence of disease progression or unacceptable toxicity. Beginning cycle 15, patients receive ibrutinib PO QD every 28 days in the absence of disease progression or unacceptable toxicity.	Drug: Ibrutinib; Given PO; Other Names: BTK Inhibitor PCI-32765; CRA-032765; Imbruvica; PCI-32765; Biological: Obinutuzumab; Given IV; Other Names: Anti-CD20 Monoclonal Antibody R7159; GA-101; GA101; Gazyva; huMAB(CD20); R7159; RO 5072759; RO-5072759; RO5072759
Experimental: Arm II (ibrutinib, obinutuzumab, venetoclax); Patients receive ibrutinib PO QD on days 1-28. Patients also receive obinutuzumab IV on days 1, 2, 8, and 15 of cycle 1, and on day 1 of cycles 2-6. Beginning cycle 3, patients also receive venetoclax PO QD on days 1-28. Treatment repeats every 28 days for 14 cycles in the absence of disease progression or unacceptable toxicity. All patients will then receive a 15th cycle of ibrutinib. Beginning cycle 16, patients who do not achieve a BM MRD negative CR, receive ibrutinib PO QD every 28 days in the absence of disease progression or unacceptable toxicity. Patients who achieve a BM MRD negative CR undergo observation every 3 cycles for 6 years, then every 6 cycles thereafter.	Drug: Ibrutinib; Given PO; Other Names: BTK Inhibitor PCI-32765; CRA-032765; Imbruvica; PCI-32765; Biological: Obinutuzumab; Given IV; Other Names: Anti-CD20 Monoclonal Antibody R7159; GA-101; GA101; Gazyva; huMAB(CD20); R7159; RO 5072759; RO-5072759; RO5072759; Other: Observation; Undergo observation; Other Names: Inspection; Visual Inspection; Drug: Venetoclax; Given PO; Other Names: ABT-0199; ABT-199; ABT199; GDC-0199; RG7601; Venclexta; Venclyxto

Outcome Measures

Primary Outcome Measures :

1. Progression-free survival (PFS) [ Time Frame: From randomization date until the earlier of disease progression or death from any cause, assessed up to 10 years ]
   PFS will be compared between the experimental and control treatment strategy groups using a stratified log-rank test (stratified on Rai stage, intermediate versus [vs.] high, and del(17p13.1) by fluorescence in situ hybridization [FISH], present vs. absent). The Kaplan-Meier method will be used to estimate PFS distributions. Five-year PFS estimates, medians, and corresponding hazard ratios will be provided with 95% confidence intervals for each treatment strategy.

Secondary Outcome Measures :

1. Bone marrow (BM) minimal residual disease (MRD)- complete response (CR) rate [ Time Frame: Up to 10 years ]
   BM MRD- CR rate will be calculated and will be estimated using the number of patients meeting the BM MRD- CR criteria divided by the total number of patients randomized to each of the treatment arms. The stratified Cochran-Mantel-Haenszel test will be used to compare the BM MRD- CR rates between treatment arms (stratified on Rai stage, intermediate vs. high, and del(17p13.1) by FISH, present vs. absent).
2. Overall survival (OS) [ Time Frame: From randomization date until death from any cause, assessed up to 10 years ]
   The Kaplan-Meier method will be used to estimate the OS distribution for each treatment strategy. Estimates at 5 years will be calculated with corresponding 95% confidence intervals, and differences in these estimates between the treatment strategies will be tested using a stratified chi-square test based on the complementary log-log transformation of the Kaplan-Meier estimates. Comparisons in OS curves between experimental and control treatment strategies will use a stratified log-rank test (stratified on Rai stage, intermediate vs. high, and del(17p13.1) by FISH, present vs. absent). Hazard ratios with 95% confidence intervals will be estimated from the corresponding, stratified proportional hazard model.
3. Incidence of adverse events [ Time Frame: Up to 10 years ]
   Will be defined as adverse events that are classified as either possibly, probably, or definitely related to study treatment, graded per National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Frequency and severity of adverse events and tolerability for each treatment strategy group will be summarized using descriptive statistics. The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns. The incidence of severe (grade 3+) adverse events or toxicities will be described.

Eligibility Criteria

• Ages Eligible for Study: 70 Years and older (Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• PRE-REGISTRATION ELIGIBILITY CRITERIA (STEP 0)
• Patients must have been diagnosed with chronic lymphocytic leukemia (CLL) and have > 5000 B-cells per uL of peripheral blood at any point during the course of their disease
• This blood submission is mandatory prior to registration/randomization to perform fluorescence in situ hybridization (FISH) centrally that will be used for stratification. It should be obtained as soon after pre-registration as possible
• REGISTRATION ELIGIBILITY CRITERIA (STEP 1)

• Patients must be diagnosed with CLL in accordance with 2018 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria that includes all of the following:

  • >= 5 x10^9 B lymphocytes (5000/uL) in the peripheral blood measured by flow cytometry at any point in the course of the disease
  • On local morphologic review, the leukemic cells must be small mature lymphocytes, and prolymphocytes must not exceed 55% of the blood lymphocytes
  • CLL cells on immunophenotype (performed locally) must reveal a clonal B-cell population, which express the B cell surface markers of CD19 and CD20, as well as the T-cell antigen CD5. Patients with bright surface immunoglobulin expression or lack of CD23 expression in > 10% of cells must lack t(11;14) translocation by interphase cytogenetics

• Patients must be intermediate or high-risk Rai stage CLL

  • Intermediate risk (formerly Rai stage I/II) is defined by lymphocytosis plus enlarged lymph nodes at any site, with or without hepatomegaly or splenomegaly
  • High risk (formerly Rai stage III/IV) is defined by lymphocytosis with or without enlarged nodes and spleen plus disease-related anemia (hemoglobin < 11 g/dL) or thrombocytopenia (platelet count < 100 x 10^9/L) that is not attributable to autoimmune hemolytic anemia or thrombocytopenia

• Patients must meet criteria for treatment as defined by 2018 IWCLL guidelines which includes at least one of the following criteria:

  • Evidence of marrow failure as manifested by the development or worsening of anemia or thrombocytopenia (not attributable to autoimmune hemolytic anemia or thrombocytopenia)
  • Massive (>= 6 cm below the costal margin), progressive or symptomatic splenomegaly
  • Massive nodes (>= 10 cm) or progressive or symptomatic lymphadenopathy
  • Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard therapy
  • Symptomatic or functional extranodal involvement (e.g. skin, kidney, lung, spine)

  • Constitutional symptoms, which include any of the following:

    • Unintentional weight loss of 10% or more within 6 months
    • Significant fatigue
    • Fevers > 100.5 degrees Fahrenheit (F) for 2 weeks or more without evidence of infection
    • Night sweats >= 1 month without evidence of infection
• Patients must not have had prior therapy for CLL (except palliative steroids or treatment of autoimmune complications of CLL with rituximab or steroids)
• Treatment with rituximab and/or high dose corticosteroids for autoimmune complications of CLL must be complete at least 4 weeks prior to enrollment. Palliative steroids must be at a dose not higher than 20 mg/day of prednisone or equivalent corticosteroid at the time of registration
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Absolute neutrophil count (ANC) >= 1,000/mm3 except if due to bone marrow involvement
• Platelet count (untransfused) >= 30,000/mm3
• Calculated (Calc.) creatinine clearance >= 40 mL/min (by Cockcroft-Gault)
• Bilirubin =< 1.5 x upper limit of normal (ULN) except if due to liver involvement, hemolysis, or Gilbert's disease
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN) except if due to liver involvement
• Patients must not have any history of Richter's transformation or prolymphocytic leukemia (prolymphocytes in blood > 55%)
• If evidence of chronic hepatitis B virus (HBV) infection, HBV viral load must be undetectable on suppressive therapy if indicated
• Please note: Intravenous immunoglobulin therapy (IVIG) can cause a false positive hepatitis B serology. If patients receiving routine IVIG have core antibody or surface antigen positivity without evidence of active viremia (negative hepatitis B deoxyribonucleic acid [DNA]) they may still participate in the study, must have hepatitis serologies and hepatitis B DNA monitored periodically by the treating physician
• If history of hepatitis C virus (HCV) infection, must be treated with undetectable HCV viral load
• Patients with class III or class IV heart failure by New York Heart Association, those with unstable angina, and those with uncontrolled arrhythmia are not eligible
• Patients who have had a myocardial infarction, intracranial bleed, or stroke within the past 6 months are not eligible
• Human immunodeficiency virus (HIV)-infected patients on effective antiretroviral therapy with undetectable viral load within 6 months are eligible for this trial
• Patients must not be receiving active systemic anticoagulation with heparin or warfarin. Patients on warfarin must discontinue the drug for at least 10 days prior to registration on the study
• Chronic concomitant treatment with strong inhibitors of CYP3A4/5 is not allowed on this study. Patients on strong CYP3A inhibitors must discontinue the drug for 14 days prior to registration on the study
• Chronic concomitant treatment with strong CYP3A4/5 inducers is not allowed. Patients must discontinue the drug 14 days prior to registration on the study
• Patients must not require more than 20 mg prednisone or equivalent corticosteroid daily
• Patients must not have uncontrolled active systemic infection requiring intravenous antibiotics
• Patients must be able to swallow capsules and not have the following conditions: disease significantly affecting gastrointestinal absorption, resection of the stomach or small bowel, partial or complete bowel obstruction
• Patients must not have a known allergy to mannitol
• Patients must not have prior significant hypersensitivity to rituximab (not including infusion reactions)
• Patients may not have had major surgery within 10 days prior to registration, or minor surgery within 7 days prior to registration. Examples of minor surgery include dental surgery, insertion of a venous access device, skin biopsy, or aspiration for a joint. The decision about whether a surgery is major or minor can be made at the discretion of the treating physician
• Patients must be able to receive either a xanthine oxidase inhibitor or rasburicase for prophylaxis/treatment of tumor lysis syndrome (TLS)
• RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2)
• Completion of treatment through cycle 14 day 28, and remain on ibrutinib therapy
• Receipt of central BM MRD results
• Response assessment completed with CR determination

Contacts and Locations

  Show 692 Study Locations

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Jennifer A Woyach; Alliance for Clinical Trials in Oncology

More Information

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT03737981 History of Changes
• Other Study ID Numbers: NCI-2018-02485; NCI-2018-02485 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); A041702 ( Other Identifier: Alliance for Clinical Trials in Oncology ); A041702 ( Other Identifier: CTEP ); U10CA180821 ( U.S. NIH Grant/Contract )
• First Posted: November 12, 2018
• Last Update Posted: October 18, 2019
• Last Verified: August 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page
• URL: https://grants.nih.gov/policy/sharing.htm

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Leukemia, B-Cell; Venetoclax; Obinutuzumab; Antineoplastic Agents; Antineoplastic Agents, Immunological