Clinical Trial: NCT03737981 - My Cancer Genome

NCT03737981

Description:

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. Venetoclax may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Giving ibrutinib and obinutuzumab with venetoclax may work better at treating chronic lymphocytic leukemia compared to ibrutinib and obinutuzumab.

Related Conditions:

Chronic Lymphocytic Leukemia

Recruiting Status:

Recruiting

Phase:

Phase 3

URL:

https://clinicaltrials.gov/show/NCT03737981

Trial Eligibility

Document

Title

Brief Title: 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
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)

Clinical Trial IDs

ORG STUDY ID: NCI-2018-02485
SECONDARY ID: NCI-2018-02485
SECONDARY ID: A041702
SECONDARY ID: A041702
SECONDARY ID: U10CA180821
NCT ID: NCT03737981

Conditions

Chronic Lymphocytic Leukemia
Small Lymphocytic Lymphoma

Interventions

Drug	Synonyms	Arms
Ibrutinib	BTK Inhibitor PCI-32765, CRA-032765, Imbruvica, PCI-32765	Arm I (ibrutinib, obinutuzumab)
Obinutuzumab	Anti-CD20 Monoclonal Antibody R7159, GA-101, GA101, Gazyva, huMAB(CD20), R7159, RO 5072759, RO-5072759, RO5072759	Arm I (ibrutinib, obinutuzumab)
Venetoclax	ABT-0199, ABT-199, ABT199, GDC-0199, RG7601, Venclexta, Venclyxto	Arm II (ibrutinib, obinutuzumab, venetoclax)

Purpose

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,
      MRD- 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 OBJECTIVES:

      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.

      II. To compare peripheral blood MRD status by standard central flow cytometry to next
      generation sequencing (NGS) using ClonoSeq technique to determine the agreement in MRD
      negativity of the two techniques.

      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, patients are followed every 6 months until 10 years from
      registration.

Trial Arms

Name	Type	Description	Interventions
Arm I (ibrutinib, obinutuzumab)	Active Comparator	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.	Ibrutinib Obinutuzumab
Arm II (ibrutinib, obinutuzumab, venetoclax)	Experimental	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.	Ibrutinib Obinutuzumab Venetoclax

Eligibility Criteria

        Inclusion Criteria:

          -  PRE-REGISTRATION ELIGIBILITY CRITERIA (STEP 0)

          -  Patients must have been diagnosed with chronic lymphocytic leukemia (CLL) (> 5000
             B-cells per uL of peripheral blood at any point during the course of their disease) or
             small lymphocytic lymphoma (SLL) with < 5000 B-cells per uL of blood but with
             disease-associated lymphadenopathy

          -  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 or SLL 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 or less peripheral blood
                  involvement but disease-associated lymphadenopathy

               -  On local morphologic review, the leukemic cells must be small mature lymphocytes,
                  and prolymphocytes must not exceed 55% of the blood lymphocytes

               -  Neoplastic 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 or SLL

               -  Intermediate risk (formerly stage I/II) is defined by lymphadenopathy and/or
                  hepatomegaly or splenomegaly without anemia or thrombocytopenia

               -  High risk (formerly stage III/IV) is defined by splenomegaly and/or anemia
                  (hemoglobin < 11g/dL) not attributable to autoimmune hemolytic anemia and/or
                  thrombocytopenia (platelets [plt] < 100 x10^9/L) not attributable to autoimmune
                  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

               -  Progressive lymphocytosis with a lymphocyte doubling time < 6 months or an
                  increase of >= 50% over a 2 month period

               -  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

          -  Treatment with rituximab and/or high dose corticosteroids for autoimmune complications
             of CLL/SLL 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

          -  Age >= 70 years or >= 65 years with the presence of del(17p) on fluorescent in situ
             hybridization (FISH)

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-2

          -  Absolute neutrophil count (ANC) >= 1,000/mm^3 except if due to bone marrow involvement

          -  Platelet count (untransfused) >= 30,000/mm^3 except if due to bone marrow involvement

          -  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

          -  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

          -  Human immunodeficiency virus (HIV)-infected patients on effective antiretroviral
             therapy with undetectable viral load within 6 months are eligible for this trial

          -  Central fluorescent in situ hybridization (FISH) blood results are mandatory prior to
             registration/randomization for it will be used for stratification

          -  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 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

        Exclusion Criteria:

          -  Patients must not have had prior therapy for CLL/SLL (except palliative steroids or
             treatment of autoimmune complications of CLL with rituximab or steroids)

          -  Patients must not have any history of Richter's transformation or prolymphocytic
             leukemia (prolymphocytes in blood > 55%)

          -  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

          -  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 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

Maximum Eligible Age:	N/A
Minimum Eligible Age:	70 Years
Eligible Gender:	All
Healthy Volunteers:	No

Primary Outcome Measures

Measure:	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
Safety Issue:
Description:	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

Measure:	Bone marrow (BM) minimal residual disease (MRD)- complete response (CR) rate
Time Frame:	Up to 10 years
Safety Issue:
Description:	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).

Measure:	Overall survival (OS)
Time Frame:	From randomization date until death from any cause, assessed up to 10 years
Safety Issue:
Description:	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.

Measure:	Incidence of adverse events
Time Frame:	Up to 10 years
Safety Issue:
Description:	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.

Details

Phase:	Phase 3
Primary Purpose:	Interventional
Overall Status:	Recruiting
Lead Sponsor:	National Cancer Institute (NCI)

Last Updated

August 27, 2021

Clinical Trials /

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