Clinical Trial: NCT03462719 - My Cancer Genome

NCT03462719

Description:

The purpose of this study is to assess progression-free survival (PFS) from treatment with ibrutinib plus venetoclax (I+VEN) compared with obinutuzumab plus chlorambucil (G-Clb) as assessed by an Independent Review Committee (IRC).

Related Conditions:

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Recruiting Status:

Active, not recruiting

Phase:

Phase 3

URL:

https://clinicaltrials.gov/show/NCT03462719

Trial Eligibility

Document

Title

Brief Title: A Study of the Combination of Ibrutinib Plus Venetoclax Versus Chlorambucil Plus Obinutuzumab for the First-line Treatment of Participants With Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)
Official Title: A Randomized, Open-label, Phase 3 Study of the Combination of Ibrutinib Plus Venetoclax Versus Chlorambucil Plus Obinutuzumab for the First-line Treatment of Subjects With Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL).

Clinical Trial IDs

ORG STUDY ID: CR108428
SECONDARY ID: 2017-004699-77
SECONDARY ID: 54179060CLL3011
NCT ID: NCT03462719

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell

Interventions

Drug	Synonyms	Arms
Ibrutinib		Treatment Arm A: Ibrutinib and Venetoclax (I+VEN)
Venetoclax		Treatment Arm A: Ibrutinib and Venetoclax (I+VEN)
Chlorambucil		Treatment Arm B: Chlorambucil and Obinutuzumab (G-Clb)
Obinutuzumab		Treatment Arm B: Chlorambucil and Obinutuzumab (G-Clb)
Ibrutinib (as Subsequent Therapy)		Treatment Arm A: Ibrutinib and Venetoclax (I+VEN)

Purpose

Detailed Description

      The hypothesis is treatment with combination of I+VEN will result in longer PFS compared with
      G-Clb in participants with previously untreated chronic lymphocytic leukemia (CLL)/ small
      lymphocytic lymphoma (SLL) who meet International Workshop on CLL (iwCLL) treatment criteria.
      The study includes screening (30 days), treatment (from randomization until treatment
      discontinuation) and follow-up phase (from treatment discontinuation until Subsequent Therapy
      Phase [if applicable], death, lost to follow up, consent withdrawal, or study end, whichever
      occurs first). Participants without progression will continue disease evaluations until
      disease progression or death. Participants from either treatment arm that develop progressive
      disease may be eligible to receive single-agent ibrutinib until disease progression or
      unacceptable toxicity (Subsequent Therapy Phase). Participation in this phase of the study is
      not mandatory and is based on investigator's discretion. Study duration is approximately 6
      years. Safety includes review of adverse events and laboratory tests performed over time.

Trial Arms

Name	Type	Description	Interventions
Treatment Arm A: Ibrutinib and Venetoclax (I+VEN)	Experimental	Participants will initially receive ibrutinib (420 mg [milligrams]/day) for 3 cycles. Venetoclax dose ramp up (from 20 to 400 mg over 5 weeks) will begin at Cycle 4 and the combination of ibrutinib and venetoclax will be given for 12 cycles (each cycle is equivalent to 28 days). Participants who subsequently develop progressive disease may enter to Subsequent Therapy Phase to receive single-agent ibrutinib until disease progression or unacceptable toxicity.	Ibrutinib Venetoclax Ibrutinib (as Subsequent Therapy)
Treatment Arm B: Chlorambucil and Obinutuzumab (G-Clb)	Active Comparator	Participants will receive chlorambucil and obinutuzumab (G-Clb) for 6 cycles. Participants will receive obinutuzumab, 1000 mg intravenously (IV) on Days 1, 8 and 15 of Cycle 1, and on Day 1 of Cycles 2 to 6 and chlorambucil 0.5 milligrams per kilogram (mg/kg) body weight, on Days 1 and 15 of Cycles 1 to 6. Participants who subsequently develop progressive disease may enter to Subsequent Therapy Phase to receive single-agent ibrutinib until disease progression or unacceptable toxicity.	Chlorambucil Obinutuzumab Ibrutinib (as Subsequent Therapy)

Eligibility Criteria

        Inclusion Criteria:

          -  Adult participants who are: (a) greater than or equal to (>=) 65 years old or, (b) 18
             to 64 years old and have at least 1 of the following:

               1. Cumulative Illness Rating Scale (CIRS) score > 6

               2. Creatinine clearance (CrCl) estimated less than (<) 70 milliliter per minute
                  (mL/min) using Cockcroft-Gault equation

          -  Diagnosis of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL)
             that meets International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria

          -  Measurable nodal disease (by computed tomography [CT]), defined as at least one lymph
             node > 1.5 centimeter (cm) in longest diameter

          -  Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Grade less than or
             equal to (<=) 2

          -  Active CLL/SLL requiring treatment per the iwCLL criteria

        Exclusion Criteria:

          -  Prior anti-leukemic therapy for CLL or SLL

          -  Presence of deletion of the short arm of chromosome 17 (del17p) or known TP53 mutation
             detected at a threshold of >10 percent (%) variable allele frequency (VAF)

          -  Major surgery within 4 weeks of first dose of study treatment

          -  Known bleeding disorders (example, von Willebrand's disease or hemophilia)

          -  Central nervous system (CNS) involvement or suspected Richter's syndrome

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

Primary Outcome Measures

Measure:	Progression-Free Survival (PFS)
Time Frame:	From date of randomization to date of disease progression (PD) or death, whichever occurs first (Up to approximately 6 years)
Safety Issue:
Description:	PFS is defined as the duration from date of randomization to date of disease progression (PD) or death, whichever occurs first. PD is defined according to the International Workshop on Chronic Lymphocytic Leukemia (iwCLL 2008 Guidelines).

Secondary Outcome Measures

Measure:	Percentage of Participants who are Minimal Residual Disease (MRD) Negative
Time Frame:	Up to approximately 6 years
Safety Issue:
Description:	MRD negative disease status is defined as less than (<) 1 chronic lymphocytic leukemia (CLL) cell per 10,000 leukocytes or < 0.01 % in the bone marrow. MRD will be assessed by flow cytometry.

Measure:	Overall Response Rate (ORR)
Time Frame:	Up to approximately 6 years
Safety Issue:
Description:	ORR: percentage of participants with CR, complete response with an incomplete marrow recovery (CRi), nodular PR (nPR) and partial response (PR), for at least 2 months. CR: lymph nodes none greater than (>) 1.5 centimeter (cm), no hepatomegaly and splenomegaly, bone marrow normocellular with less than (<) 30% lymphocytes and no lymphoid nodules, blood lymphocytes<4,000 per microliter (mcL), platelet count>100,000/mcL, hemoglobin >11 gram per deciliter (g/dL), neutrophils >1500/mcL. CRi: complete response with a peripheral cytopenia and incomplete recovery of the bone marrow, manifested by persistent cytopenias. nPR: response that meets criteria for CR, but bone marrow biopsy shows lymphoid nodules. PR: at least 50% reduction in at least 2 Group A (lymphadenopathy, hepatomegaly, splenomegaly, blood lymphocytes and marrow infiltrates) and improvement in at least 1 Group B (platelet count, hemoglobin and neutrophils).

Measure:	Complete Response (CR) Rate
Time Frame:	Up to approximately 6 years
Safety Issue:
Description:	CR is lymph nodes none > 1.5 cm, no hepatomegaly and splenomegaly, < 30% lymphocytes, bone marrow normocellular and no lymphoid nodules.

Measure:	Duration of Response (DOR)
Time Frame:	From the date of initial documentation of a response to the date of first documented evidence of progressive disease or death (up to approximately 6 years)
Safety Issue:
Description:	DOR is defined as duration in days from the date of initial documentation of a response to the date of first documented evidence of progressive disease or death. Response and PD are defined according to iwCLL 2008 Guidelines.

Measure:	Overall Survival (OS)
Time Frame:	From the date of randomization to the date of death from any cause (up to approximately 6 years)
Safety Issue:
Description:	OS is defined as the time from the date of randomization to the date of the participant's death from any cause.

Measure:	Time-to-Next Treatment
Time Frame:	From date of randomization to the start date of any anti-leukemic therapy subsequent to the study treatment (up to approximately 6 years)
Safety Issue:
Description:	The time from date of randomization to the start date of any anti-leukemic therapy subsequent to the study treatment.

Measure:	Time to Worsening as Measured by European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)
Time Frame:	From the date of randomization to the start date of worsening (up to approximately 6 years)
Safety Issue:
Description:	Worsening in functional and global QoL scales is defined by clinically important negative change. Differences >= 10 points on EORTC scales are considered clinically important.

Measure:	Time to Worsening as Measured by Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Total Score
Time Frame:	From the date of randomization to the start date of worsening (up to approximately 6 years)
Safety Issue:
Description:	Worsening is defined by clinically important negative change. A difference of >= 3 points in FACIT-Fatigue score is considered clinically important.

Measure:	Time to Worsening as Measured by Using EuroQol 5 Dimension 5 Level questionnaire (EQ-5D 5L)
Time Frame:	From the date of randomization to the start date of worsening (up to approximately 6 years)
Safety Issue:
Description:	Worsening is defined by clinically important negative change. A minimum difference of >= 0.07 points change in utility score is considered clinically important; for the VAS health rating, a minimum important difference is >= 7 points change.

Measure:	Number of Participants with Adverse Events (AEs) as a Measure of Safety and Tolerability
Time Frame:	Up to approximately 18 months
Safety Issue:
Description:	An AE is any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product.

Measure:	Number of Participants with Abnormal Clinical Laboratory Findings
Time Frame:	Up to approximately 18 months
Safety Issue:
Description:	The number of participants with abnormal clinical laboratory findings will be reported.

Measure:	Percentage of Participants with Sustained Hemoglobin Improvement
Time Frame:	Up to approximately 6 years
Safety Issue:
Description:	The percentage of study participants with sustained hemoglobin improvement from baseline will be reported

Measure:	Percentage of Participants with Sustained Platelet Improvement
Time Frame:	Up to approximately 6 years
Safety Issue:
Description:	Sustained platelet improvement rate is defined as the percentage of participants who achieve a sustained increase of platelet levels from baseline.

Measure:	Concentration at End of Dosing Interval (24h) at Steady-state (Ctrough, ss)
Time Frame:	Day 1 of Cycles 2, 3, 5 and 6 (each cycle is defined as 28 days) (up to approximately 6 years)
Safety Issue:
Description:	Ctrough,ss is defined as concentration at the end of dosing interval (24h) at steady-state. Ibrutinib and venetoclax Ctrough, ss data will be evaluated.

Details

Phase:	Phase 3
Primary Purpose:	Interventional
Overall Status:	Active, not recruiting
Lead Sponsor:	Janssen Research & Development, LLC

Last Updated

July 23, 2021

Clinical Trials /

A Study of the Combination of Ibrutinib Plus Venetoclax Versus Chlorambucil Plus Obinutuzumab for the First-line Treatment of Participants With Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)