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A Study of Venetoclax in Combination With Obinutuzumab in Participants With Chronic Lymphocytic Leukemia

Primary Purpose

Lymphocytic Leukemia, Chronic

Status

Completed

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

Obinutuzumab

Venetoclax

About this trial

This is an interventional treatment trial for Lymphocytic Leukemia, Chronic

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Diagnosis of relapsing/refractory or previously untreated chronic lymphocytic leukemia
Eastern Cooperative Oncology Group (ECOG) performance score of less than or equal to (</=) 1
Adequate bone marrow function
Adequate coagulation, renal and hepatic function
For all participants, agreement to remain abstinent or use contraceptive methods that result in a failure rate of less than (<) 1% per year during the treatment period and for at least 90 days (30 days for women) after the last dose of venetoclax or 18 months after the last dose of obinutuzumab, whichever is longer

Exclusion Criteria:

Participants who have undergone allogenic stem cell transplant are ineligible unless they meet the following criteria, a) participants who are off all immunosuppressive therapy, b) participants who have no signs and/or symptoms of acute or chronic graft versus host disease, or c) participants must have appropriate hematology counts
Infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C
Uncontrolled autoimmune hemolytic anemia or thrombocytopenia
Investigational or anti-cancer therapy within 5 half-lives prior to the first dose of study drug
History of significant renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, cardiovascular, or hepatic disease

Sites / Locations

UCSD Moores Cancer Center
Colorado Blood Cancer Institute (CBCI) at Presbyterian/ St. Luke's Medical Center
Weill Cornell Medical College-New York Presbyterian Hospital
Ohio State University Comprehensive Cancer Center
Oncology Associates of Oregon
SCRI-Tennessee Oncology
The Methodist Hospital Research Institute; Academic Office of Clinical Trials
St James University Hospital
Leicester Royal Infirmary NHS Trust
Barts and The London School of Medicine and Dentistry; Queen Mary, University of London

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Experimental

Arm Label

Dose-Finding: Schedule A: Relapsed/Refractory CLL

Dose-Finding: Schedule B: Relapsed/Refractory CLL

Dose-Finding: Schedule A: Previously Untreated CLL

Dose-Finding: Schedule B: Previously Untreated CLL

Safety Expansion: Relapsed/Refractory CLL

Safety Expansion: Previously Untreated CLL

Arm Description

All 4 cohorts will begin venetoclax administration after the ramp-up period of 5 weeks. In 4 cohorts of participants with relapsed/refractory CLL escalating doses of venetoclax will be administered in combination with fixed dose obinutuzumab in the dose-finding stage. In Schedule A, venetoclax will be introduced before obinutuzumab. Schedule A will be explored prior to Schedule B.

In 4 cohorts of participants with relapsed/refractory CLL escalating doses of venetoclax will be administered in combination with fixed dose obinutuzumab in the dose-finding stage. In Schedule B, venetoclax will be introduced after obinutuzumab. Schedule A will be explored prior to Schedule B.

All 4 cohorts will begin venetoclax administration after the ramp-up period of 5 weeks. In 4 cohorts of participants with previously untreated CLL escalating doses of venetoclax will be administered in combination with fixed dose obinutuzumab in the dose-finding stage. In Schedule A, venetoclax will be introduced before obinutuzumab. Schedule A will be explored prior to Schedule B.

In 4 cohorts of participants with previously untreated CLL escalating doses of venetoclax will be administered in combination with fixed dose obinutuzumab in the dose-finding stage. In Schedule B, venetoclax will be introduced after obinutuzumab. Schedule A will be explored prior to Schedule B.

In participants with relapsed/refractory CLL a recommended dose of venetoclax will be administered in combination with obinutuzumab in the safety expansion stage. Schedule A or B will be used for the expansion cohort after a review of available safety data from the dose finding stage.

In participants with previously untreated CLL a recommended dose of venetoclax will be administered in combination with obinutuzumab in the safety expansion stage. Schedule A or B will be used for the expansion cohort after a review of available safety data from the dose finding stage.

Outcomes

Primary Outcome Measures

Percentage of Participants With Dose Limiting Toxicities (DLTs)

Maximum Tolerated Dose (MTD) of Venetoclax in Combination with Obinutuzumab

Secondary Outcome Measures

Percentage of Participants with Adverse Events

Percentage of Participants with Anti-Therapeutic Antibodies (ATAs) to Obinutuzumab

Area Under the Concentration-Time Curve (AUC) of Venetoclax

Time to Maximum Observed Plasma Concentration (Tmax) of Venetoclax

Maximal Plasma Concentration (Cmax) of Venetoclax

Minimum Plasma Concentration (Cmin) of Venetoclax

Cmax of Obinutuzumab

Cmin of Obinutuzumab

Percentage of Participants with Confirmed Complete Response (CR) as Determined by Standard CLL Response Criteria

Percentage of Participants with Objective Response (Partial Response [PR] or CR [Including Cytopenic CR] as Determined by Standard CLL Response Criteria

Duration of Objective Response as Determined by Standard CLL Response Criteria

Overall Survival

Progression-Free Survival as Determined by Standard CLL Response Criteria

Change from Baseline in Number of B-Cells

Change from Baseline in Number of T-Cells

Change from Baseline in Number of Natural Killer (NK) Cells

Change from Baseline in Serum Immunoglobulin Level

Full Information

NCT ID

NCT01685892

First Posted

September 12, 2012

Last Updated

January 7, 2020

Sponsor

Genentech, Inc.

Collaborators

AbbVie (prior sponsor, Abbott)

1. Study Identification

Unique Protocol Identification Number

NCT01685892

Brief Title

A Study of Venetoclax in Combination With Obinutuzumab in Participants With Chronic Lymphocytic Leukemia

Official Title

A Phase Ib Multicenter Dose-Finding and Safety Study of Venetoclax and Obinutuzumab in Patients With Relapsed or Refractory or Previously Untreated Chronic Lymphocytic Leukemia

Study Type

Interventional

2. Study Status

Record Verification Date

January 2020

Overall Recruitment Status

Completed

Study Start Date

November 29, 2012 (Actual)

Primary Completion Date

May 21, 2018 (Actual)

Study Completion Date

August 23, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Genentech, Inc.

Collaborators

AbbVie (prior sponsor, Abbott)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

This multi-center, open-label, dose-finding study will evaluate the safety and pharmacokinetics as well as the preliminary efficacy of venetoclax (GDC-0199; ABT-199) administered in combination with obinutuzumab to participants with relapsed/refractory or previously untreated chronic lymphocytic leukemia (CLL). The study is comprised of two stages for each participant population: a dose-finding stage and a safety-expansion stage. The dose-finding stage will explore multiple doses of venetoclax to be used in combination with a fixed dose of obinutuzumab. The dose-finding stage will also explore two schedules for drug administration, Schedule A (venetoclax introduced before obinutuzumab) and Schedule B (venetoclax introduced after obinutuzumab).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Lymphocytic Leukemia, Chronic

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Sequential Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

82 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Dose-Finding: Schedule A: Relapsed/Refractory CLL

Arm Type

Experimental

Arm Description

Arm Title

Dose-Finding: Schedule B: Relapsed/Refractory CLL

Arm Type

Experimental

Arm Description

Arm Title

Dose-Finding: Schedule A: Previously Untreated CLL

Arm Type

Experimental

Arm Description

Arm Title

Dose-Finding: Schedule B: Previously Untreated CLL

Arm Type

Experimental

Arm Description

Arm Title

Safety Expansion: Relapsed/Refractory CLL

Arm Type

Experimental

Arm Description

Arm Title

Safety Expansion: Previously Untreated CLL

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Obinutuzumab

Other Intervention Name(s)

GA101; RO5072759

Intervention Description

Participants will receive IV infusion of obinutuzumab 100 milligrams (mg) on Day 1 of Cycle 1, 900 mg on Day 2 of Cycle 1, and 1000 mg on Days 8 and 15 of Cycle 1 and on Day 1 of Cycles 2-6.

Intervention Type

Drug

Intervention Name(s)

Venetoclax

Other Intervention Name(s)

ABT-199, GDC-0199

Intervention Description

Participants will receive multiple doses of venetoclax orally once daily.

Primary Outcome Measure Information:

Title

Percentage of Participants With Dose Limiting Toxicities (DLTs)

Time Frame

Schedule (Sch) A (Cycle 1 Day 1 to Day 21), Sch B (Cycle 1 Day 22 to Cycle 2 Day 28) (1 Cycle=28 days)

Title

Maximum Tolerated Dose (MTD) of Venetoclax in Combination with Obinutuzumab

Time Frame

Sch A (Cycle 1 Day 1 to Day 21), Sch B (Cycle 1 Day 22 to Cycle 2 Day 28) (1 Cycle=28 days)

Secondary Outcome Measure Information:

Title

Percentage of Participants with Adverse Events

Time Frame

Baseline up to end of study (up to approximately 5 years and 5 months)

Title

Percentage of Participants with Anti-Therapeutic Antibodies (ATAs) to Obinutuzumab

Time Frame

Baseline up to Cycle 6 (1 Cycle=28 days)

Title

Area Under the Concentration-Time Curve (AUC) of Venetoclax

Time Frame

Baseline up to Cycle 6 (1 Cycle=28 days)

Title

Time to Maximum Observed Plasma Concentration (Tmax) of Venetoclax

Time Frame

Baseline up to Cycle 6 (1 Cycle=28 days)

Title

Maximal Plasma Concentration (Cmax) of Venetoclax

Time Frame

Baseline up to Cycle 6 (1 Cycle=28 days)

Title

Minimum Plasma Concentration (Cmin) of Venetoclax

Time Frame

Baseline up to Cycle 6 (1 Cycle=28 days)

Title

Cmax of Obinutuzumab

Time Frame

Baseline up to Cycle 6 (1 Cycle=28 days)

Title

Cmin of Obinutuzumab

Time Frame

Baseline up to Cycle 6 (1 Cycle=28 days)

Title

Percentage of Participants with Confirmed Complete Response (CR) as Determined by Standard CLL Response Criteria

Time Frame

Baseline up to end of study (up to approximately 5 years and 5 months)

Title

Percentage of Participants with Objective Response (Partial Response [PR] or CR [Including Cytopenic CR] as Determined by Standard CLL Response Criteria

Time Frame

Baseline up to end of study (up to approximately 5 years and 5 months)

Title

Duration of Objective Response as Determined by Standard CLL Response Criteria

Time Frame

Baseline up to end of study (up to approximately 5 years and 5 months)

Title

Overall Survival

Time Frame

Baseline up to death or end of study (up to approximately 5 years and 5 months)

Title

Progression-Free Survival as Determined by Standard CLL Response Criteria

Time Frame

Baseline up to end of study (up to approximately 5 years and 5 months)

Title

Change from Baseline in Number of B-Cells

Time Frame

Baseline up to end of study (up to approximately 5 years and 5 months)

Title

Change from Baseline in Number of T-Cells

Time Frame

Baseline up to end of study (up to approximately 5 years and 5 months)

Title

Change from Baseline in Number of Natural Killer (NK) Cells

Time Frame

Baseline up to end of study (up to approximately 5 years and 5 months)

Title

Change from Baseline in Serum Immunoglobulin Level

Time Frame

Baseline up to end of study (up to approximately 5 years and 5 months)

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Diagnosis of relapsing/refractory or previously untreated chronic lymphocytic leukemia Eastern Cooperative Oncology Group (ECOG) performance score of less than or equal to (</=) 1 Adequate bone marrow function Adequate coagulation, renal and hepatic function For all participants, agreement to remain abstinent or use contraceptive methods that result in a failure rate of less than (<) 1% per year during the treatment period and for at least 90 days (30 days for women) after the last dose of venetoclax or 18 months after the last dose of obinutuzumab, whichever is longer Exclusion Criteria: Participants who have undergone allogenic stem cell transplant are ineligible unless they meet the following criteria, a) participants who are off all immunosuppressive therapy, b) participants who have no signs and/or symptoms of acute or chronic graft versus host disease, or c) participants must have appropriate hematology counts Infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C Uncontrolled autoimmune hemolytic anemia or thrombocytopenia Investigational or anti-cancer therapy within 5 half-lives prior to the first dose of study drug History of significant renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, cardiovascular, or hepatic disease

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Clinical Trials

Organizational Affiliation

Genentech, Inc.

Official's Role

Study Director

Facility Information:

Facility Name

UCSD Moores Cancer Center

City

La Jolla

State/Province

California

ZIP/Postal Code

92093

Country

United States

Facility Name

Colorado Blood Cancer Institute (CBCI) at Presbyterian/ St. Luke's Medical Center

City

Denver

State/Province

Colorado

ZIP/Postal Code

80218

Country

United States

Facility Name

Weill Cornell Medical College-New York Presbyterian Hospital

City

New York

State/Province

New York

ZIP/Postal Code

10021

Country

United States

Facility Name

Ohio State University Comprehensive Cancer Center

City

Columbus

State/Province

Ohio

ZIP/Postal Code

43210

Country

United States

Facility Name

Oncology Associates of Oregon

City

Springfield

State/Province

Oregon

ZIP/Postal Code

97477

Country

United States

Facility Name

SCRI-Tennessee Oncology

City

Nashville

State/Province

Tennessee

ZIP/Postal Code

37203

Country

United States

Facility Name

The Methodist Hospital Research Institute; Academic Office of Clinical Trials

City

Houston

State/Province

Texas

ZIP/Postal Code

77030

Country

United States

Facility Name

St James University Hospital

City

Leeds

ZIP/Postal Code

LS9 7TF

Country

United Kingdom

Facility Name

Leicester Royal Infirmary NHS Trust

City

Leicester

ZIP/Postal Code

LE1 5WW

Country

United Kingdom

Facility Name

Barts and The London School of Medicine and Dentistry; Queen Mary, University of London

City

London

ZIP/Postal Code

E1 2AD

Country

United Kingdom

12. IPD Sharing Statement

Citations:

PubMed Identifier

30862645

Citation

Flinn IW, Gribben JG, Dyer MJS, Wierda W, Maris MB, Furman RR, Hillmen P, Rogers KA, Iyer SP, Quillet-Mary A, Ysebaert L, Walter HS, Verdugo M, Klein C, Huang H, Jiang Y, Lozanski G, Pignataro DS, Humphrey K, Mobasher M, Kipps TJ. Phase 1b study of venetoclax-obinutuzumab in previously untreated and relapsed/refractory chronic lymphocytic leukemia. Blood. 2019 Jun 27;133(26):2765-2775. doi: 10.1182/blood-2019-01-896290. Epub 2019 Mar 12.

Results Reference

derived

PubMed Identifier

35708885

Citation

Samineni D, Gibiansky L, Wang B, Vadhavkar S, Rajwanshi R, Tandon M, Sinha A, Al-Sawaf O, Fischer K, Hallek M, Salem AH, Li C, Miles D. Pharmacokinetics and Exposure-Response Analysis of Venetoclax + Obinutuzumab in Chronic Lymphocytic Leukemia: Phase 1b Study and Phase 3 CLL14 Trial. Adv Ther. 2022 Aug;39(8):3635-3653. doi: 10.1007/s12325-022-02170-w. Epub 2022 Jun 16.

Results Reference

derived

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A Study of Venetoclax in Combination With Obinutuzumab in Participants With Chronic Lymphocytic Leukemia

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