A Study to Compare the Efficacy and Safety of a Combined Regimen of Obinutuzumab and Venetoclax (GDC-0199/ABT-199) Versus Obinutuzumab and Chlorambucil in Previously Untreated Patients with CLL and Coexisting Medical Conditions

Overview

Sponsor-declared trial summary

Key facts

Sponsor

F. Hoffmann-La Roche AG

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

18 Dec 2014 → 29 Aug 2025

Decision date (initial)

2023-12-15

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

F. Hoffmann-La Roche AG

External identifiers

EU CT number

2023-504034-22-00

EudraCT number

2014-001810-24

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

To determine efficacy by investigator-assessed progression-free survival (PFS) of a combined regimen of obinutuzumab + venetoclax compared with obinutuzumab + chlorambucil (GClb) in previously untreated patients with CLL who have coexisting medical conditions

Secondary objectives 6

1. To determine efficacy as assessed by additional outcome measures, including PFS assessed by Independent Review Committee [IRC], overall response, complete response, and Minimal residual disease (MRD) response rate as measured by allele-specific oligonucleotide polymerase chain reaction [ASO-PCR]
2. To evaluate the safety of the combination of obinutuzumab and venetoclax, compared with GClb, in patients with previously untreated CLL and coexisting medical conditions, focusing on the nature, frequency, and severity of Grade 3 and 4 adverse events and of serious adverse events
3. To characterize the pharmacokinetics of venetoclax and of obinutuzumab [including population pharmacokinetics (PK) [pop-PK] techniques]. Standard non-compartmental analysis (NCA)/descriptive tables, listings, and graphs (TLGs) and pop-PK approaches will be considered
4. To compare disease and treatment-related symptoms following treatment with the combination of obinutuzumab + venetoclax compared with GClb in patients with previously untreated CLL and coexisting medical conditions as measured by M.D. Anderson Symptom Inventory (MDASI-CLL)
5. To evaluate changes in role functioning and global health status/quality of life (QoL) following treatment with the combination of obinutuzumab + venetoclax compared with GClb in patients with previously untreated CLL and coexisting medical conditions between arms as measured by European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30)
6. To compare the health utility effects of treatment with combination of obinutuzumab and venetoclax compared with GClb in patients with previously untreated CLL and coexisting medical conditions measured by the EuroQol 5 Dimension questionnaire (EQ-5D-3L)

Conditions and MedDRA coding

Chronic Lymphocytic Leukemia (CLL)

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. Documented previously untreated CLL according to the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria
2. CLL requiring treatment according to IWCLL criteria
3. Total Cumulative Illness Rating Scale (CIRS) score > 6 or creatinine clearance (CrCl) < 70 mL/min
4. Adequate marrow function independent of growth factor or transfusion support within 2 weeks of screening as per protocol, unless cytopenia is due to marrow involvement of CLL
5. Adequate liver function
6. Life expectancy > 6 months

Exclusion criteria 6

1. Transformation of CLL to aggressive Non-Hodgkin's lymphoma (Richter’s transformation or pro-lymphocytic leukemia)
2. Patients with a history of confirmed progressive multifocal leukoencephalopathy (PML)
3. An individual organ/ system impairment score of 4 as assessed by the CIRS definition limiting the ability to receive the treatment regimen of this trial with the exception of eyes, ears, nose, throat organ system
4. Patients with uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia
5. Hypersensitivity to chlorambucil, obinutuzumab, or Venetoclax or to any of the excipients
6. Patients with active infections requiring intravenous (IV) treatment (grade 3 or 4) within the last two months prior to enrollment

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Progression-free survival (PFS), defined as the time from randomization to the first occurrence of progression, relapse or death from any cause as assessed by the investigator using IWCLL criteria

Secondary endpoints 15

1. 1. PFS based on IRC-assessments, defined as the time from randomization to the first occurrence of progression or relapse or death from any cause
2. 2. Objective response rate ([ORR] defined as rate of a clinical response of complete response [CR], CR with incomplete bone marrow recovery [CRi] or partial response [PR]) as determined by the investigator, according to the IWCLL criteria
3. 3. Complete response rate (defined as rate of a clinical response of CR or CRi) at the completion of treatment assessment, as determined by the investigator according to the IWCLL guidelines)
4. 4. Minimal residual disease (MRD) response rate (determined as the proportion of patients with MRD-negativity) measured in the peripheral blood at the completion of treatment assessment and also MRD response rate as measured in the bone marrow at the completion of treatment, both measured by ASO-PCR
5. 5. Overall survival (OS), defined as the time between the date of randomization and the date of death due to any cause. Patients who were not reported as having died at the time of the analysis will be censored at the date when they were last known to be alive
6. 6. MRD response rates in the peripheral blood at completion of combination treatment assessment (Cycle 9, Day 1 or 3 months after last IV infusion) and also MRD response rate as measured in the bone marrow, both measured by ASO-PCR
7. 7. Overall response rate (ORR) at completion of combination treatment response assessment (Cycle 7, Day 1 or 28 days after last IV infusion)
8. 8. Duration of response, defined as the time from the first occurrence of a documented Overall survival (OS) (CR, CRi or PR) to the time of progressive disease (PD) as determined by the investigator, or death from any cause
9. 9. Best response achieved (CR, CRi, PR, stable disease, or PD) up to and including the assessment at completion of treatment assessment (within 3 months of last day of treatment)
10. 10. Event-free survival (EFS), defined as the time between date of randomization and the date of disease progression/relapse as assessed by the investigator, death, or start of a new anti-leukemic therapy. Patients without an EFS event will be will be censored on the date of the last disease assessment.
11. 11. Time to new anti-leukemic treatment, defined as the time between the date of randomization and the date of first intake of new anti leukemic therapy. Patients who have not taken new anti-leukemic therapy will be censored at their last assessment prior to the analysis or date of death
12. 12. Incidence of adverse events assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0
13. 13. Incidence of severe adverse events
14. 14. Incidence of adverse events of special interest
15. 15. To characterize the pharmacokinetics of venetoclax and of obinutuzumab (including population PK [pop-PK] techniques)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 5

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

F. Hoffmann-La Roche AG

Sponsor organisation

F. Hoffmann-La Roche AG

Address

Grenzacherstrasse 124

City

Basel

Postcode

4058

Country

Switzerland

Scientific contact point

Organisation

F. Hoffmann-La Roche AG

Contact name

Trial Information System - TISL

Public contact point

Organisation

F. Hoffmann-La Roche AG

Contact name

Trial Information System - TISL

Third parties 7

Locations

11 EU/EEA countries · 66 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 56 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications