Obinutuzumab in Combination With Venetoclax in Previously Untreated Follicular Lymphoma Patients

NCT02877550 | Completed Phase 1 DMC

• 2 other identifiers: SAKK 35/152017-001175-23
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 6

Brief Summary

Follicular lymphoma (FL) is an indolent yet incurable lymphoma characterized by initial responses to standard therapies, invariably followed by shorter disease free intervals. Obinutuzumab, a novel type II, anti-CD20 monoclonal antibody has been approved in combination with chlorambucil for the treatment of previously untreated chronic lymphocytic leukemia (CLL) and in combination with bendamustine followed by obinutuzumab alone for FL who did not respond to, or who progressed during or after treatment with rituximab or a rituximab-containing regimen, or in relapse after such treatment. Additionally, venetoclax, a small molecule Bcl-2 inhibitor, showed single agent activity in relapsed/refractory (R/R) CLL and other B-cell lymphomas, including R/R FL. Preclinical evidence suggests a synergism of the two drugs in vitro as well as in different lymphoma in vivo models. Based on single agent clinical activity and on the preclinical data of the combination of both drugs and aiming to develop a new chemotherapy-free combination regimen, this trial plans to evaluate the combination of obinutuzumab and venetoclax in previously untreated FL patients in need of systemic therapy. This phase I study will provide information on the safety and tolerability together with evidence of preliminary antitumor activity. Combination treatment consists of a 6 cycles of 28 days each. The combination therapy is followed by a 2 years maintenance with obinutuzumab. Dosing of obinutuzumab is as per Swissmedic approval in FL.Venetoclax will be administered in different dose levels according to the trial design.

Conditions

Follicular Lymphoma

Keywords

untreated Follicular lymphoma; non-Hodgkin lymphoma; Obinutuzumab; Gazyva; Gazyvaro; Venetoclax; Venclexta

Outcome Measures

Primary Outcomes (1)

• Dose limiting toxicities (DLT) during the first cycle

  The primary endpoint is the frequency of DLTs which are relevant for the determination of the maximum tolerated dose (MTD) in the dose escalation phase of the trial.

  Day 28 of the first cycle

Secondary Outcomes (6)

• Adverse events (AEs)

  at 6 months (combination therapy) and at 2 years (maintenance therapy)

• Laboratory safety variables

  at 6 months (combination therapy) and at 2 years (maintenance therapy)

• Complete response (CR)

  at 6 months and 30 months

• Overall response (OR) based on best response observed during combination therapy.

  at 6 months, based on best response observed during combination therapy, at 30 months and based on best response observed during whole therapy (combination and maintenance)

• Duration of response

  at 2.5 years

Study Arms (1)

Part A - dose escalation and part B - dose expansion

EXPERIMENTAL

Part A: dose escalation: Combination therapy N= 4-18 pts Cycle 1-6 (1 cycle = 28 days) Obinutuzumab: 1000 mg, i.v. infusion; d1, 8, 15 C1 and d1 C2-6 Venetoclax: p.o. once daily according to dose level (DL) Part B - dose expansion: Combination therapy N= up to 25 pts Cycle 1-6 (1 cycle = 28 days) Obinutuzumab: 1000 mg, i.v. infusion d1, 8, 15 C1 and d1 C2-6 Venetoclax: p.o. once daily according to MTD Part A and part B are followed (in case of no PD) by an obinutuzumab maintenance therapy for 2 years

Drug: Obinutuzumab; Drug: Venetoclax

Interventions

Obinutuzumab DRUG

Obinutuzumab: 1000 mg, i.v. infusion; d1, 8, 15 C1 and d1 C2-6

Also known as: GA101, Gazyvaro, Gazyva

Part A - dose escalation and part B - dose expansion

Venetoclax DRUG

p.o. once daily according to dose level (DL) or MTD

Also known as: ABT-199, GDC-0199, Venclexta

Part A - dose escalation and part B - dose expansion

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent according to ICH/GCP regulations before registration.
• Histological diagnosis of FL CD20+; grade 1, 2, 3a; stage III+IV; stage II not suitable for radiotherapy; all FLIPI
• In need of first systemic therapy
• At least one two-dimensionally measurable nodal lesion with a longest diameter (LDi) ˃15 mm or a measurable extra nodal lesion with a LDi ˃ 10 mm in CT, PET/CT scan (preferable) or MRI, according to Cheson et al, 2014
• Bone marrow biopsy within 6 months.
• Age18-80 years
• WHO performance status 0-2
• Adequate bone marrow function
• Adequate hepatic function
• Adequate renal function

You may not qualify if:

• FL stage I
• Transformation to high-grade DLBCL prior to therapy
• FL grade 3 b
• Indolent lymphoma other than FL
• Known primary central nervous system (CNS) lymphoma
• Known CNS or leptomeningeal involvement
• Previous systemic FL therapies
• History of other malignancy that could affect compliance with the protocol or interpretation of results
• Concurrent treatment with other experimental drugs or other anticancer therapy in a clinical trial within 30 days prior to registration.
• Live-virus vaccines treatment within 28 days prior to registration
• Patients regularly taking corticosteroids during the last 30 days, unless administered at a dose equivalent to prednisone ≤ 15 mg/day for indications other than lymphoma or lymphoma-related symptoms
• Women who are breastfeeding
• Severe or uncontrolled cardiovascular disease (congestive heart failure NYHA III or IV), unstable angina pectoris, history of myocardial infarction within the last six months, serious arrhythmias requiring medication (with exception of atrial fibrillation or paroxysmal supraventricular tachycardia), uncontrolled hypertension (sustained systolic blood pressure \> 150 mm Hg and/or diastolic \> 100 mm Hg despite antihypertensive therapy)
• History of cerebrovascular accident or intracranial hemorrhage within 6 months prior to registration
• Known history of

Sponsors & Collaborators

• Swiss Cancer Institute: lead

Study Sites (6)

Universitaetsspital Basel

Basel, 4031, Switzerland

Location

Istituto Oncologico della Svizzera Italiana

Bellinzona, 6500, Switzerland

Location

Inselspital, Bern

Bern, CH-3010, Switzerland

Location

Kantonsspital Graubünden

Chur, 7000, Switzerland

Location

Hopital Cantonal Universitaire de Geneve

Geneva, CH-1211, Switzerland

Location

Kantonsspital - St. Gallen

Sankt Gallen, CH-9007, Switzerland

Location

Related Publications (1)

• Stathis A, Mey U, Schar S, Hitz F, Pott C, Mach N, Krasniqi F, Novak U, Schmidt C, Hohloch K, Kienle DL, Hess D, Moccia AA, Unterhalt M, Eckhardt K, Hayoz S, Forestieri G, Rossi D, Dirnhofer S, Ceriani L, Sartori G, Bertoni F, Buske C, Zucca E, Hiddemann W. SAKK 35/15: a phase 1 trial of obinutuzumab in combination with venetoclax in patients with previously untreated follicular lymphoma. Blood Adv. 2022 Jul 12;6(13):3911-3920. doi: 10.1182/bloodadvances.2021006520.

  PMID: 35537101 DERIVED

MeSH Terms

Conditions

Lymphoma, Follicular; Lymphoma, Non-Hodgkin

Interventions

obinutuzumab; venetoclax

Condition Hierarchy (Ancestors)

Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Study Officials

• Anastasios Stathis, MD

  IOSI -Ospedale San Giovanni, Bellinzona

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 19, 2016
• First Posted: August 24, 2016
• Study Start: February 15, 2017
• Primary Completion: April 28, 2020
• Study Completion: May 4, 2022
• Last Updated: June 10, 2022

Record last verified: 2022-06

Data Sharing

• IPD Sharing: Will not share

Locations

CH (6)