Obinutuzumab in Combination With Venetoclax in Previously Untreated Follicular Lymphoma Patients

• Status: Active, not recruiting
• Trial end date: 2021-12-01
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 1
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Swiss Group for Clinical Cancer Research
• Treatments: Obinutuzumab; Venetoclax

Criteria

Inclusion Criteria:

• 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

• Women of childbearing potential have a negative serum (beta-human chorionic gonadotropin [β-hCG]) pregnancy test within 3 days before inclusion into the trial.

Exclusion Criteria:

• 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

• human immunodeficiency virus (HIV)

• active/chronic Hepatitis C

• active/chronic Hepatitis B Virus infection (HBsAg+ and/or HBcAb+)

• or any active systemic infection requiring intravenous (iv) antimicrobial treatment.

Patients with a history of recurring or chronic infections may be included in the study but caution should be exercised and an infectious disease expert should be consulted before enrollment in the trial.

• Requires anticoagulation with vitamin K antagonists (e.g. phenprocoumon, warfarin)

• Coagulation parameters

• INR ˃1.5x ULN

• PT or PTT/aPTT ˃1.5x ULN

• Requires treatment with strong CYP3A inhibitors (such as fluconazole, ketoconazole, and clarithromycin) and strong CYP3A inducers (such as rifampin, carbamazepine, phenytoin, St. John's wort) 7 days prior to registration

• Any concomitant drugs contraindicated for use with the trial drugs according to the approved product information (if applicable) or most recent IB (if approved product information not available)

• Known hypersensitivity to trial drugs or to any component of the trial drugs

• History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies. Known sensitivity or allergy to murine products

• Any other serious underlying medical, psychiatric, psychological, familial or geographical condition, which in the judgment of the investigator may interfere with the planned staging, treatment, affect patient compliance or place the patient at high risk from treatment-related complications.

• Psychiatric disorder precluding understanding information of trial-related topics, giving informed consent