Obinutuzumab in Combination With Venetoclax in Previously Untreated Follicular Lymphoma Patients
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|ClinicalTrials.gov Identifier: NCT02877550|
Recruitment Status : Active, not recruiting
First Posted : August 24, 2016
Last Update Posted : November 7, 2019
|Condition or disease||Intervention/treatment||Phase|
|Follicular Lymphoma||Drug: Obinutuzumab Drug: Venetoclax||Phase 1|
Follicular lymphoma is an indolent yet incurable lymphoma characterized by a relapsing-remitting course with initial responses to standard therapies, invariably followed by shorter disease free intervals. In recent years, significant treatment improvements have been achieved, mainly due to the introduction of the anti-CD20 monoclonal antibody rituximab in standard therapies. Unfortunately, most patients invariably relapse and require additional treatment. Therefore new therapies are needed in order to further improve treatment outcomes.
Recent advances in preclinical research and the improved knowledge of the molecular biology of lymphomas have permitted the development of a high number of new therapeutic compounds that inhibit components of altered signaling pathways that drive the genesis of lymphomas and their progression. Additionally, improvements in monoclonal antibody technology have permitted the development of new and active monoclonal antibodies that recognize different antigens on the surface of the lymphoma cells.
Obinutuzumab, a type II, anti-CD20 monoclonal antibody has been clinically tested both as single agent as well as in combination with chemotherapy or targeted agents, showing significant clinical activity in CLL and in FL patients that were refractory to rituximab.
Additionally venetoclax, a small molecule Bcl-2 inhibitor has recently advanced into clinical trials, showing a good safety profile and signs of single agent activity in CLL and other B-cell lymphomas, including patients with relapsed/refractory FL. There is interest to further investigate venetoclax in FL, given that the pathogenesis of this lymphoma relies on the chromosomal translocation t(14;18)(q32;q21), which is present in nearly all cases and results in constitutive overexpression of the BCL2 gene, allowing B cells to abrogate the default germinal center apoptotic program.
The combination of these two compounds is interesting given their single agent activity observed in FL. Preclinical studies have demonstrated a synergism both in vitro as well as in vivo models in different lymphomas and the two compounds are currently investigated in combination studies in CLL and with the chemotherapy CHOP regimen in non-Hodgkin lymphomas.
Based on the single agent activity of the two compounds and aiming to develop a new chemotherapy-free combination regimen, this SAKK trial plans to evaluate the combination of obinutuzumab and venetoclax in previously untreated FL patients in need of systemic therapy. There are data with venetoclax in combination with rituximab and bendamustine in relapsed or refractory Non-Hodgkin lymphoma (NHL) patients. No significant safety signal has been observed.
In the indication CLL the combination of obinutuzumab and venetoclax is currently investigated in a phase I dose finding trial (NCT01685892). In the currently ongoing CLL 14 trial the combination of obinutuzumab plus venetoclax is randomly compared to obinutuzumab plus chlorambucil within a prospective phase III study. Nevertheless, to the best of our knowledge, the proposed trial is one of the first trials worldwide investigating the combination treatment of obinutuzumab with venetoclax in FL as first line treatment. Given the need to further improve chemotherapy-free approaches in the first-line treatment of patients with FL in need of systemic therapy, this combination may provide an opportunity for an active and well tolerated regimen that does not present the short and long term toxicities of chemotherapy.
This phase I study will provide information on the safety and tolerability together with evidence of preliminary antitumor activity of obinutuzumab in combination with venetoclax in the first line treatment of FL.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||25 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase I Trial of Obinutuzumab in Combination With Venetoclax in Previously Untreated Follicular Lymphoma Patients|
|Actual Study Start Date :||February 15, 2017|
|Estimated Primary Completion Date :||June 2021|
|Estimated Study Completion Date :||December 2021|
Experimental: Part A - dose escalation and part B - dose expansion
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
Obinutuzumab: 1000 mg, i.v. infusion; d1, 8, 15 C1 and d1 C2-6
p.o. once daily according to dose level (DL) or MTD
- Dose limiting toxicities (DLT) during the first cycle [ Time Frame: Day 28 of 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.
- Adverse events (AEs) [ Time Frame: at 6 months (combination therapy) and at 2 years (maintenance therapy) ]
- Laboratory safety variables [ Time Frame: at 6 months (combination therapy) and at 2 years (maintenance therapy) ]
- Complete response (CR) [ Time Frame: at 6 months and 30 months ]
- Overall response (OR) based on best response observed during combination therapy. [ Time Frame: 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 [ Time Frame: at 2.5 years ]
- Progression free survival (PFS) [ Time Frame: at 12 months, at 30 months ]
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02877550
|Basel, Switzerland, 4031|
|Istituto Oncologico della Svizzera Italiana|
|Bellinzona, Switzerland, 6500|
|Bern, Switzerland, CH-3010|
|Chur, Switzerland, 7000|
|Hopital Cantonal Universitaire de Geneve|
|Geneva, Switzerland, CH-1211|
|Kantonsspital - St. Gallen|
|St. Gallen, Switzerland, CH-9007|
|Study Chair:||Anastasios Stathis, MD||IOSI -Ospedale San Giovanni, Bellinzona|