Obinutuzumab in Combination With Venetoclax in Previously Untreated Follicular Lymphoma Patients
Condition: Follicular Lymphoma
MeSH terms: Lymphoma; Lymphoma, Follicular
Study type: Interventional
Phase: Phase 1

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.
    

Detailed description: 
      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.
    

Intervention name(s): Obinutuzumab; Venetoclax
Intervention type(s): Drug; Drug
Intervention description(s): 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
Other intervention name(s): GA101; Gazyvaro; Gazyva; ABT-199; GDC-0199; Venclexta
Intervention MeSH terms: Venetoclax; Obinutuzumab
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: untreated Follicular lymphoma; non-Hodgkin lymphoma; Obinutuzumab; Gazyva; Gazyvaro; Venetoclax; Venclexta