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Follicular LymphomaPhase 1NCT02877550

Obinutuzumab in Combination With Venetoclax in Previously Untreated Follicular Lymphoma Patients

A Phase 1 study testing Obinutuzumab and Venetoclax in people with Follicular Lymphoma, run by Swiss Cancer Institute at 6 sites in Switzerland.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 18 to 80 years
Conditions the study is for
Follicular Lymphoma
What is being tested?
Obinutuzumab and Venetoclax
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
25 participants
Where
6 sitesSwitzerland
Study dates
15 Feb 2017to 4 May 2022
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 80 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
Show all 11Show fewer
  • 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.

Who cannot join

  • 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
Show all 30Show fewer
  • 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

Trial locations and contacts

6 sites in 1 country.

6 sites in 1 country

Switzerland6 sites

  • Universitaetsspital Basel

    Basel, 4031

  • Istituto Oncologico della Svizzera Italiana

    Bellinzona, 6500

  • Inselspital, Bern

    Bern, CH-3010

  • Kantonsspital Graubünden

    Chur, 7000

  • Hopital Cantonal Universitaire de Geneve

    Geneva, CH-1211

  • Kantonsspital - St. Gallen

    Sankt Gallen, CH-9007

Other trials in Switzerland

About this study

Official title: A Phase I Trial of Obinutuzumab in Combination With Venetoclax in Previously Untreated Follicular Lymphoma Patients

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.

Read the 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.

Keywords
untreated Follicular lymphoma, non-Hodgkin lymphoma, Obinutuzumab, Gazyva, Gazyvaro, Venetoclax, Venclexta
Medical subject headings
Lymphoma, Follicular, Lymphoma, Non-Hodgkin

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • ObinutuzumabDrug

    Also called GA101, Gazyvaro, Gazyva

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

  • VenetoclaxDrug

    Also called ABT-199, GDC-0199, Venclexta

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

Study groups in NCT02877550
Study groupRoleWhat they receive
Part A - dose escalation and part B - dose expansionExperimentalPart 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
Receives: Drug: Obinutuzumab; Drug: Venetoclax

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: Day 28 of the first cycle

Secondary outcomes (6)

  1. Adverse events (AEs)

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

  2. Laboratory safety variables

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

  3. Complete response (CR)

    Measured: at 6 months and 30 months

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

    Measured: 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)

  5. Duration of response

    Measured: at 2.5 years

  6. Progression free survival (PFS)

    Measured: at 12 months, at 30 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted24 Aug 2016 (estimated)
  2. Study start15 Feb 2017
  3. Primary completion28 Apr 2020
  4. Study completion4 May 2022

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
25 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02877550
Sponsor's protocol ID
SAKK 35/15
Other IDs
2017-001175-23, 2017
Status last verified
Jun 2022
First submitted
19 Aug 2016
Last updated
10 Jun 2022
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • 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.

    PubMed 35537101

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Obinutuzumab and Venetoclax in people with Follicular Lymphoma, run by Swiss Cancer Institute at 6 sites in Switzerland.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 11 inclusion and 30 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 10 Jun 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 6 sites in Switzerland. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Dose limiting toxicities (DLT) during the first cycle (time frame: Day 28 of the first cycle). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02877550, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Jun 2022.

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