Triple Therapy for Follicular Lymphoma

(LEVERAGE Trial)

Not currently recruiting at 2 trial locations

Overseen By John Seymour, MBBS, FRACP, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Peter MacCallum Cancer Centre, Australia

Must not be taking: Strong CYP3A inhibitors, Strong CYP3A inducers

Disqualifiers: CNS lymphoma, Prior systemic therapy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of three treatments—venetoclax (Venclexta), obinutuzumab, and lenalidomide—on individuals with follicular lymphoma, a type of blood cancer. The goal is to evaluate how effectively these treatments work together for patients who have not yet received other treatments for their condition. Participants will initially receive all three treatments for six months and, based on their response, may continue with maintenance therapy for up to two years. Individuals diagnosed with follicular lymphoma that meets specific size or stage criteria may be suitable for this trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this combination therapy.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot take certain medications like strong CYP3A inhibitors or inducers, and you should avoid grapefruit and similar fruits close to the trial start. It's best to discuss your current medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that the combination of obinutuzumab, venetoclax, and lenalidomide is being tested for safety in patients with newly diagnosed follicular lymphoma. Previous studies have found that obinutuzumab and venetoclax can be safely used together in patients who need treatment, suggesting that the combination might be well-tolerated.

In the past, patients receiving these treatments generally did not experience many severe side effects. However, these are early findings, and more research is needed to confirm the safety of this combination for everyone.

Prospective trial participants should discuss potential risks and benefits with their healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment combination because it targets follicular lymphoma in a new way. Unlike standard treatments that typically focus on chemotherapy or single-agent therapy, this triple therapy combines lenalidomide, obinutuzumab, and venetoclax to attack the cancer on multiple fronts. Obinutuzumab is a monoclonal antibody that targets the CD20 protein on B-cells, venetoclax disrupts the BCL-2 protein to induce cancer cell death, and lenalidomide modulates the immune system to enhance its cancer-fighting capabilities. This multi-pronged approach not only aims to increase effectiveness but also potentially reduces the chances of the cancer developing resistance.

What evidence suggests that this trial's treatments could be effective for follicular lymphoma?

Research has shown that a combination of three drugs—obinutuzumab, venetoclax, and lenalidomide—may effectively treat follicular lymphoma. In this trial, participants will receive this combination therapy, which blocks pathways that help cancer cells grow and survive. Studies have indicated that patients with newly diagnosed follicular lymphoma responded well, with their tumors shrinking. This treatment leverages each drug's strengths to attack the cancer in different ways. Early results suggest this combination could be a strong option for patients who haven't received prior treatment. ^{1 2 4 6 7}

Are You a Good Fit for This Trial?

This trial is for adults with untreated follicular lymphoma who have measurable disease, normal organ function, and an ECOG performance status ≤ 2. They must not have other active cancers or infections, no history of certain brain events within the last 6 months, and cannot be pregnant. Participants should agree to use effective contraception during the study.

Inclusion Criteria

Patient has provided written informed consent.

I meet at least one criterion for needing treatment for my lymphoma.

- International normalized ratio >1.5 x ULN for patients not receiving therapeutic anticoagulation

Exclusion Criteria

Presence of positive test results for hepatitis B virus (HBV), hepatitis B surface antigen (HBsAg), or hepatitis C (HCV) antibody.

I have not had major surgery or unhealed wounds in the last 4 weeks.

I have received treatment other than steroids for my follicular lymphoma.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Treatment

Participants receive 6 cycles of induction treatment with venetoclax, obinutuzumab, and lenalidomide

6 months

Maintenance Treatment

Participants in CR or SD/PR receive up to 2 years of maintenance therapy based on PET-CT results

Up to 2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

What Are the Treatments Tested in This Trial?

Interventions

• Lenalidomide
• Obinutuzumab
• Venetoclax

Trial Overview The study tests a combination therapy using Venetoclax, Lenalidomide, and Obinutuzumab in patients with treatment-naïve follicular lymphoma. It involves an initial half-year induction phase followed by up to two years of maintenance treatment based on response to induction.

How Is the Trial Designed?

Group I: Obinutuzumab+venetoclax+lenalidomide Experimental Treatment 3 Interventions

Patients in both dose escalation and dose expansion will receive 6 cycles of induction treatment consisting of obinutuzumab (flat dose of 1000mg) and protocol defined dose levels of venetoclax and lenalidomide.

Lenalidomide is already approved in European Union, United States for the following indications:

Approved in European Union as Revlimid for:

• Multiple myeloma
• Myelodysplastic syndromes
• Mantle cell lymphoma
• Follicular lymphoma
• Marginal zone lymphoma

Approved in United States as Revlimid for:

• Multiple myeloma
• Myelodysplastic syndromes
• Mantle cell lymphoma
• Follicular lymphoma
• Marginal zone lymphoma

Who Is Running the Clinical Trial?

Peter MacCallum Cancer Centre, Australia

Lead Sponsor

Trials

102

Recruited

23,700+

Published Research Related to This Trial

In the phase III AUGMENT trial, lenalidomide combined with rituximab significantly improved progression-free survival in patients with relapsed or refractory follicular lymphoma compared to placebo, showing particular benefit for elderly patients.

Lenalidomide has an acceptable safety profile, although it can cause more frequent cases of severe neutropenia, which can be managed with dosage adjustments and growth factor support.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenalidomide: A Review in Previously Treated Follicular Lymphoma. Blair, HA.[2021]

The combination of venetoclax and obinutuzumab was found to be safe and well-tolerated in patients with relapsed/refractory or previously untreated chronic lymphocytic leukemia, with no dose-limiting toxicities observed during the study.

The treatment resulted in a high overall response rate of 95% in relapsed/refractory patients and 100% in previously untreated patients, with significant rates of undetectable minimal residual disease, indicating effective disease control.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1b study of venetoclax-obinutuzumab in previously untreated and relapsed/refractory chronic lymphocytic leukemia. Flinn, IW., Gribben, JG., Dyer, MJS., et al.[2021]

In a phase 2 study involving 89 patients with relapsed or refractory follicular lymphoma, 79% achieved an overall response after treatment with lenalidomide and obinutuzumab, demonstrating significant efficacy in this patient population.

The treatment had a manageable safety profile, with common adverse events including neutropenia and asthenia, and serious adverse events reported in 34% of patients, indicating that while effective, careful monitoring for side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Obinutuzumab combined with lenalidomide for relapsed or refractory follicular B-cell lymphoma (GALEN): a multicentre, single-arm, phase 2 study. Morschhauser, F., Le Gouill, S., Feugier, P., et al.[2019]

Venetoclax is an effective oral treatment for relapsed or refractory chronic lymphocytic leukemia (CLL), showing durable responses and a manageable safety profile in clinical trials, including patients with poor prognostic factors.

In combination with rituximab, venetoclax significantly improved progression-free survival and achieved undetectable minimal residual disease compared to bendamustine plus rituximab, with benefits lasting for at least 36 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: A Review in Relapsed/Refractory Chronic Lymphocytic Leukemia. Scott, LJ.[2020]

The combination of venetoclax, ibrutinib, and obinutuzumab is well tolerated in patients with relapsed and untreated mantle cell lymphoma (MCL), with no dose-limiting toxicities reported and a maximum tolerated dose of 400 mg per day established for venetoclax.

High response rates were observed, with a complete response rate of 67% in relapsed patients and 86.6% in untreated patients, along with significant minimal residual disease clearance in 71.5% of relapsed and 100% of untreated patients after three cycles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib, obinutuzumab, and venetoclax in relapsed and untreated patients with mantle cell lymphoma: a phase 1/2 trial. Le Gouill, S., Morschhauser, F., Chiron, D., et al.[2021]

Venetoclax is an oral medication that selectively inhibits the BCL-2 protein, which helps cancer cells survive, thereby restoring the ability of these malignant cells to undergo programmed cell death (apoptosis).

It has been approved in the USA for treating chronic lymphocytic leukaemia (CLL) in patients with a specific genetic marker (17p deletion) who have already undergone at least one prior therapy, and it is being studied for various other blood cancers and conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: First Global Approval. Deeks, ED.[2018]

Venetoclax is a highly effective treatment for relapsed or refractory chronic lymphocytic leukemia (CLL), achieving response rates of about 80% in clinical trials involving 240 patients from 2011 to 2016.

While venetoclax has an acceptable safety profile, common side effects include neutropenia and diarrhea, and there is a risk of tumor lysis syndrome (TLS), which can be managed through careful dose ramp-up and patient education, leading to no reported TLS events in ongoing trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . Brumbaugh Paradis, H., Alter, D., Llerandi, D.[2018]

In the phase III CLL14 trial, a 12-month treatment with venetoclax combined with obinutuzumab significantly improved progression-free survival and rates of undetectable minimal residual disease compared to traditional chemoimmunotherapy with chlorambucil and obinutuzumab in patients with untreated chronic lymphocytic leukaemia.

Venetoclax + obinutuzumab is a well-tolerated, chemotherapy-free treatment option for CLL, with manageable side effects like neutropenia, making it suitable for patients who cannot undergo intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: A Review in Previously Untreated Chronic Lymphocytic Leukaemia. Blair, HA.[2021]

Obinutuzumab, combined with bendamustine, significantly prolonged progression-free survival (PFS) in patients with indolent non-Hodgkin's lymphoma, particularly benefiting those with follicular lymphoma, as shown in the phase III GADOLIN study.

The treatment was generally well-tolerated, with mild to moderate infusion-related reactions being the most common side effects, while neutropenia was the most frequent severe adverse event, indicating a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Obinutuzumab: A Review in Rituximab-Refractory or -Relapsed Follicular Lymphoma. Dhillon, S.[2018]

Citations

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Obinutuzumab, Lenalidomide and Venetoclax in Patients with ... We designed a phase Ib/II study of obinutuzumab, lenalidomide and venetoclax in patients with treatment-naïve follicular lymphoma.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03980171

NCT03980171 | Study of Lenalidomide, Venetoclax and ... Patients will receive induction treatment for 0.5 years with venetoclax, obinutuzumab and lenalidomide followed by maintenance treatment for upto 2 years.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10526830/

Targeted Therapy in Follicular Lymphoma: Towards a ... Targeted therapies in FL show promise by inhibiting key molecular pathways responsible for cancer proliferation and survival, reducing toxicity, and ...

4. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/4410/529982/Obinutuzumab-Lenalidomide-and-Venetoclax-for-the

Obinutuzumab, Lenalidomide and Venetoclax for the Initial ... We designed a phase Ib/II study of obinutuzumab (OBI), lenalidomide (LEN) and venetoclax (VEN) in patients (pts) with treatment-naïve FL.

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9278307/

SAKK 35/15: a phase 1 trial of obinutuzumab in combination ... Obinutuzumab can be safely combined with venetoclax in patients with previously untreated follicular lymphoma in need of systemic therapy.

6. ash.confex.com ash.confex.com/ash/2024/webprogram/Paper199108.html

Paper: Obinutuzumab, Lenalidomide and Venetoclax for ... There is a need for effective novel treatments with favorable safety profiles. Methods. We designed a phase Ib/II study of obinutuzumab (OBI), lenalidomide (LEN) ...

7. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0006497124071684

Obinutuzumab, Lenalidomide and Venetoclax for the Initial ... We designed a phase Ib/II study of obinutuzumab (OBI), lenalidomide (LEN) and venetoclax (VEN) in patients (pts) with treatment-naïve FL.