ALX148 + Rituximab + Lenalidomide for Lymphoma

Recruiting in Palo Alto (17 mi)

Overseen by Paolo Strati

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Strong CYP3A inhibitors

Disqualifiers: CNS lymphoma, Burkitt lymphoma, HIV, others

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This phase I/II trial finds out the best dose, possible benefits and/or side effects of ALX148 in combination with rituximab and lenalidomide in treating patients with indolent and aggressive B-cell non-Hodgkin lymphoma. Immunotherapy with ALX148, may induce changes in body's immune system and may interfere with the ability of cancer cells to grow and spread. Chemotherapy drugs, such as lenalidomide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Rituximab is a monoclonal antibody that binds to a protein called CD20 found on B-cells, and may kill cancer cells. Giving ALX148 in combination with rituximab and lenalidomide may help to control the disease.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you require chronic treatment with strong CYP3A inhibitors or if you are on systemic immunosuppressant therapy. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug combination ALX148, Rituximab, and Lenalidomide for treating lymphoma?

Research shows that the combination of lenalidomide and rituximab is effective in treating certain types of lymphoma, including follicular and mantle-cell lymphoma, especially in patients who have not responded to rituximab alone. This combination has been shown to improve progression-free survival, which means patients live longer without their disease getting worse. ^{1 2 3 4 5}

Is the combination of ALX148, Rituximab, and Lenalidomide safe for humans?

The combination of Lenalidomide and Rituximab has a manageable safety profile, with common side effects like neutropenia (low white blood cell count) and mild skin reactions, which are generally manageable with dose adjustments. Lenalidomide has been studied in various lymphomas and is considered safe, with most side effects being predictable and manageable. However, specific safety data for ALX148 (Evorpacept) in combination with these drugs is not provided in the available research. ^{5 6 7 8 9}

What makes the drug combination of ALX148, Lenalidomide, and Rituximab unique for treating lymphoma?

This drug combination is unique because it includes ALX148, a novel agent that may enhance the immune system's ability to fight cancer, alongside Lenalidomide and Rituximab, which have shown effectiveness in overcoming resistance to Rituximab in certain lymphomas. This combination could potentially offer a new option for patients with relapsed or refractory lymphoma. ^{1 5 10 11 12}

Research Team

Paolo Strati

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for adults with various types of B-cell non-Hodgkin lymphoma, including those who haven't had treatment or have tried at least one therapy without success. Participants should be in good physical condition, not have HIV or active hepatitis, and must not be pregnant. They can't join if they've had certain recent surgeries, uncontrolled diseases, a history of severe allergies to study drug components, or are on strong immune system suppressants.

Inclusion Criteria

I have not received any systemic treatment for my lymphoma.

ANC >= 1,000/mm^3

Hemoglobin > 8 g/dL

Exclusion Criteria

Your expected lifespan is less than 6 months.

History of hemolytic transfusion reaction secondary to allo-antibodies

I have trouble swallowing pills or have a digestive condition.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ALX148, rituximab, and lenalidomide. ALX148 is administered IV on days 1, 8, 15, and 22, or days 1 and 15, or day 1 depending on dose level. Rituximab is administered IV on days 1, 8, 15, and 22 of cycle 1, then on day 1 of cycles 2-6. Lenalidomide is taken orally daily on days 1-21 of cycles 1-6. Cycles repeat every 28 days.

6 cycles (approximately 6 months)

Multiple visits per cycle for IV administration

Follow-up

Participants are monitored for safety and effectiveness after treatment completion. Follow-up occurs at 7 and 30 days post-treatment, then up to 3 years.

Up to 3 years

Follow-up visits at 7 and 30 days, then periodic visits up to 3 years

Treatment Details

Interventions

• ALX148 (CD47 Antagonist)
• Lenalidomide (Anti-metabolites)
• Rituximab (Monoclonal Antibodies)

Trial Overview The trial tests the combination of ALX148 (an immunotherapy), rituximab (a monoclonal antibody), and lenalidomide (a chemotherapy drug) to see how well they work together against indolent and aggressive B-cell non-Hodgkin lymphoma. It aims to find the best dose and assess benefits/side effects.

Participant Groups

Group I: Treatment (ALX148, rituximab, lenalidomide) Experimental Treatment 3 Interventions

Patients receive ALX148 IV over 1 hour once on days 1, 8, 15 and 22, or days 1 and 15, or day 1 depending on dose level. Patients also receive rituximab IV over 4-6 hours on days 1, 8, 15 and 22 of cycle 1, then on day 1 of cycles 2-6, and lenalidomide PO QD on days 1-21 of cycles 1-6. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Dr. Peter WT Pisters

M.D. Anderson Cancer Center

Chief Executive Officer since 2017

MD from University of Western Ontario

Dr. Jeffrey E. Lee

M.D. Anderson Cancer Center

Chief Medical Officer

MD from Stanford University School of Medicine

Findings from Research

In a phase II trial involving 50 patients with indolent B-cell or mantle cell lymphomas who were previously resistant to rituximab, the combination of lenalidomide and rituximab resulted in a significant increase in overall response rate from 30.2% after lenalidomide alone to 62.8% after adding rituximab.

The median progression-free survival for patients receiving the lenalidomide-rituximab combination was 22.2 months, which was significantly longer than the 9.13 months observed with prior rituximab treatment, indicating that this combination can effectively overcome previous resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination of Lenalidomide and Rituximab Overcomes Rituximab Resistance in Patients with Indolent B-cell and Mantle Cell Lymphomas. Chong, EA., Ahmadi, T., Aqui, NA., et al.[2022]

Lenalidomide is an effective and well-tolerated treatment for multiple myeloma and shows promise for patients with follicular lymphoma, diffuse large B-cell lymphoma, and transformed large cell lymphoma.

The review highlights the potential of lenalidomide, especially in combination with rituximab, as a therapeutic option, aiming to guide future clinical studies to enhance survival rates for these lymphoma types.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunomodulation therapy with lenalidomide in follicular, transformed and diffuse large B cell lymphoma: current data on safety and efficacy. Desai, M., Newberry, KJ., Romaguera, J., et al.[2021]

The combination of lenalidomide and rituximab (LR) showed a significantly higher overall response rate (76%) compared to lenalidomide alone (53%) in patients with recurrent follicular lymphoma, indicating that LR is more effective in treating this condition.

Both treatment regimens had similar rates of severe adverse events (grade 3 to 4), but lenalidomide alone resulted in more treatment failures, suggesting that LR may provide a better balance of efficacy and tolerability.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized Trial of Lenalidomide Alone Versus Lenalidomide Plus Rituximab in Patients With Recurrent Follicular Lymphoma: CALGB 50401 (Alliance). Leonard, JP., Jung, SH., Johnson, J., et al.[2022]

The maximum tolerated dose (MTD) of lenalidomide when combined with rituximab for treating relapsed or refractory mantle-cell lymphoma (MCL) was determined to be 20 mg, with the combination showing a manageable safety profile despite some grade 3-4 hematological toxicities.

In a phase 2 trial involving 44 patients, the combination therapy resulted in a 57% overall response rate, with 36% achieving a complete response and a median overall survival of 24.3 months, indicating its efficacy in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenalidomide in combination with rituximab for patients with relapsed or refractory mantle-cell lymphoma: a phase 1/2 clinical trial. Wang, M., Fayad, L., Wagner-Bartak, N., et al.[2023]

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 rituximab and lenalidomide (R2) significantly improves treatment efficacy for recurrent non-Hodgkin lymphoma compared to rituximab alone, leading to its approval for use in previously treated patients with follicular and marginal zone lymphoma.

R2 has a manageable safety profile, with common adverse events including grade 3/4 neutropenia, skin rashes, and gastrointestinal issues, indicating that while it is effective, careful monitoring and management of side effects are necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of Adverse Events From the Combination of Rituximab and Lenalidomide in the Treatment of Patients With Follicular and Low-Grade Non-Hodgkin Lymphoma. Cheson, BD., Morschhauser, F., Martin, P.[2021]

Lenalidomide, especially when combined with rituximab (the 'R(2)' regimen), shows enhanced efficacy in treating indolent B-cell and mantle cell lymphomas, even in patients resistant to rituximab, while maintaining a manageable safety profile.

The most common serious side effect is asymptomatic neutropenia, which can be managed through dose adjustments, and while immune-related symptoms like rash are more frequent with the R(2) regimen, they are generally low-grade and manageable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical experience with lenalidomide alone or in combination with rituximab in indolent B-cell and mantle cell lymphomas. Ruan, J., Shah, B., Martin, P., et al.[2020]

In a phase I study involving 21 elderly patients with untreated diffuse large B-cell lymphoma, the combination of lenalidomide and standard chemotherapy resulted in a high overall response rate of 90%, with 81% achieving complete remission.

The maximum tolerated dose of lenalidomide was determined to be 15 mg/day, with manageable safety concerns, including hematologic toxicities like neutropenia in 28% of treatment courses, indicating that this regimen is safe for elderly patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenalidomide plus cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab is safe and effective in untreated, elderly patients with diffuse large B-cell lymphoma: a phase I study by the Fondazione Italiana Linfomi. Chiappella, A., Tucci, A., Castellino, A., et al.[2021]

In a study of 33 patients with aggressive non-Hodgkin's lymphoma, the combination of Rituxan (rituximab) and CHOP chemotherapy resulted in a high overall response rate of 94%, with 61% achieving a complete response.

The treatment was well-tolerated, with common side effects like fever and chills, and did not hinder the completion of the full six-course regimen, indicating both safety and efficacy in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of rituximab in combination with chop chemotherapy in patients with previously untreated, aggressive non-Hodgkin's lymphoma. Vose, JM., Link, BK., Grossbard, ML., et al.[2022]

In a phase II study involving 30 patients with relapsed/refractory indolent non-Hodgkin lymphoma, the combination of lenalidomide and rituximab achieved a high overall response rate of 74%, with 44% of patients experiencing complete responses.

The treatment demonstrated a median progression-free survival of 12.4 months, and while there were some significant adverse events like neutropenia and lymphopenia, the overall toxicity was considered acceptable, indicating a promising safety profile for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenalidomide plus rituximab can produce durable clinical responses in patients with relapsed or refractory, indolent non-Hodgkin lymphoma. Tuscano, JM., Dutia, M., Chee, K., et al.[2018]

Lenalidomide shows modest effectiveness in treating recurrent diffuse large B cell lymphoma, with response rates between 19% and 28%, particularly in patients with activated B cell (ABC) lymphoma due to its ability to inhibit a key driver of these cancers.

Ongoing trials are investigating whether combining lenalidomide with standard chemotherapy (R/CHOP) can improve survival rates, and its potential role in maintenance therapy and in patients at high risk for central nervous system involvement.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Checking in on Lenalidomide in Diffuse Large B Cell Lymphoma. Goldfinger, M., Xu, M., Bertino, JR., et al.[2020]

In a phase 2 trial involving 27 patients with rituximab-resistant B-cell lymphomas, the combination of lenalidomide, low-dose dexamethasone, and rituximab resulted in a significant increase in overall response rates from 29% after initial treatment to 58% after adding rituximab.

The median progression-free survival for patients was 23.7 months, indicating that this combination therapy not only enhances response rates but also provides durable benefits for patients with difficult-to-treat lymphomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined lenalidomide, low-dose dexamethasone, and rituximab achieves durable responses in rituximab-resistant indolent and mantle cell lymphomas. Ahmadi, T., Chong, EA., Gordon, A., et al.[2018]

References

1. United States pubmed.ncbi.nlm.nih.gov

Combination of Lenalidomide and Rituximab Overcomes Rituximab Resistance in Patients with Indolent B-cell and Mantle Cell Lymphomas. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Immunomodulation therapy with lenalidomide in follicular, transformed and diffuse large B cell lymphoma: current data on safety and efficacy. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

Randomized Trial of Lenalidomide Alone Versus Lenalidomide Plus Rituximab in Patients With Recurrent Follicular Lymphoma: CALGB 50401 (Alliance). [2022]

4. England pubmed.ncbi.nlm.nih.gov

Lenalidomide in combination with rituximab for patients with relapsed or refractory mantle-cell lymphoma: a phase 1/2 clinical trial. [2023]

5. New Zealand pubmed.ncbi.nlm.nih.gov

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

6. United States pubmed.ncbi.nlm.nih.gov

Management of Adverse Events From the Combination of Rituximab and Lenalidomide in the Treatment of Patients With Follicular and Low-Grade Non-Hodgkin Lymphoma. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Clinical experience with lenalidomide alone or in combination with rituximab in indolent B-cell and mantle cell lymphomas. [2020]

8. Italy pubmed.ncbi.nlm.nih.gov

Lenalidomide plus cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab is safe and effective in untreated, elderly patients with diffuse large B-cell lymphoma: a phase I study by the Fondazione Italiana Linfomi. [2021]

9. United States pubmed.ncbi.nlm.nih.gov

Phase II study of rituximab in combination with chop chemotherapy in patients with previously untreated, aggressive non-Hodgkin's lymphoma. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Lenalidomide plus rituximab can produce durable clinical responses in patients with relapsed or refractory, indolent non-Hodgkin lymphoma. [2018]

11. United States pubmed.ncbi.nlm.nih.gov

Checking in on Lenalidomide in Diffuse Large B Cell Lymphoma. [2020]

12. United States pubmed.ncbi.nlm.nih.gov

Combined lenalidomide, low-dose dexamethasone, and rituximab achieves durable responses in rituximab-resistant indolent and mantle cell lymphomas. [2018]