ALX148 + Rituximab + Lenalidomide for Lymphoma

Overseen By Paolo Strati, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Strong CYP3A inhibitors

Disqualifiers: CNS lymphoma, Burkitt lymphoma, HIV, others

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

Compensation: Varies

Number of Visits: 7

Duration: 6 cycles (approximately 6 months)

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of drugs—ALX148 (Evorpacept), rituximab, and lenalidomide—to treat B-cell non-Hodgkin lymphoma. The goal is to determine the best dose and assess whether this combination can stop cancer from growing and spreading by boosting the immune system and killing cancer cells. Eligible participants have B-cell non-Hodgkin lymphoma, have tried other treatments, and experience high tumor burden symptoms like night sweats or unintended weight loss.

As a Phase 1/Phase 2 trial, this research aims to understand how the treatment works in people and measure its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking cancer treatment advancements.

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.

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

Previous studies have tested ALX148 in patients with advanced cancers, including lymphoma. The results showed that ALX148 is generally well-tolerated, with some patients experiencing mild to moderate side effects. No severe or life-threatening reactions specific to ALX148 were reported.

Lenalidomide, a chemotherapy drug used for various cancers, including certain lymphomas, has been associated with serious blood-related side effects, such as low white blood cell counts (neutropenia). Monitoring blood levels during treatment is important.

Rituximab, another part of this trial, has a well-known safety profile. While effective, it can cause infusion reactions, which are common but usually manageable with monitoring and supportive care. Severe reactions are rare but can occur, especially during the first infusion.

Overall, these treatments have been extensively studied in different settings. Each has its own possible side effects, but they are generally considered manageable with proper medical supervision. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of ALX148 with Rituximab and Lenalidomide for treating lymphoma because it introduces a novel approach to targeting cancer cells. ALX148 is a CD47 blocker, which helps the immune system recognize and attack cancer cells more effectively. This mechanism is different from traditional treatments that mainly focus on directly killing cancer cells or stopping their growth. By enhancing the immune response, this combination has the potential to improve treatment outcomes for patients who may not respond well to current therapies.

What evidence suggests that ALX148 in combination with rituximab and lenalidomide could be effective for lymphoma?

Research has shown that combining ALX148, rituximab, and lenalidomide may help treat B-cell non-Hodgkin lymphoma. Participants in this trial will receive this combination treatment. ALX148, also known as evorpacept, helps the immune system find and attack cancer cells by blocking a signal that hides them. Lenalidomide stops cancer cells from growing and spreading. Rituximab targets a specific protein on B-cells to destroy them. Early studies suggest this combination can slow cancer progression, offering hope for better disease control. ^{4 6 7 8 9}

Who Is on the Research Team?

Paolo Strati

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• ALX148
• Lenalidomide
• Rituximab

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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 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]

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]

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]

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]

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]

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 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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12370181/

A Phase I Trial of Evorpacept, Lenalidomide and Rituximab ... Evorpacept (ALX148) is a novel CD47 blocker that abrogates interactions between lymphoma cells and SIRPα+ macrophages. Methods. Adult patients ...

2. aacrjournals.org aacrjournals.org/cancerres/article/85/8_Supplement_2/LB369/761908/Abstract-LB369-Final-results-of-a-phase-I-trial-of

Abstract LB369: Final results of a phase I trial of evorpacept ... Final results of a phase I trial of evorpacept (ALX148), lenalidomide, and rituximab for patients with B-cell non-Hodgkin lymphoma [abstract].

3. alxoncology.com alxoncology.com/wp-content/uploads/2025/05/AACR-2025-Final-Results-from-Phase-1-of-evorpacept-lenalidomide-rituximab-for-B-cell-NHL.pdf

Final results of a phase I trial of evorpacept ( ... A phase 2 study investigating its efficacy in pts with previously untreated and high tumor burden iNHL has completed enrollment. Final results of a phase I ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT05025800

NCT05025800 | ALX148, Rituximab and Lenalidomide for ... 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 ...

5. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40729376/

A Phase I Trial of Evorpacept, Lenalidomide and Rituximab for ... Evorpacept (ALX148) is a novel CD47 blocker that abrogates interactions between lymphoma cells and SIRPα+ macrophages. Methods: Adult patients ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT03013218

A Study of Evorpacept (ALX148) in Patients With Advanced ... A phase 1, dose escalation study of evorpacept (ALX148) in patients with advanced solid tumors and lymphoma. Detailed Description ... safety, PK, and PD study of ...

7. ir.alxoncology.com ir.alxoncology.com/news-releases/news-release-details/alx-oncology-reports-encouraging-clinical-data-evorpacept

Release Details The Phase 1/2 IST is an ongoing, open-label, single arm clinical trial designed to evaluate the safety, tolerability, and efficacy of evorpacept.

8. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40207726/

Evorpacept plus rituximab for the treatment of relapsed or ... We present the safety, pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity of evorpacept, a novel fusion protein comprising ...

9. medchemexpress.com medchemexpress.com/evorpacept.html?srsltid=AfmBOop5rROt8yvFW3SX6carflu6NSaCk8dRfKyB3Yr9xrlf3rZM22Ul

Evorpacept (ALX148) | CD47 Inhibitor | MedChemExpress Evorpacept is a high affinity CD47-blocking fusion protein with an inactive human immunoglobulin Fc region. - Mechanism of Action & Protocol.