Rituximab + Immunotherapy for Follicular Lymphoma

No longer recruiting at 6 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Dana-Farber Cancer Institute

Must not be taking: Anticancer therapies, Investigational agents

Disqualifiers: Autoimmune disease, Brain metastases, HIV, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 11

Duration: 6 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores new drug combinations to potentially treat follicular lymphoma, a type of blood cancer. Researchers are testing combinations of four drugs—Rituximab, Utomilumab, Avelumab (also known as MSB0010718C or Bavencio), and PF-04518600—to evaluate their effectiveness together. People with follicular lymphoma who have had previous treatments that did not work or have received limited treatment beyond basic therapies might be suitable for this trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive these new drug combinations.

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 be on anticancer therapies or investigational agents close to the start of the study. It's best to discuss your specific medications with the study team.

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

Research has shown that the treatments in this trial have promising safety results from earlier studies. Here's a simple breakdown:

1. **Rituximab**: The FDA has approved this drug for other uses, indicating general safety. However, some patients have experienced serious reactions, such as infections and issues during infusions.

2. **Utomilumab and Avelumab**: Past studies have tested these drugs with rituximab. Researchers chose the doses based on safety information. Most side effects were mild to moderate and manageable.

3. **PF-04518600**: This drug has been tested alone and in combination with others. Early studies showed it is generally safe, with only mild side effects reported and no major safety concerns.

Overall, these treatments have been tested in various combinations and doses without major safety problems. Most side effects have been mild to moderate, which is a positive sign for their safety in humans. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for follicular lymphoma because they combine innovative immunotherapy agents with the established drug rituximab. Unlike standard care options like single-agent rituximab or chemotherapy, these treatments incorporate avelumab, utomilumab, and PF04518600, which are designed to enhance the immune system's ability to target and destroy cancer cells. Avelumab is a PD-L1 inhibitor, helping the immune system recognize and attack cancer, while utomilumab stimulates T-cell activity, and PF04518600 targets the OX40 pathway to boost the immune response. By utilizing these novel mechanisms, these treatments may offer more potent and targeted options for patients, potentially leading to better outcomes.

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

Research has shown that rituximab, one of the treatments in this trial, can help treat follicular lymphoma when combined with other therapies. Participants in this trial may receive rituximab with Utomilumab, which boosts the immune system and has shown activity in treating B-cell lymphomas. Another option is Avelumab, an immune therapy that might improve outcomes when used with rituximab and other drugs. Additionally, PF-04518600, which also targets the immune system, is being studied in combination with rituximab. Although data on these combinations remain early, each treatment arm in this trial has shown potential in improving cancer treatment. ^{1 2 3 6 7}

Who Is on the Research Team?

Caron A. Jacobson, MD

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

This trial is for adults over 18 with follicular lymphoma that's relapsed after treatment or hasn't been treated yet, except those with severe allergies to monoclonal antibodies, autoimmune diseases, active infections, other cancers within the last three years (some exceptions apply), and certain heart conditions. Participants need functioning major organs and can't be pregnant or breastfeeding.

Inclusion Criteria

I have follicular lymphoma, grade 1-3A, and have been treated with or without anti-CD-20 therapy.

Exclusion Criteria

Patients currently receiving anticancer therapies or who have received anticancer therapies within 28 days of the start of study drug (including chemotherapy, radiation therapy, antibody based therapy, etc.), or 56 days for radioimmunotherapy. Steroids for symptom palliation are allowed, but must be either discontinued or on stable doses of < 10mg daily of prednisone (or the equivalent) at the time of initiation of protocol therapy, Patients may not be receiving any other investigational agents, or have received investigational agents within 4 weeks (or 3 half-lives, whichever is longer) of beginning treatment, History of severe allergic or anaphylactic reactions to monoclonal antibody therapy unless in consultation with an allergy specialist they are deemed eligible for retreatment with desensitization, Patients who have previously received therapy with any drug that works by a similar mechanism of action as any drug being tested in a given cohort will be excluded from that cohort but will be allowed to enroll in other open cohorts, Patients who have undergone prior allogeneic stem cell transplantation, Patients with a history of or active autoimmune disease (except controlled asthma, Hashimoto thyroiditis, atopic dermatitis, and/or vitiligo), or requiring systemic corticosteroids at a dose of 10mg prednisone equivalent daily. Patients with a history of autoimmune disease who never required corticosteroids and with no evidence of disease activity, and in whom the risk of reactivation is felt not to be serious, may be enrolled after discussion with the overall study chair. Exceptions to this are patients with a history of inflammatory bowel disease (ulcerative colitis and Crohn's disease). These patients are excluded regardless of whether their disease is active or inactive, Patients with active pneumonitis or colitis, or patients with chronic liver disease and/or cirrhosis, Patients, who have had a major surgery or significant traumatic injury within 4 weeks of start of study drug, patients who have not recovered from the side effects of any major surgery (defined as requiring general anesthesia) or patients that may require major surgery during the course of the study, Patients with known leptomeningeal or brain metastases. Imaging or spinal fluid analysis to exclude CNS involvement is not required, unless there is clinical suspicion by the treating investigator, Patients with known HIV infection or hepatitis B or C infection. Testing for HIV is optional. Testing for hepatitis B and C is mandatory. Patients with hepatitis B core Ab positivity but negative surface antigen and negative viral load may be enrolled if they can be treated with a prophylactic agent (eg, entecavir); patients with hepatitis C seropositivity who have undergone successful treatment with negative viral load can also be enrolled, Patients with a systemic fungal, bacterial, viral, or other infection not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment), Prior history of another malignancy (except for non-melanoma skin cancer or in situ cervical or breast cancer) unless disease free for at least three years. Patients with prostate cancer are allowed if PSA is less than 1, Patients should not have received immunization with attenuated live vaccine within one week of study entry or during study period, Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods. Women of child bearing potential (WOCBP) or male study participants of reproductive potential must agree to use double barrier birth control method of contraception during the course of the study treatment period and for 3 months after completing study treatment. WOCBP are defined as sexually mature women who have not undergone a hysterectomy or who are not postmenopausal (no menses) for at least 12 consecutive months. WOCBP must have a negative urine or serum pregnancy test within 14 days prior to administration of treatment, History of noncompliance to medical regimens, Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as: New York Heart Association Class III or IV cardiac disease, including pre-existing clinically significant arrhythmia, congestive heart failure, or cardiomyopathy, Patients with a history of previous anthracycline treatment and are at risk of cardiac failure (New York Heart Association Class II or above) are excluded from cohorts A2, A3, and B2 (cohorts that include PF04518600), Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction within 6 months of start of study drug, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease, Patients with any one of the following currently on or in the previous 6 months will be excluded from cohorts A2, A3, and B2 (any cohort that includes treatment with PF04518600) myocardial infarction, congenital long QT syndrome, torsade's de points, left anterior hemiblock (bifascicular block), unstable angina, coronary/peripheral artery bypass graft, cerebrovascular accident, transient ischemic attack or symptomatic pulmonary embolism or other clinically significant episode of thrombo-embolic disease*. Ongoing cardiac dysrhythmias of NCI CTCAE grade > 2, atrial fibrillation of any grade, or QTcF interval >470msec at screening (except in case of right bundle branch block, these cases must be discussed with the principal investigator). *Cases must be discussed in detail with the principal investigator to judge eligibility. Anticoagulation (heparin only, no vitamin K antagonists or factor Xa inhibitors will be allowed if indicated, Other uncontrolled intercurrent illness that would limit adherence to study requirements

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Rituximab, Utomilumab, Avelumab, and/or PF-04518600 in various combinations. Rituximab is administered for four weekly treatments in cycle 1, while other drugs are administered at specified intervals.

6 months

Visits every 2-4 weeks depending on drug regimen

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with assessments for progression-free survival and overall survival.

24 months

Contact every 3 months

Long-term follow-up

Participants are monitored for overall survival with less frequent contact.

3 years

Contact every 6 months

What Are the Treatments Tested in This Trial?

Interventions

• Avelumab
• PF04518600
• Rituximab
• Utomilumab

Trial Overview The study tests combinations of Rituximab with new drugs Utomilumab and Avelumab as potential treatments for follicular lymphoma. It aims to find out how well these drug combos work together in patients who have had previous treatments or are newly diagnosed.

How Is the Trial Designed?

Group I: Rituximab+Utomilumab+PF04518600-0.3mg Experimental Treatment 3 Interventions

* Rituximab is administered intravenously per institutional standards for four weekly treatments for cycle 1 only * Utomilumab is administered intravenously over 1 hour once every 4 weeks * PF-04518600 is administered intravenously over 1 hour on day 1 and day 15, 0.3mg/kg

Group II: Rituximab+Utomilumab+Avelumab-3mg Experimental Treatment 3 Interventions

* Rituximab is administered intravenously per institutional standards for four weekly treatments for cycle 1 only * Utomilumab is administered intravenously over 1 hour once every 4 weeks * Avelumab is administered intravenously over 1 hour once every 2 weeks, 3mg/kg

Group III: Rituximab+Utomilumab+Avelumab-10mg Experimental Treatment 3 Interventions

* Rituximab is administered intravenously per institutional standards for four weekly treatments for cycle 1 only * Utomilumab is administered intravenously over 1 hour once every 4 weeks * Avelumab is administered intravenously over 1 hour once every 2 weeks, 10mg/kg

Group IV: Rituximab+PF04518600-0.3mg+Avelumab-3mg Experimental Treatment 3 Interventions

* Rituximab is administered intravenously per institutional standards for four weekly treatments for cycle 1 only * Utomilumab is administered intravenously over 1 hour once every 4 weeks * Avelumab is administered intravenously over 1 hour once every 2 weeks, 3mg/kg

Group V: Rituximab+PF04518600-0.3mg+Avelumab-10mg Experimental Treatment 3 Interventions

* Rituximab is administered intravenously per institutional standards for four weekly treatments for cycle 1 only * Utomilumab is administered intravenously over 1 hour once every 4 weeks * Avelumab is administered intravenously over 1 hour once every 2 weeks, 10mg/kg

Group VI: Rituximab+PF04518600-0.3mg Experimental Treatment 2 Interventions

* Rituximab is administered intravenously per institutional standards for four weekly treatments for cycle 1 only * PF-04518600 is administered intravenously over 1 hour on day 1 and day 15, 0.3mg/kg

Group VII: PF04518600-0.3mg Experimental Treatment 1 Intervention

-PF-04518600 is administered intravenously over 1 hour on day 1 and day 15, 0.3mg/kg

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

Approved in European Union as Bavencio for:

• Merkel cell carcinoma
• Renal cell carcinoma
• Urothelial carcinoma

Approved in United States as Bavencio for:

• Merkel cell carcinoma
• Renal cell carcinoma
• Urothelial carcinoma

Approved in Japan as Bavencio for:

• Merkel cell carcinoma
• Renal cell carcinoma
• Urothelial carcinoma

Who Is Running the Clinical Trial?

Dana-Farber Cancer Institute

Lead Sponsor

Trials

1,128

Recruited

382,000+

Pfizer

Industry Sponsor

Trials

4,712

Recruited

50,980,000+

Known For

Vaccine Innovations

Top Products

Viagra, Zoloft, Lipitor, Prevnar 13

Albert Bourla

Pfizer

Chief Executive Officer since 2019

PhD in Biotechnology of Reproduction, Aristotle University of Thessaloniki

Patrizia Cavazzoni

Pfizer

Chief Medical Officer

MD from McGill University

Published Research Related to This Trial

Rituximab is an effective treatment for follicular lymphoma (FL), improving outcomes when used in combination with traditional chemotherapy, and has shown significant benefits as a maintenance therapy without increasing side effects or compromising patients' quality of life.

Despite its long history of use, new safety alerts and side effects have emerged that clinicians need to be aware of, highlighting the importance of ongoing monitoring and management in patients receiving rituximab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Critical appraisal of rituximab in the maintenance treatment of advanced follicular lymphoma. Aguiar-Bujanda, D., Blanco-Sánchez, MJ., Hernández-Sosa, M., et al.[2022]

Rituximab is the first monoclonal antibody approved for treating B-cell lymphomas, showing significant effectiveness in conditions like follicular lymphoma, mantle cell lymphoma, and diffuse large B-cell lymphoma.

The combination of rituximab with standard chemotherapy agents (cyclophosphamide, doxorubicin, vincristine, and prednisone) has achieved the highest efficacy reported for treating diffuse large B-cell lymphoma and follicular lymphoma, while maintaining low toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evolving role of rituximab in the treatment of patients with non-Hodgkin's lymphoma. Traullé, C., Coiffier, BB.[2015]

Rituximab, an anti-CD20 antibody, has significantly improved outcomes for patients with follicular lymphoma (FL), achieving long-term remission and prolonged failure-free survival, especially when used as a first-line treatment.

The drug not only works effectively on its own but also enhances the effectiveness of chemotherapy and other targeted therapies, making it a crucial component in the treatment of FL and a benchmark for developing new anti-CD20 monoclonal antibodies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab: a benchmark in the development of chemotherapy-free treatment strategies for follicular lymphomas. Karmali, R., Kimby, E., Ghielmini, M., et al.[2020]

Ofatumumab, a fully humanized anti-CD20 monoclonal antibody, demonstrated an overall response rate (ORR) of 84% in patients with untreated, low/intermediate-risk advanced-stage follicular lymphoma, indicating strong efficacy as a single-agent treatment.

The treatment was well tolerated, with no severe infusion reactions or serious infections reported, and a low discontinuation rate of 6%, suggesting that ofatumumab is a safe alternative to rituximab for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 2 multicentre study of single-agent ofatumumab in previously untreated follicular lymphoma: CALGB 50901 (Alliance). Rosenbaum, CA., Jung, SH., Pitcher, B., et al.[2021]

Obinutuzumab, when compared to rituximab, significantly improves progression-free survival (PFS) in patients with CD20 positive B-cell non-Hodgkin lymphomas, but it also increases the incidence of serious adverse events (AEs).

Ofatumumab is less effective than rituximab in terms of overall response rate (ORR), while 90Y-ibritumomab tiuxetan shows a higher ORR but does not improve other survival metrics compared to rituximab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of new anti-CD20 monoclonal antibodies versus rituximab for induction therapy of CD20+ B-cell non-Hodgkin lymphomas: a systematic review and meta-analysis. Luo, C., Wu, G., Huang, X., et al.[2023]

In a phase 2 study involving 80 adults with untreated follicular lymphoma, the combination of ibrutinib and rituximab showed a high overall response rate of 85% in the first treatment arm and 75% in the second arm, indicating strong efficacy.

The treatment was generally well-tolerated, with common side effects including fatigue, diarrhea, and nausea, while serious adverse events were rare, suggesting a favorable safety profile for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The combination of ibrutinib and rituximab demonstrates activity in first-line follicular lymphoma. Fowler, NH., Nastoupil, L., De Vos, S., et al.[2021]

Rituximab is highly effective for treating low-grade CD20+ lymphoma, especially when combined with chemotherapy, which is the standard treatment for follicular lymphoma (FL).

The efficacy of rituximab can be enhanced by combining it with biological agents like interferon-alpha-2a, bortezomib, or lenalidomide, but more research is needed to determine the best combinations and timing of these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biological therapy doublets: pairing rituximab with interferon, lenalidomide, and other biological agents in patients with follicular lymphoma. Kimby, E.[2021]

Rituximab maintenance therapy significantly improves progression-free survival in patients with follicular lymphoma after initial treatment, regardless of tumor burden or patient characteristics, based on multiple randomized studies.

Key questions remain about the best administration schedule, duration of treatment, and the cost-effectiveness of rituximab maintenance, especially for patients previously treated with bendamustine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antibody Therapy Maintenance in Follicular Lymphoma. Golfier, C., Salles, G.[2021]

Rituximab, a monoclonal antibody targeting CD20 on B lymphocytes, significantly prolongs progression-free survival in patients with follicular lymphoma when used as a two-year maintenance therapy after initial treatment, compared to observation.

The maintenance therapy with rituximab also delays the need for subsequent lymphoma treatments and has an acceptable safety profile, showing no new or unexpected adverse events compared to the initial induction therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab: as first-line maintenance therapy following rituximab-containing therapy for follicular lymphoma. Croxtall, JD.[2021]

In a study of 60 patients with symptomatic or bulky follicular lymphoma, a combination of short-course chemoimmunotherapy (CHOP-R) followed by radioimmunotherapy (RIT) led to a significant increase in complete response (CR) rates, from 40% after CHOP-R to 82% after RIT, as assessed by imaging.

The study found that patients who did not achieve a complete metabolic response on PET imaging after CHOP-R had a higher risk of relapse, highlighting the importance of early PET assessment in predicting treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of short-course CHOP-R followed by 90Y-ibritumomab tiuxetan and extended rituximab in previously untreated follicular lymphoma. Jacobs, SA., Swerdlow, SH., Kant, J., et al.[2016]

In a phase I study involving 67 patients with relapsed/refractory follicular lymphoma and other CD20+ non-Hodgkin lymphomas, the combination of utomilumab and rituximab showed a favorable safety profile, with no dose-limiting toxicities and mostly mild adverse events like fatigue.

The treatment demonstrated clinical activity with an objective response rate of 21.2%, including complete and partial responses, suggesting that the effectiveness may depend on the patient's immune function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-in-Human Study of Utomilumab, a 4-1BB/CD137 Agonist, in Combination with Rituximab in Patients with Follicular and Other CD20+ Non-Hodgkin Lymphomas. Gopal, AK., Levy, R., Houot, R., et al.[2021]

The use of the anti-CD20 monoclonal antibody rituximab has significantly improved survival rates in patients with follicular lymphoma (FL), especially when used in combination with chemotherapy for both induction and maintenance therapy.

Radioimmunotherapy (RIT) using radiolabelled anti-CD20 mAbs, such as (90)Y Ibritumomab tiuxetan and (131)I Tositumomab, has shown high response rates and durable remissions, particularly when used as consolidation therapy after initial treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

How have outcomes for patients with follicular lymphoma changed with the addition of monoclonal antibodies? Illidge, T., Chan, C.[2019]

In a phase 2 trial involving 128 patients with untreated high-risk follicular lymphoma, the combination of ofatumumab and bendamustine showed a complete response (CR) rate of 62%, while adding bortezomib did not significantly improve CR rates, which were 60%.

Both treatment arms had similar rates of severe toxicities, but a higher percentage of patients in the bortezomib group required dose modifications and early treatment discontinuation, indicating that the addition of bortezomib may lead to more treatment challenges without added benefit.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized trial of ofatumumab and bendamustine versus ofatumumab, bendamustine, and bortezomib in previously untreated patients with high-risk follicular lymphoma: CALGB 50904 (Alliance). Blum, KA., Polley, MY., Jung, SH., et al.[2020]

Citations

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First-in-human study of an OX40 (ivuxolimab) and 4-1BB ... Ivuxolimab (PF-04518600) and utomilumab (PF-05082566) are humanized agonistic IgG2 monoclonal antibodies against OX40 and 4-1BB, ...

2. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/66/NCT02315066/Prot_000.pdf

a phase 1, open-label, dose escalation study of pf- ... PF-04518600 and 100 mg utomilumab. Preliminary efficacy data as of 24 May 2017, indicated that there were 2 ongoing partial responses (PR) ...

3. sigma.larvol.com sigma.larvol.com/product.php?e1=542367&tab=newstrac

ivuxolimab (PF-04518600) News Our results support a possible role for 4-1BB agonist therapy in FL and suggest that features of the tumor microenvironment and stool microbiome may be ...

4. nature.com nature.com/articles/s41392-020-0113-2

Advances in targeted therapy for malignant lymphoma The results showed that at a median follow-up of 24.6 months, the 2-year modified PFS rates in the A+AVD and ABVD groups were 82.1% and 77.2%, ...

5. immuno-oncologynews.com immuno-oncologynews.com/2020/07/22/ema-reviewing-liso-cell-car-t-cell-therapy-for-relapsed-refractory-lymphomas/

EMA to Review Liso-cel as CAR T-cell Therapy for ... “With more than 30% of patients diagnosed with diffuse large B-cell lymphoma ultimately relapsing after initial therapy and an expected overall ...

6. esmoopen.com esmoopen.com/article/S2059-7029(20)30004-1/fulltext

New pathways in immune stimulation: targeting OX40 Published data from phase 1 trials showed that the safety profile seems to be maintained even in combination strategies. In a phase 1 trial that included ...

7. memoinoncology.com memoinoncology.com/follicular-lymphoma-efficacy-and-safety-updates/

Follicular lymphoma: Efficacy and safety updates At ASH 2024, promising efficacy and safety data were reported for the five molecules nemtabrutinib, zanubrutinib, BGB-16673, epcoritamab, and mosunetuzumab [1-6] ...