CC-99282 + Rituximab for Non-Hodgkin's Lymphoma

Overseen By The Ohio State Comprehensive Cancer Center

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Nathan Denlinger

Must not be taking: CYP3A inhibitors, CYP3A inducers

Disqualifiers: Pregnancy, Breastfeeding, Heart failure, 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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 265

Duration: 24 months

18 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I trial tests the safety, side effects and best dose of CC-99282 with rituximab for the treatment of patients who have received chimeric antigen receptor (CAR) T cell therapy for non-Hodgkins lymphoma and in whom have had a sub-optimal response early on to CAR T-cell therapy. Immunotherapy with CC-99282 may induce changes in the body's immune system and may interfere with the ability of tumor cells to grow and spread. Rituximab is a monoclonal antibody. It binds to a protein called CD20, which is found on B cells (a type of white blood cell) and some types of cancer cells. This may help the immune system kill cancer cells. Giving CC-99282 with rituximab may be a safe and effective treatment option for patients who have received CAR-T cell therapy for relapsed or refractory non-Hodgkin's lymphoma.

Will I have to stop taking my current medications?

You may need to stop taking certain medications, especially strong CYP3A inhibitors and inducers, before joining the trial. If you are on moderate CYP3A inhibitors or inducers, a washout period (time without taking these medications) of at least 14 days or 5 half-lives is required before starting the study treatment.

What data supports the effectiveness of the drug Rituximab for treating non-Hodgkin's lymphoma?

Rituximab has been shown to improve survival in patients with non-Hodgkin's lymphoma when added to standard chemotherapy, and it induces responses in almost half of patients with relapsed follicular/low-grade non-Hodgkin's lymphoma. It is effective as a single agent or in combination with other treatments, providing long-term remissions and improved survival rates. ^{1 2 3 4 5}

Is the combination of CC-99282 and Rituximab safe for humans?

Rituximab has been used in many patients and is generally well-tolerated, with common side effects like fevers and chills during the first infusion. Serious reactions are rare but can include heart and lung issues, especially in patients with high numbers of cancer cells or existing heart problems. ^{1 3 6 7 8}

What makes the drug CC-99282 + Rituximab unique for treating non-Hodgkin's lymphoma?

The combination of CC-99282 with Rituximab is unique because Rituximab is a monoclonal antibody that targets the CD20 antigen on B-cells, which is effective in treating various B-cell non-Hodgkin's lymphomas, and CC-99282 may enhance this effect, potentially offering a novel approach to treatment. ^{1 2 9 10 11}

Research Team

Nathan Denlinger, DO, MS

Principal Investigator

Ohio State University Comprehensive Cancer Center

Eligibility Criteria

This trial is for patients with various types of Non-Hodgkin's Lymphoma who have had a less than ideal response to CAR T-cell therapy. It's important that participants haven't responded well to this prior treatment and are now looking for additional options.

Inclusion Criteria

Written informed consent obtained to participate in the study and Health Insurance Portability and Accountability Act (HIPAA) authorization for release of personal health information

Aspartate aminotransferase (AST) ≤ 3.0 × ULN (obtained within 14 days prior to initiating study treatment)

Females of childbearing potential must have a negative serum pregnancy test within 3 days prior to enrollment. Pregnancy tests must be medically supervised with a minimum sensitivity of 25mIU/ml. NOTE: a female of childbearing potential is a female who: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months, i.e. has had menses at any time in the preceding 24 consecutive months. Documentation of postmenopausal status must be provided. Further information on pregnancy testing and the definition of a female of childbearing potential located in the CC-99282 pregnancy prevention plan document

Exclusion Criteria

I have not received CD19.CAR-T therapy for conditions outside those specified.

I am not using strong medication that affects liver enzymes.

I do not have severe heart problems, uncontrolled seizures, or very high blood pressure.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Patients receive rituximab IV on day 1 of each cycle and CC-99282 PO QD on days 1-14 of each cycle. Treatment repeats every 28 days for up to 6 cycles of rituximab and up to 24 cycles of CC-99282.

24 months

Monthly visits for up to 24 cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 months

Visits at days 240, 365, 455, 547, 637, and 730

Treatment Details

Interventions

• CC-99282
• Rituximab

Trial Overview The trial is testing the combination of a new immunotherapy drug, CC-99282, with an established cancer drug called Rituximab. The study aims to find the safest dose and observe how these drugs affect the immune system in attacking lymphoma cells post CAR-T therapy.

Participant Groups

Group I: Treatment (rituximab, CC-99282) Experimental Treatment 6 Interventions

Patients receive rituximab IV on day 1 of each cycle and CC-99282 PO QD on days 1-14 of each cycle. Treatment repeats every 28 days for up to 6 cycles of rituximab and up to 24 cycles of CC-99282 in the absence of disease progression or unacceptable toxicity. Patients also undergo PET/CT and collection of blood samples throughout the trial. Patients may undergo biopsy at screening.

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

Approved in United States as Rituxan for:

• Non-Hodgkin's lymphoma
• Chronic lymphocytic leukemia
• Rheumatoid arthritis
• Granulomatosis with polyangiitis
• Microscopic polyangiitis

Approved in European Union as MabThera for:

• Non-Hodgkin's lymphoma
• Chronic lymphocytic leukemia
• Rheumatoid arthritis
• Granulomatosis with polyangiitis
• Microscopic polyangiitis

Approved in Canada as Rituxan for:

• Non-Hodgkin's lymphoma
• Chronic lymphocytic leukemia
• Rheumatoid arthritis
• Granulomatosis with polyangiitis
• Microscopic polyangiitis

Who Is Running the Clinical Trial?

Nathan Denlinger

Lead Sponsor

Trials

1

Recruited

20+

Bristol-Myers Squibb

Industry Sponsor

Trials

2,731

Recruited

4,127,000+

Headquarters

New York City, USA

Known For

Oncology & Cardiovascular

Top Products

Eliquis, Opdivo, Revlimid, Orencia

Christopher Boerner

Bristol-Myers Squibb

Chief Executive Officer since 2023

PhD in Business Administration from the Haas School of Business, University of California, Berkeley; BA in Economics and History from Washington University in St. Louis

Deepak L. Bhatt

Bristol-Myers Squibb

Chief Medical Officer since 2024

MD from Yale University; MSc in Clinical Epidemiology from the University of Pennsylvania

Findings from Research

Rituximab was the first monoclonal antibody approved for cancer therapy and has significantly improved survival rates in patients with diffuse large cell lymphoma when combined with CHOP chemotherapy.

Initially approved in 1997 for relapsed or refractory low-grade or follicular, CD20-positive, B-cell non-Hodgkin's lymphoma, rituximab is also being researched for other B-cell malignancies and nonmalignant diseases like autoimmune disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab: review and clinical applications focusing on non-Hodgkin's lymphoma. King, KM., Younes, A.[2015]

Rituximab, a chimeric anti-CD20 monoclonal antibody, has shown to induce responses in nearly 50% of patients with relapsed follicular/low-grade non-Hodgkin's lymphoma, with complete remissions occurring in 6% of cases, highlighting its efficacy in treating this type of cancer.

The drug is generally well tolerated, with common side effects being mild to moderate fevers and chills, and it is also effective against various other B-cell malignancies, suggesting its potential for broader applications in both cancer treatment and autoimmune disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab: clinical development and future directions. Cheson, BD.[2019]

In a phase II trial involving 123 patients with advanced indolent lymphoma, the combination of interferon-alpha2a (IFN) with extended dosing of rituximab significantly improved response rates, with 94% of patients achieving an overall response compared to 78% with rituximab alone.

The addition of IFN not only increased the number of patients achieving complete responses (CR) but also helped maintain these responses for over 24 months in 72% of patients, indicating that this combination therapy can lead to long-term benefits without the need for chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term molecular remissions in patients with indolent lymphoma treated with rituximab as a single agent or in combination with interferon alpha-2a: a randomized phase II study from the Nordic Lymphoma Group. Kimby, E., Jurlander, J., Geisler, C., et al.[2021]

Rituximab, when added to standard chemotherapy, significantly improved survival rates in patients with non-Hodgkin's lymphoma.

In patients with chronic B-cell lymphocytic leukemia, the addition of rituximab to fludarabine-based regimens enhanced both response rates and overall survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Review of the safety and feasibility of rapid infusion of rituximab. Atmar, J.[2022]

Rituximab has been shown to significantly improve progression-free and overall survival in patients with non-Hodgkin's lymphoma, based on a systematic review of 23 randomized controlled trials.

The treatment is particularly effective when added to chemotherapy for aggressive B-cell lymphomas and for both initial and subsequent treatments of indolent B-cell lymphomas, as well as for maintenance therapy in responding patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab in lymphoma: a systematic review and consensus practice guideline from Cancer Care Ontario. Cheung, MC., Haynes, AE., Meyer, RM., et al.[2018]

In a study of 40 patients with low-grade or follicular B-cell non-Hodgkin's lymphoma, the combination of Rituxan (Rituximab) and CHOP chemotherapy resulted in a high overall response rate of 95%, with 55% achieving complete remission.

The combination therapy showed promising safety, with common side effects being manageable, and it also indicated potential for clearing minimal residual disease, as evidenced by the conversion of the bcl-2 translocation from positive to negative in several patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of patients with low-grade B-cell lymphoma with the combination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy. Czuczman, MS., Grillo-López, AJ., White, CA., et al.[2022]

Rituximab is the first FDA-approved monoclonal antibody for cancer treatment, specifically targeting the CD20 antigen on B cells, and has shown efficacy in treating relapsed low-grade and follicular non-Hodgkin's lymphoma in multicenter studies.

The treatment is generally well-tolerated, with side effects mainly consisting of mild fevers and chills during the first infusion, and its low immunogenicity allows for potential future treatments without significant complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of rituximab, the new FDA-approved antibody. Leget, GA., Czuczman, MS.[2019]

Rituximab, the first monoclonal antibody approved for cancer treatment, has been administered to approximately 36,000 patients, showing efficacy in treating relapsed or refractory CD20+ low-grade non-Hodgkin's lymphoma.

Serious infusion-related reactions, including cardiopulmonary issues and tumor lysis syndrome, occur in a small percentage of patients (0.04% to 0.07%), with higher risks in those with many circulating malignant cells or pre-existing cardiovascular conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimizing the use of rituximab for treatment of B-cell non-Hodgkin's lymphoma: a benefit-risk update. Kunkel, L., Wong, A., Maneatis, T., et al.[2022]

In a study involving four patients with primary refractory or early relapsed T cell rich B cell lymphomas (TCRBCL), the combination of rituximab with chemotherapy (vinorelbine and gemcitabine) resulted in three complete responses and one partial response, demonstrating significant efficacy.

The treatment was well-tolerated, with no significant adverse effects reported, suggesting that rituximab combined with chemotherapy could be a promising option for treating TCRBCL and warrants further investigation in larger trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab in combination with vinorelbine/gemcitabine chemotherapy in patients with primary refractory or early relapsed T cell rich B cell lymphoma. A pilot study. Xiros, N., Economopoulos, T., Valsami, S., et al.[2022]

The CHOEA-7 chemotherapy regimen, which includes cyclophosphamide, doxorubicin, vincristine, etoposide, and ara-C, has shown excellent results in treating patients with CD 20-positive non-Hodgkin's lymphoma.

Adding rituximab to the CHOEA-7 regimen (RCHOEA-7) further enhances treatment efficacy, indicating a promising approach for improving outcomes in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Results of dose-intense, dose-impact weekly combination chemotherapy with rituximab for patients with CD 20-positive B-cell non-Hodgkin's lymphoma]. Uzuka, Y., Saitou, Y., Saitou, K., et al.[2015]

In a phase II study involving 37 patients with relapsed or refractory low-grade or follicular B-cell non-Hodgkin's lymphoma, Rituximab was found to be well tolerated, with most adverse events being mild and decreasing with subsequent infusions.

The treatment resulted in a 57% overall response rate, with 14% achieving a complete response and 43% a partial response, indicating significant clinical activity and suggesting that extended Rituximab treatment may be effective for this patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Extended Rituximab (anti-CD20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma. Piro, LD., White, CA., Grillo-López, AJ., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Rituximab: review and clinical applications focusing on non-Hodgkin's lymphoma. [2015]

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

Rituximab: clinical development and future directions. [2019]

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

Long-term molecular remissions in patients with indolent lymphoma treated with rituximab as a single agent or in combination with interferon alpha-2a: a randomized phase II study from the Nordic Lymphoma Group. [2021]

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

Review of the safety and feasibility of rapid infusion of rituximab. [2022]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Rituximab in lymphoma: a systematic review and consensus practice guideline from Cancer Care Ontario. [2018]

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

Treatment of patients with low-grade B-cell lymphoma with the combination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy. [2022]

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

Use of rituximab, the new FDA-approved antibody. [2019]

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

Optimizing the use of rituximab for treatment of B-cell non-Hodgkin's lymphoma: a benefit-risk update. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Rituximab in combination with vinorelbine/gemcitabine chemotherapy in patients with primary refractory or early relapsed T cell rich B cell lymphoma. A pilot study. [2022]

10. Japan pubmed.ncbi.nlm.nih.gov

[Results of dose-intense, dose-impact weekly combination chemotherapy with rituximab for patients with CD 20-positive B-cell non-Hodgkin's lymphoma]. [2015]

11. England pubmed.ncbi.nlm.nih.gov

Extended Rituximab (anti-CD20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma. [2022]