Nivolumab + ASTX727 for B-Cell Lymphoma

Recruiting at 9 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: Immunosuppressants, Corticosteroids

Disqualifiers: Pregnancy, Autoimmune disease, Uncontrolled illness, others

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

Compensation: Varies

Number of Visits: 15

Duration: 12 months

32 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the combination of nivolumab and ASTX727 to treat B-cell lymphoma that has returned or isn't responding to standard treatments. Nivolumab is an immunotherapy that enables the immune system to attack cancer cells, while ASTX727 (also known as Inaqovi) prolongs the presence of another drug, decitabine, in the body to enhance its effectiveness against cancer. This trial targets individuals with B-cell lymphoma who have exhausted other treatments and have no curative options available. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering patients a chance to be among the first to receive this new 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 participate if you need systemic corticosteroids or other immunosuppressive medications within 14 days of starting the study drugs. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that the combination of nivolumab and ASTX727, which includes the drugs decitabine and cedazuridine, is being tested for safety in people with B-cell lymphoma. Nivolumab helps the immune system attack cancer cells. ASTX727 consists of decitabine, which aids in creating healthy blood cells and eliminating abnormal ones, and cedazuridine, which enhances decitabine's effectiveness.

Studies have found that nivolumab is generally well-tolerated, with some experiencing mild to moderate side effects like tiredness and skin reactions. Decitabine and cedazuridine have been used together for other conditions and are considered safe, with common side effects including low blood cell counts, which doctors monitor closely.

As this is a Phase 1 trial, the main goal is to understand the safety and side effects when these drugs are used together. Participation helps researchers determine the best dose and assess how the combination works in treating cancer. Always consult the trial staff and your healthcare provider to understand the potential risks and benefits before joining. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about combining Nivolumab with Decitabine and Cedazuridine for B-cell lymphoma because this approach could offer a new mechanism of action compared to existing treatments like chemotherapy and traditional immunotherapies. Nivolumab is a PD-1 checkpoint inhibitor, which helps the immune system recognize and attack cancer cells more effectively. Meanwhile, Decitabine and Cedazuridine work to modify the expression of genes in cancer cells, potentially making them more susceptible to immune system attacks. This combination could provide a more targeted and effective treatment option, especially for patients who do not respond well to standard therapies.

What evidence suggests that this treatment might be an effective treatment for B-cell lymphoma?

Studies have shown that nivolumab, a treatment that aids the immune system in fighting cancer, can be effective against certain types of lymphoma. In some patients, it prevented cancer progression for 18 months, achieving an 85% success rate. This trial will administer a combination of nivolumab with decitabine and cedazuridine. Decitabine and cedazuridine work together to halt cancer cell growth by supporting healthy bone marrow and eliminating abnormal cells, enhancing decitabine's effectiveness in the body. Although more research is needed, using nivolumab with decitabine and cedazuridine shows promise for treating B-cell lymphoma that has returned or is unresponsive to other treatments. ^{1 3 6 7 8}

Who Is on the Research Team?

Catherine S. Diefenbach

Principal Investigator

Laura and Isaac Perlmutter Cancer Center at NYU Langone

Are You a Good Fit for This Trial?

Adults with relapsed or refractory B-cell lymphoma, including DLBCL, who have tried at least one other treatment and are not eligible for a transplant. They must be in relatively good health (ECOG/Karnofsky >=80%), have certain blood cell counts, no severe liver or kidney issues, and no uncontrolled illnesses. HIV-positive patients on effective therapy can join; those with hepatitis must be treated. Participants must agree to use effective contraception.

Inclusion Criteria

My brain scans show no worsening after treatment for brain metastases.

I am mostly self-sufficient and can carry out daily activities.

Your platelet count should be at least 75,000/mcL, unless you have bone marrow involvement, in which case lower values may be allowed.

Exclusion Criteria

I am not pregnant or breastfeeding.

You cannot be taking any experimental drugs at the same time.

I have recovered from side effects of previous cancer treatments, except for hair loss.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive decitabine and cedazuridine orally once daily on days 1-3 or 1-5 of each cycle and nivolumab intravenously on day 15 of each cycle. Treatment repeats every 28 days for 12 cycles.

12 months

Monthly visits for 12 cycles

Extension

Participants with complete response, partial response, or stable disease after 12 cycles receive decitabine and cedazuridine for an additional 12 months.

12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment completion.

24 months

Every 3 months

What Are the Treatments Tested in This Trial?

Interventions

• Decitabine and Cedazuridine
• Nivolumab

Trial Overview The trial is testing the safety and optimal dosage of Nivolumab combined with ASTX727 (Decitabine and Cedazuridine) for B-cell lymphoma that's returned or hasn't responded to treatment. The goal is to see if this combo can help the immune system fight cancer better by stopping tumor growth.

How Is the Trial Designed?

Group I: Treatment (nivolumab, decitabine and cedazuridine) Experimental Treatment 5 Interventions

Patients receive decitabine and cedazuridine PO QD on days 1-3 or 1-5 of each cycle and nivolumab IV over 30 minutes on day 15 of each cycle. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. Patients with CR, PR, or SD after 12 cycles receive decitabine and cedazuridine for an additional 12 months. Patients also undergo PET/CT and collection of blood samples throughout the trial.

Decitabine and Cedazuridine is already approved in European Union, United States for the following indications:

Approved in European Union as Inaqovi for:

• Acute myeloid leukemia (AML) in adults who are ineligible for standard induction chemotherapy

Approved in United States as ASTX727 for:

• Adult patients with newly diagnosed acute myeloid leukemia (AML) who are 75 years or older, or who have comorbidities precluding intensive induction chemotherapy

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Oral azacitidine (CC-486) has been shown to improve overall survival as maintenance therapy for older patients with acute myeloid leukemia who are in complete remission, highlighting its efficacy in this specific patient population.

The combination of decitabine and cedazuridine (ASTX727) is approved for treating adult patients with myelodysplastic syndromes and chronic myelomonocytic leukemia, particularly those with intermediate-1 or higher risk, indicating its targeted therapeutic application.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The path to approval for oral hypomethylating agents in acute myeloid leukemia and myelodysplastic syndromes. Kipp, D., H Wei, A.[2022]

The phase 2 study found that oral cedazuridine/decitabine (100 mg/35 mg) provided similar systemic exposure and DNA demethylation compared to standard IV decitabine (20 mg/m2) in patients with myelodysplastic syndromes or chronic myelomonocytic leukemia, indicating comparable efficacy.

Clinical responses were observed in 60% of patients, with 21% achieving a complete response, while the most common serious side effects included neutropenia (46%) and thrombocytopenia (38%), highlighting the treatment's safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral cedazuridine/decitabine for MDS and CMML: a phase 2 pharmacokinetic/pharmacodynamic randomized crossover study. Garcia-Manero, G., Griffiths, EA., Steensma, DP., et al.[2021]

In a trial involving 56 patients with relapsed/refractory diffuse large B-cell lymphoma, the combination of decitabine with the RDHAP regimen showed a higher duration of remission compared to RDHAP alone, indicating potential benefits in treatment longevity.

The overall response rates were similar between the decitabine-RDHAP group (40%) and the RDHAP group (33%), but both regimens had comparable safety profiles, suggesting that decitabine-RDHAP is a well-tolerated option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Decitabine combined with RDHAP regimen in relapsed/refractory diffuse large B cell lymphoma. Kong, X., Zhang, X., Ding, M., et al.[2023]

Genomic profiling identified at least 5 subtypes of diffuse large B-cell lymphoma (DLBCL), with the MCD/C5 cluster showing specific genetic alterations, which were modeled in mice to study their behavior and treatment responses.

The study demonstrated that combined BTK/BCL2 inhibition was effective in treating these genetically altered lymphomas in mouse models and showed promising results in five out of six relapsed/refractory DLBCL patients, indicating a potential new therapeutic strategy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Distinct Genetically Determined Origins of Myd88/BCL2-Driven Aggressive Lymphoma Rationalize Targeted Therapeutic Intervention Strategies. Flümann, R., Hansen, J., Pelzer, BW., et al.[2023]

In a pilot clinical trial involving 7 patients with relapsed lymphoid malignancies, the combination of decitabine and the CDA-inhibitor tetrahydrouridine showed some clinical improvements in 4 patients, but treatment interruptions due to neutropenia limited the effectiveness of the therapy.

Preclinical studies suggested that alternating decitabine with 5-azacytidine and using additional inhibitors could enhance the treatment's effectiveness against lymphoma while reducing the risk of neutropenia, indicating the need for regimen innovations to improve outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A pilot clinical trial of oral tetrahydrouridine/decitabine for noncytotoxic epigenetic therapy of chemoresistant lymphoid malignancies. Hill, B., Jagadeesh, D., Pohlman, B., et al.[2022]

In refractory diffuse large B-cell lymphoma (DLBCL), particularly the activated B-cell-like (ABC) subtype, the p53 DNA damage response plays a crucial role in suppressing tumor progression driven by NF-κB activation and impaired B-cell differentiation.

Combining PD-1 blockade with anti-CD20 therapy showed promising results in mice, enhancing T-cell reactivation and improving long-term survival, suggesting that this combination could be an effective immunotherapy strategy for ABC-DLBCL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PD-1/PD-L1 immune checkpoint and p53 loss facilitate tumor progression in activated B-cell diffuse large B-cell lymphomas. Pascual, M., Mena-Varas, M., Robles, EF., et al.[2021]

Inqovi, a combination of decitabine and cedazuridine, was approved by the FDA for treating myelodysplastic syndromes (MDS) based on a phase III study involving 133 adults, showing similar effectiveness to intravenous decitabine.

The treatment demonstrated a complete remission rate of 21% in one study and 18% in another, with a median duration of remission lasting around 7.5 to 8.7 months, while adverse reactions were consistent with those seen in IV decitabine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Decitabine and Cedazuridine Tablets for Myelodysplastic Syndromes. Kim, N., Norsworthy, KJ., Subramaniam, S., et al.[2023]

The fixed-dose oral combination of decitabine and cedazuridine (Inqovi®) has been approved for treating myelodysplastic syndromes (MDS) and chronic myelomonocytic leukaemia (CMML), enhancing the oral bioavailability of decitabine through the inhibition of cytidine deaminase by cedazuridine.

Decitabine is already an established treatment for MDS and CMML, and the combination therapy has shown promise in ongoing clinical studies for other cancers like acute myeloid leukaemia (AML), glioma, and solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Decitabine/Cedazuridine: First Approval. Dhillon, S.[2021]

In a phase II study involving 28 patients with treatment-naive diffuse large B-cell lymphoma (DLBCL), the combination of avelumab and rituximab followed by R-CHOP chemotherapy showed a high overall response rate of 89%, indicating strong efficacy of this treatment strategy.

The treatment had an acceptable safety profile, with only 11% of patients experiencing grade 3/4 immune-related adverse events, well below the predefined threshold of 30%, suggesting that this immune priming approach is both effective and safe.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune priming with avelumab and rituximab prior to R-CHOP in diffuse large B-cell lymphoma: the phase II AvR-CHOP study. Manos, K., Chong, G., Keane, C., et al.[2023]

In a phase II trial involving 51 patients with relapsed/refractory classical Hodgkin lymphoma (cHL) who previously failed anti-PD-1 therapy, the combination of decitabine and camrelizumab showed a high objective response rate of 52% in the test cohort and 68% in the expansion cohort, indicating its efficacy as a treatment option.

Patients receiving this combination therapy experienced a median progression-free survival of 20.0 months in the test cohort and 21.6 months in the expansion cohort, which is significantly longer than the outcomes from prior anti-PD-1 monotherapy, suggesting durable benefits from this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of Decitabine plus Anti-PD-1 Camrelizumab in Patients with Hodgkin Lymphoma Who Progressed or Relapsed after PD-1 Blockade Monotherapy. Wang, C., Liu, Y., Dong, L., et al.[2022]

In a phase II study involving 121 patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), nivolumab showed a low overall response rate of 10% in those who failed autologous hematopoietic cell transplantation (auto-HCT) and 3% in those ineligible for auto-HCT, indicating limited efficacy in this patient population.

Despite the low response rates, nivolumab demonstrated a favorable safety profile, with only 24% of patients experiencing grade 3 or 4 adverse events, primarily neutropenia and thrombocytopenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab for Relapsed/Refractory Diffuse Large B-Cell Lymphoma in Patients Ineligible for or Having Failed Autologous Transplantation: A Single-Arm, Phase II Study. Ansell, SM., Minnema, MC., Johnson, P., et al.[2019]

In a study of 61 patients with relapsed/refractory classical Hodgkin lymphoma, the combination of decitabine and camrelizumab resulted in a significantly higher complete remission rate of 79% compared to 32% with camrelizumab alone, indicating enhanced efficacy of the combination therapy.

The median progression-free survival (PFS) was 35.0 months for the decitabine-plus-camrelizumab group versus 15.5 months for camrelizumab monotherapy, suggesting that the combination therapy not only improves remission rates but also prolongs the time patients remain free from disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improved clinical outcome in a randomized phase II study of anti-PD-1 camrelizumab plus decitabine in relapsed/refractory Hodgkin lymphoma. Liu, Y., Wang, C., Li, X., et al.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05272384

Study Details | NCT05272384 | Testing the Combination of ... This phase I trial tests the safety, side effects, and best dose of nivolumab in combination with ASTX727 in treating B-cell lymphoma that has come back ...

2. ctsearchsupport.org ctsearchsupport.org/clinical-trials/testing-the-combination-of-nivolumab-and-astx727-for-relapsed-or-refractory-b-cell-lymphoma

Two drugs, ASTX727 and nivolumab , to treat lymphoma ... ASTX727 is the combination of cedazuridine and decitabine . Cedazuridine is a drug that blocks CDA in certain cells. Decitabine is is a drug ...

3. cancer.gov cancer.gov/research/participate/clinical-trials/intervention/decitabine-and-cedazuridine?pn=1

Clinical Trials Using Decitabine and Cedazuridine - NCI Review the clinical trials studying decitabine and cedazuridine on this list and use the filters to refine the results by age and location.

4. clinicaltrials.ucbraid.org clinicaltrials.ucbraid.org/lymphoma

Lymphoma clinical trials at University of California Health This phase I trial tests the safety, side effects, and best dose of nivolumab in combination with ASTX727 in treating B-cell lymphoma that has ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10526852/

Optimizing Treatment for Relapsed/Refractory Classic ... Among patients who would have been eligible for the AETHERA trial, 18-month PFS was 85% [60]. Similar outcomes have been reported with nivolumab monotherapy.

6. sigma.larvol.com sigma.larvol.com/ott.php?e1=1558&e2=8282&sourcepg=TZ&sr=now&er=1+month&ipwnd=on&rlink=,sourcepg=TZ,itype=0,1&rflag=1&page=2

Online Trial Tracker ChiCTR1800019288: A clinical trial for safety and efficient of CD19CART cells combination with nivolumab in the treatment of refractory/relapsed B cell lymphoma ...

7. withpower.com withpower.com/trial/phase-1-lymphoma-4-2022-be164

Nivolumab + ASTX727 for B-Cell Lymphoma This trial tests a combination of nivolumab and ASTX727 in patients with B-cell lymphoma that has come back or is not responding to treatment.

8. clinicaltrials.gov clinicaltrials.gov/study/NCT06357858?term=ASTX727&rank=2

ASTX727 and Nivolumab in Squamous Cell Carcinoma of the ... The goal of this clinical trial is to see if the combination of experimental drug ASTX727 and Nivolumab enhances the antitumor immune response in ...