Nivolumab + ASTX727 for B-Cell Lymphoma

Recruiting at 6 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

Trial Summary

What is the purpose of this trial?

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. Nivolumab helps the immune system attack cancer, while ASTX727 enhances the effectiveness of another drug. The goal is to find a safe and effective dose for these patients.

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.

What data supports the effectiveness of the drug Nivolumab + ASTX727 for B-Cell Lymphoma?

Research shows that combining decitabine, a component of ASTX727, with PD-1 inhibitors (a type of drug that includes nivolumab) has shown positive results in treating certain types of lymphoma, like Hodgkin lymphoma, especially in patients who did not respond well to PD-1 inhibitors alone. ^{1 2 3 4 5}

Is the combination of Nivolumab and ASTX727 safe for humans?

The combination of decitabine and cedazuridine (ASTX727) has been studied for safety in humans, showing common side effects like neutropenia (low white blood cell count) and thrombocytopenia (low platelet count). These side effects were consistent with those seen in intravenous decitabine treatments. Further studies are needed to assess the safety of combining this with Nivolumab. ^{1 3 6 7 8}

What makes the drug Nivolumab + ASTX727 unique for B-Cell Lymphoma?

This drug combination is unique because it combines Nivolumab, an immune checkpoint inhibitor that blocks the PD-1 pathway to help the immune system attack cancer cells, with ASTX727, which includes Decitabine and Cedazuridine to enhance the effectiveness of the immune response by modifying DNA. This approach targets both immune evasion and genetic instability in B-cell lymphoma, offering a novel strategy compared to traditional chemotherapy. ^{2 9 10 11 12}

Research Team

Catherine S. Diefenbach

Principal Investigator

Laura and Isaac Perlmutter Cancer Center at NYU Langone

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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]

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]

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]

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 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 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]

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 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]

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]

References

1. United States 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. [2022]

2. England 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. [2021]

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

Decitabine/Cedazuridine: First Approval. [2021]

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

The path to approval for oral hypomethylating agents in acute myeloid leukemia and myelodysplastic syndromes. [2022]

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

Decitabine combined with RDHAP regimen in relapsed/refractory diffuse large B cell lymphoma. [2023]

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

FDA Approval Summary: Decitabine and Cedazuridine Tablets for Myelodysplastic Syndromes. [2023]

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

Oral cedazuridine/decitabine for MDS and CMML: a phase 2 pharmacokinetic/pharmacodynamic randomized crossover study. [2021]

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

A pilot clinical trial of oral tetrahydrouridine/decitabine for noncytotoxic epigenetic therapy of chemoresistant lymphoid malignancies. [2022]

9. United States 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. [2021]

10. United States 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. [2019]

11. England 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. [2023]

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

Distinct Genetically Determined Origins of Myd88/BCL2-Driven Aggressive Lymphoma Rationalize Targeted Therapeutic Intervention Strategies. [2023]