Nadunolimab + Azacitidine for Preleukemia and Acute Myeloid Leukemia

Overseen By Gautam Borthakur, MBBS

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Anti-TNF drugs

Disqualifiers: Diabetes, Hypertension, HIV, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 24 cycles

40 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety and effectiveness of combining three drugs—nadunolimab, azacitidine (Vidaza), and venetoclax—on preleukemia and acute myeloid leukemia (AML). The researchers aim to determine if targeting specific leukemia cells with these treatments offers a promising option for high-risk patients. Individuals with intermediate to very high-risk myelodysplastic syndromes (MDS) or those with relapsed or hard-to-treat AML might be suitable candidates. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this potentially groundbreaking therapy.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop all current medications, but you cannot use chemotherapeutic or anti-leukemic agents during the study, except for certain cases like intrathecal therapy or specific doses of cytarabine and hydroxyurea. There is a 7-day washout period for cytarabine before starting the study therapy.

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

Earlier research has assessed the safety of combining nadunolimab and azacitidine. Initial results suggest that this combination might be safe and manageable for patients with certain blood cancers. The study examines how well patients tolerate this treatment and aims to determine the optimal dose.

For venetoclax, more information is available. Studies have shown that venetoclax, already approved by the FDA for other blood cancers, has a predictable safety profile. Doctors generally know what side effects might occur and how to manage them. It is considered manageable for patients with acute myeloid leukemia (AML).

Overall, while the safety of nadunolimab combined with azacitidine is still under evaluation, venetoclax has a known safety record. This can offer reassurance to those considering joining the trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the treatment combination of Nadunolimab, Azacitidine, and Venetoclax for preleukemia and acute myeloid leukemia (AML) because of its novel approach to targeting cancer cells. Unlike the standard of care, which typically includes chemotherapy drugs like Cytarabine and Decitabine, this combination leverages Nadunolimab's unique ability to inhibit the CD40-CD40L pathway, potentially enhancing the immune response against leukemia cells. Additionally, the combination with Venetoclax, a BCL-2 inhibitor, helps induce cancer cell death more effectively, while Azacitidine works to alter the DNA of cancer cells, slowing their growth. This multifaceted attack on leukemia cells presents a promising new avenue for treatment, aiming to improve outcomes for patients who may not respond well to existing therapies.

What evidence suggests that this trial's treatments could be effective for preleukemia and acute myeloid leukemia?

This trial will evaluate the combination of azacitidine with nadunolimab for patients with high-risk preleukemia and acute myeloid leukemia (AML). Studies have shown that azacitidine with venetoclax helps certain AML patients live longer than azacitidine alone. Research indicates that nadunolimab, a special type of antibody, targets the root cells of leukemia, potentially preventing disease progression. Early findings suggest that adding nadunolimab to azacitidine could enhance treatment effectiveness. The trial aims to determine if this combination can improve patient outcomes. ^{2 3 5 6 7}

Who Is on the Research Team?

Gautam Borthakur, M.D.

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for patients with high-risk Myelodysplastic Syndrome (MDS) or Acute Myelogenous Leukemia (AML). Participants should not have received certain prior treatments and must meet specific health conditions. Detailed inclusion and exclusion criteria are provided to determine eligibility.

Inclusion Criteria

Serum biochemical values within specified limits

I am sterile or agree to use contraception.

I've had temporary treatments like apheresis or low-dose cytarabine, but not as part of my main cancer therapy.

Exclusion Criteria

I do not have any severe or uncontrolled medical conditions.

I have not received a live vaccine in the last 28 days.

I am willing and able to follow the study rules.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive nadunolimab in combination with azacitidine, with or without venetoclax, for up to 24 cycles

24 cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Azacitidine
• Nadunolimab
• Venetoclax

Trial Overview

The trial tests the safety and optimal dose of Nadunolimab, alone or combined with Azacitidine and/or Venetoclax, in treating MDS/AML. It aims to see if targeting leukemia stem cells with this combination can be an effective treatment strategy.

How Is the Trial Designed?

Group I: ARM 2: Relapsed/refractory AML Experimental Treatment 3 Interventions

Group II: ARM 1B: Cycle 2-24 for non responder after Cycle 1 Combo Experimental Treatment 3 Interventions

Group III: ARM 1A: Cycle 2-24 for responder after Cycle 1 Mono Experimental Treatment 3 Interventions

Group IV: ARM 1: All Patients Cycle 1 Experimental Treatment 1 Intervention

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

Approved in European Union as Vidaza for:

• Acute myeloid leukemia
• Chronic myelomonocytic leukemia
• Myelodysplastic syndromes

Approved in United States as Vidaza for:

• Myelodysplastic syndromes
• Chronic myelomonocytic leukemia

Approved in Canada as Vidaza for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in Japan as Vidaza for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

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 study of 50 adults with acute myeloid leukemia (AML) in Mexico and Peru, venetoclax-based therapy showed a high complete response rate of 78.6% in newly diagnosed patients and 45.5% in those with relapsed/refractory disease, indicating its efficacy in treating AML.

The median overall survival was 9.6 months for newly diagnosed patients and 8 months for relapsed/refractory patients, suggesting that venetoclax is a viable treatment option even in real-world settings, despite common hematologic toxicities and dose adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax-based combinations for acute myeloid leukemia: optimizing their use in Latin-America. Gómez-De León, A., Demichelis-Gómez, R., Pinedo-Rodríguez, A., et al.[2022]

In the HiDDAV study involving 42 newly diagnosed AML patients, higher doses of venetoclax (600 mg daily) were found to be tolerable but did not show significant clinical improvement compared to the standard 400 mg dose.

The study revealed that using minimal residual disease (MRD) status to guide the discontinuation of azacitidine did not lead to better outcomes in terms of duration of response or overall survival, suggesting that alternative strategies are needed to optimize treatment regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Higher-dose venetoclax with measurable residual disease-guided azacitidine discontinuation in newly diagnosed acute myeloid leukemia. Gutman, JA., Winters, A., Kent, A., et al.[2023]

In a study of 13 patients with acute leukemia treated with venetoclax and azacitidine, 46% developed COVID-19, highlighting a significant risk associated with this treatment during the pandemic.

The study found that 33% of those who contracted COVID-19 died from the virus, indicating that COVID-19 can lead to severe outcomes in patients receiving AZA-VEN therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SARS-CoV-2 Infection in Patients Treated with Azacitidine and Venetoclax for Acute Leukemia: A Report of a Case Series Treated in a Single Institution. Drozd-Sokołowska, J., Mądry, K., Barankiewicz, J., et al.[2023]

In a study of 35 patients with relapsed or refractory acute myeloid leukaemia (R/R AML) treated with venetoclax-azacitidine (VEN-AZA), the complete remission rate was significantly higher at 48.6% compared to 15% in a historical cohort treated with azacitidine (AZA).

Patients receiving VEN-AZA also showed a trend towards longer overall survival (12.8 months) compared to those treated with AZA (7.3 months), indicating that VEN-AZA may offer a more effective treatment option for R/R AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azacitidine-venetoclax versus azacitidine salvage treatment for primary induction failure or first relapsed acute myeloid leukaemia patients. Petit, C., Saillard, C., Mohty, B., et al.[2023]

In a study of 60 patients with acute myeloid leukemia (AML), the combination of venetoclax and azacitidine (Ven+AZA) demonstrated a high response rate, with 70.8% of previously untreated patients unfit for standard chemotherapy achieving complete remission (CR) or CR with incomplete hematological recovery (CRi) after one cycle.

Ven+AZA was found to be safe and tolerable, with some patients achieving minimal residual disease (MRD) negativity, particularly in those with favorable genetic mutations like NPM1, IDH1/IDH2, and TP53, indicating its potential effectiveness in specific patient subgroups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Short-term efficacy of venetoclax combined with azacitidine in acute myeloid leukemia: a single-institution experience]. Yu, WJ., Jia, JS., Wang, J., et al.[2022]

Outpatient induction therapy using low-dose venetoclax combined with itraconazole and azacitidine is feasible and safe for newly diagnosed acute myeloid leukemia (ND-AML) patients, with 77.7% of participants completing the first treatment cycle as outpatients.

The treatment showed promising efficacy, with a composite complete response rate of 53.9% after the first cycle and 85.7% after the second cycle, indicating that this regimen could be a viable option for patients eligible for intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low dose venetoclax plus itraconazole outpatient induction in newly diagnosed acute myeloid leukemia: A phase 2 study. De la Garza-Salazar, F., Colunga-Pedraza, PR., Gómez-Almaguer, D., et al.[2023]

In a phase 1/2 study involving six Japanese patients aged 60 and older with acute myeloid leukaemia, the combination of venetoclax and azacitidine demonstrated a high response rate, with 83% of patients achieving a response, including three complete remissions.

The treatment was generally well tolerated, with a median overall survival of 15.7 months, although some patients experienced serious adverse events, including grade 3 fungal pneumonia, which required treatment adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax in combination with azacitidine in Japanese patients with acute myeloid leukaemia: phase 1 trial findings. Taniguchi, S., Yamauchi, T., Choi, I., et al.[2021]

In a Japanese subgroup of the phase 3 VIALE-A trial, venetoclax-azacitidine significantly improved overall survival rates compared to placebo-azacitidine, with 67% of patients alive at 12 months versus 46% in the placebo group.

The treatment also resulted in a high complete response (CR) and CR with incomplete hematologic recovery (CRi) rate of 67%, while maintaining a safety profile similar to the global study, indicating it is a viable first-line treatment for Japanese patients with acute myeloid leukemia ineligible for intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax plus azacitidine in Japanese patients with untreated acute myeloid leukemia ineligible for intensive chemotherapy. Yamamoto, K., Shinagawa, A., DiNardo, CD., et al.[2023]

In a phase II study involving 60 older or unfit patients with newly diagnosed acute myeloid leukemia (AML), the combination of venetoclax with cladribine and low-dose cytarabine alternating with venetoclax and 5-azacitidine resulted in a high composite complete response rate of 93%.

The treatment showed promising overall survival and disease-free survival rates, with only one death occurring within 4 weeks, indicating that this regimen is effective and has a favorable safety profile for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Study of Venetoclax Added to Cladribine Plus Low-Dose Cytarabine Alternating With 5-Azacitidine in Older Patients With Newly Diagnosed Acute Myeloid Leukemia. Kadia, TM., Reville, PK., Wang, X., et al.[2023]

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