Rezatapopt + Azacitidine for Acute Myeloid Leukemia and Myelodysplastic Syndrome

Overseen By Courtney DiNardo, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Chemotherapy, Immunotherapy

Disqualifiers: Acute promyelocytic leukemia, HIV, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 12 months

24 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of Rezatapopt and Azacitidine (a chemotherapy drug) to evaluate their effectiveness in treating certain blood cancers. It targets individuals with Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS) who have the TP53Y220C genetic mutation. The goal is to discover new treatment options for those whose cancer has returned or not responded to initial treatments. This study may suit individuals diagnosed with AML or MDS and identified with a TP53Y220C mutation. 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 new treatment combination.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot have received chemotherapy, targeted therapy, immunotherapy, or investigational anticancer agents within 14 days before starting the study drug.

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

Research has shown that combining rezatapopt with azacitidine might be safe and manageable for treating certain blood cancers. In studies, patients with specific genetic changes in their blood cancers, such as acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), received this treatment. The goal is to target a protein mutation linked to these cancers.

Researchers aim to find the highest safe dose of rezatapopt when used with azacitidine. This early-phase study tests the treatment for safety, and some evidence suggests it is manageable for patients. However, as this is a new combination, the complete safety profile is still under evaluation. Participants in the study report various side effects, and researchers closely monitor these to ensure patient safety.

Those considering joining this trial should discuss the potential risks and benefits with their healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Rezatapopt is unique because it introduces a new mechanism of action by targeting a protein known as Bcl-2, which helps cancer cells survive. Unlike the standard treatments for Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS), which often rely on chemotherapy and hypomethylating agents like azacitidine alone, Rezatapopt, when combined with azacitidine, aims to enhance the killing of cancer cells by overcoming resistance mechanisms. Researchers are excited about this combination because it has the potential to improve treatment outcomes by effectively targeting and eliminating cancer cells that are otherwise resistant to existing therapies.

What evidence suggests that the treatments in this trial could be effective for acute myeloid leukemia and myelodysplastic syndrome?

Research suggests that using rezatapopt with azacitidine, the combination studied in this trial, might help treat certain blood cancers with a specific genetic change called the TP53 Y220C mutation. Rezatapopt is designed to attach to this altered protein and may help it function normally again, potentially slowing cancer cell growth. Studies have shown that azacitidine, when combined with treatments like rezatapopt, might improve patient outcomes. Although early results are promising, further research is needed to confirm the effectiveness of this combination. ^{1 2 4 5 6}

Who Is on the Research Team?

Courtney DiNardo, MD

Principal Investigator

The University of Texas MD Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with TP53Y220C mutant myeloid malignancies, such as AML or MDS. Participants must have a specific mutation frequency, be in good enough health to perform daily activities (ECOG ≤2), and agree to use contraception. It's not for those with severe leukemia complications, recent major surgery, active infections including HIV/HBV/HCV, unresolved toxicities from past cancer treatments, or CNS involvement by leukemia.

Inclusion Criteria

I am following the required guidelines for pregnancy prevention.

My cancer has a specific TP53 mutation.

Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

My leukemia is causing severe, life-threatening complications.

I have been diagnosed with acute promyelocytic leukemia.

I had major surgery less than 2 weeks ago.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive rezatapopt daily and azacitidine by IV for 7 days per cycle

12 months

Inpatient or outpatient basis

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Azacitidine
• Rezatapopt
• Venetoclax

Trial Overview The study tests Rezatapopt combined with Azacitidine or both Azacitidine and Venetoclax in patients with certain genetic mutations causing blood cancers like AML and MDS. The trial is non-randomized phase Ib which means it's early in testing the safety and how well these drugs work together.

How Is the Trial Designed?

Group I: Rezatapopt + Azacitidine Experimental Treatment 2 Interventions

Participants will receive treatment on an inpatient or outpatient basis. Every cycle participants will take rezatapopt daily and receive azacitidine by IV for 7 days.

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+

Memorial Sloan Kettering Cancer Center (MSK)

Collaborator

Trials

1

Recruited

20+

PMV Pharmaceuticals, Inc

Industry Sponsor

Trials

6

Recruited

340+

Published Research Related to This Trial

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 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]

In patients with newly diagnosed unfit acute myeloid leukemia (AML), the combination of azacitidine and venetoclax is a standard first-line treatment.

However, patients with TP53-mutated AML and poor-risk cytogenetics do not benefit from adding venetoclax to azacitidine, suggesting that alternative treatment regimens should be considered for these individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TP53 or Not TP53: That Is the Question. Green, SD., Zeidner, JF.[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 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 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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06616636?term=AREA%5BBasicSearch%5D(AREA%5BBasicSearch%5D(a%200371))&rank=4

NCT06616636 | A Phase Ib Study of Rezatapopt in ... To assess duration of response in patients receiving rezatapopt in combination with AZA; Characterize the pharmacokinetics of rezatapopt in combination with AZA.

2. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2024-08191

Rezatapopt in Combination with Azacitidine with or without ... Giving rezatapopt in combination with azacitidine and venetoclax may be safe, tolerable and/or effective in treating patients with TP53Y220C mutant relapsed, ...

3. withpower.com withpower.com/trial/rezatapopt-azacitidine-for-acute-myeloid-leukemia-and-myelodysplastic-syndrome-1f5bd

Rezatapopt + Azacitidine for Acute Myeloid Leukemia and ... The combination of Venetoclax and Azacitidine has been studied in patients with acute myeloid leukemia, showing common side effects like blood-related ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12507176/

A First-in-Class Small Molecule p53 Y220C Mutant Protein ... In addition, rezatapopt is in a Phase Ib clinical trial (NCT06616636) in combination with azacitidine for patients with TP53 Y220C mutant myeloid malignancies ( ...

5. mdanderson.org mdanderson.org/patients-family/diagnosis-treatment/clinical-trials/clinical-trials-index/clinical-trials-detail.ID2024-0371.html

A Phase Ib study of Rezatapopt in combination with ... A Phase Ib study of Rezatapopt in combination with Azacitidine in patients with Relapsed/Refractory TP53 Y220C mutant myeloid malignancies (Acute Myeloid ...

6. ctsearchsupport.org ctsearchsupport.org/clinical-trials/a-phase-ib-study-of-rezatapopt-in-combination-with-azacitidine-or-azacitidine-and-venetoclax-in-patients-with-tp53y220c-mutant-myeloid-malignancies-acute-myeloid-leukemia-or-myelodysplastic-syndrome

Trial Summary | NMDP℠ CTSS To find out:The highest dose of rezatapopt that's safe to give with azacitidineIf rezatapopt is safe and works well to treat TP53Y220C+ AML ...