Olutasidenib + Venetoclax + Azacitidine for Acute Myeloid Leukemia

(OLUVENAZA Trial)

Overseen By Justin Watts, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Justin Watts, MD

Must not be taking: CYP3A inhibitors, CYP3A inducers

Disqualifiers: Relapsed AML, APL, FLT3-ITD, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 12 months

16 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new combination treatment for individuals with acute myeloid leukemia (AML), a type of blood cancer. The researchers aim to determine if the combination of olutasidenib (an experimental treatment), venetoclax, and azacitidine results in different side effects and improved outcomes compared to standard chemotherapy. Individuals recently diagnosed with AML and possessing a specific genetic mutation called IDH1 might be suitable candidates. The trial will monitor patient responses to this new treatment combination over several months. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial requires a washout period (time without taking certain medications) of 7 to 14 days or 5 half-lives for participants taking strong CYP3A inhibitors or inducers before starting the study medication. Azoles are allowed with dose adjustments for venetoclax.

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

Research shows that the combination of olutasidenib, venetoclax, and azacitidine is generally well-tolerated by people with acute myeloid leukemia (AML). Studies have found that this combination has manageable side effects.

In these studies, patients experienced high response rates and long-lasting remissions with fewer severe side effects compared to other treatments. The safety of olutasidenib with azacitidine is similar to using each drug individually, with no new safety issues identified.

Overall, while some side effects may occur, this combination treatment is considered tolerable and effective for many patients. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Olutasidenib, Venetoclax, and Azacitidine for treating Acute Myeloid Leukemia (AML) because it targets the disease in a novel way. Olutasidenib works by inhibiting a specific mutation called IDH1, which is not typically addressed by standard AML treatments like chemotherapy or standalone Azacitidine. Venetoclax, meanwhile, targets and disrupts cancer cell survival mechanisms, making the leukemia cells more susceptible to treatment. This combination aims to offer a more effective approach by attacking the cancer from different angles, potentially leading to better outcomes than existing therapies.

What evidence suggests that this combination treatment could be effective for acute myeloid leukemia?

Research shows that a combination of the drugs olutasidenib, venetoclax, and azacitidine can help treat acute myeloid leukemia (AML). In this trial, participants will receive this combination treatment. Studies have found that olutasidenib, when used with azacitidine, leads to lasting complete remissions in patients whose AML has returned or is difficult to treat. Additionally, patients who received olutasidenib after fewer previous treatments experienced better response rates and longer survival. This suggests that this combination treatment might provide better results than traditional chemotherapy for some AML patients. ^{1 2 4 5 6}

Who Is on the Research Team?

Justin Watts, MD

Principal Investigator

University of Miami

Are You a Good Fit for This Trial?

This trial is for patients with newly diagnosed Acute Myeloid Leukemia (AML) who have a specific mutation called IDH1 and are fit for intensive chemotherapy. The study is open to both adults and children with this type of leukemia.

Inclusion Criteria

My organs are functioning well.

Baseline QT interval corrected using the Fridericia equation (QTcF) ≤ 480 msec

I agree not to donate eggs or sperm during the trial.

Exclusion Criteria

Participant plans to become pregnant or father a child while enrolled in this study or within 3 months after last dose of study treatment

My leukemia has spread to my brain or spinal cord.

I have been treated with specific inhibitors before.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive combination treatment of Olutasidenib, Venetoclax, and Azacitidine orally for up to 12 cycles, each cycle lasting 28 days

12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Long-term Follow-up

Overall survival (OS) is assessed, defined as the elapsed time in months from the start of treatment until death from any cause

36 months

What Are the Treatments Tested in This Trial?

Interventions

• Azacitidine
• Olutasidenib
• Venetoclax

Trial Overview The study tests a combination treatment using three drugs: Olutasidenib, Venetoclax, and Azacitidine. It aims to compare the effectiveness and side effects of this regimen against standard chemotherapy treatments for AML.

How Is the Trial Designed?

Group I: OLUVENAZA Treatment Group Experimental Treatment 3 Interventions

Participants in this group will receive combination treatment of Olutasidenib, Venetoclax and Azacitidine orally for up to 12 cycles, each cycle lasting 28 days. Total participation duration is about 14 months

Who Is Running the Clinical Trial?

Justin Watts, MD

Lead Sponsor

Trials

2

Recruited

30+

Rigel Pharmaceuticals

Industry Sponsor

Trials

37

Recruited

4,000+

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 a study of 6 children with refractory or relapsed acute myeloid leukemia (AML), the combination of venetoclax, azacitidine, and cladribine (VAC regimen) resulted in significant treatment responses, with 4 achieving complete remission and 1 showing partial remission.

Despite severe side effects like grade IV neutropenia and thrombocytopenia, there were no treatment-related deaths or infections, indicating that the VAC regimen is both effective and safe for this vulnerable patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Safety and the Short-Term Efficacy of Venetoclax Combined with Azacitidine Followed by Cladribine in Children with Refractory/Relapsed Acute Myeloid Leukemia]. DU, WW., Liu, SX., Wang, Y., et al.[2023]

In a study of 57 elderly patients (average age 69.9 years) with acute myeloid leukemia, the combination of venetoclax and azacitidine (VEN + AZA) showed a high overall response rate of 87.5% and a complete remission (CR) rate of 68.8%, indicating strong efficacy in this population.

The treatment was associated with a median overall survival (OS) of 11.5 months, and achieving minimal residual disease (MRD) negativity (<0.1%) was more common with VEN + AZA compared to traditional chemotherapy, although older patients (≥75 years) and those with higher ECOG scores faced more challenges in achieving MRD negativity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-institution experience of venetoclax combined with azacitidine in newly diagnosed acute myeloid leukemia patients. Yu, H., Wang, C., Lei, Y., et al.[2023]

In a study of 20 elderly patients with relapsed refractory acute myeloid leukemia (AML), the combination of azacytidine and venetoclax showed a total treatment efficiency of 90%, significantly higher than the 40% efficiency observed with azacytidine alone.

The combination treatment improved hematological parameters, such as platelet and white blood cell counts, while maintaining a similar safety profile to azacytidine alone, indicating it is a promising option for enhancing treatment efficacy in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analysis of the Clinical Efficacy of Azacytidine + Venetoclax in the Treatment of Elderly Patients with Relapsed Refractory Acute Myeloid Leukemia. Wang, W., Luo, Q., Chen, Q., et al.[2023]

In a pooled analysis of treatment-naïve patients with FLT3-mutant acute myeloid leukemia, the combination of venetoclax and azacitidine resulted in a significantly higher composite complete remission rate (67%) compared to azacitidine alone (36%), with a median overall survival of 12.5 months versus 8.6 months.

The treatment was found to be safe, with no unexpected toxicities reported, indicating that venetoclax + azacitidine is a promising option for older patients or those with comorbidities who are ineligible for intensive therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of FLT3 Mutation on Outcomes after Venetoclax and Azacitidine for Patients with Treatment-Naïve Acute Myeloid Leukemia. Konopleva, M., Thirman, MJ., Pratz, KW., 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]

A lower dosage of Venetoclax (100 mg) combined with Azacitidine showed favorable outcomes in newly diagnosed acute myeloid leukemia (AML) patients, with a median overall survival of 17 months and an overall response rate of 69.4% based on a study of 36 patients.

The study suggests that even with dose reductions of Venetoclax, the combination therapy remains effective, indicating a potential strategy to manage therapy-related toxicity while still achieving significant treatment responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced duration and dosage of venetoclax is efficient in newly diagnosed patients with acute myeloid leukemia. Cui, J., Chen, X., Li, C., 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 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 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 study of 86 patients with relapsed or refractory acute myeloid leukemia (RR-AML) treated with venetoclax combinations, the complete remission rate was 24%, and the overall response rate was 31%, indicating that venetoclax is an effective treatment option for this patient group.

Azacitidine combined with venetoclax showed significantly better outcomes than low-dose cytarabine with venetoclax, with median overall survival of 25 months compared to 3.9 months, highlighting the importance of treatment choice in improving survival in RR-AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical and molecular predictors of response and survival following venetoclax therapy in relapsed/refractory AML. Stahl, M., Menghrajani, K., Derkach, A., et al.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11736922/

Olutasidenib in combination with azacitidine induces ... Olutasidenib in combination with azacitidine induces durable complete remissions in patients with relapsed or refractory mIDH1 acute myeloid ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06782542

Study Details | NCT06782542 | Olutasidenib, Venetoclax ... Determine how well the combination treatment of olutasidenib, venetoclax, and azacitidine works compared to the usual chemotherapy treatment that people with ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.6545

A phase 2 study of olutasidenib in relapsed/refractory acute ... Conclusions: Higher response rates (including CR and CRh) and greater survival were observed in patients receiving OLU following 1-2 versus ≥3 ...

4. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2025-02985

Olutasidenib, Venetoclax, and Azacitidine for the Treatment ... This phase II trial tests the safety and side effects of olutasidenib, venetoclax, and azacitidine and how well they work in treating patients with newly ...

5. ashpublications.org ashpublications.org/bloodadvances/article/9/20/5293/546206/Olutasidenib-alone-or-combined-with-azacitidine-in

Olutasidenib alone or combined with azacitidine in patients ... Olutasidenib alone or with azacitidine elicited high response rates and durable remissions in intermediate- to very high-risk mIDH1 MDS.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT06782542?term=OLUTASIDENIB&rank=7

Olutasidenib, Venetoclax, and Azacitidine in IDH1 Mutated ... The purpose of this study is as follows: Determine whether people receiving the combination treatment of olutasidenib , venetoclax, and azacitidine have the ...