Revumenib + Standard Treatments for Acute Myeloid Leukemia

Recruiting at 1 trial location

Overseen By Richard Stone, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Maximilian Stahl, MD

Must be taking: Menin inhibitors

Must not be taking: CYP3A4 inducers, QTc prolonging

Disqualifiers: CNS involvement, HIV, Hepatitis, others

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

Compensation: Varies

Number of Visits: 1

22 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine a safe and effective dose of a new drug, revumenib, when combined with standard treatments for Acute Myeloid Leukemia (AML). It targets individuals with a specific genetic profile, specifically those with NPM1 and FLT3 mutations. Participants will receive a combination of revumenib, midostaurin (a targeted therapy), cytarabine (a chemotherapy drug), and daunorubicin (another chemotherapy drug) to evaluate the efficacy of these drugs together. This trial suits those newly diagnosed with AML who have these mutations and have not yet received treatment, except for specific short-term interventions. 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.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot have taken strong CYP3A4 inducers within 7 days before starting the study. Also, drugs that prolong QTc should be avoided if possible.

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

Research has shown that revumenib is generally safe for individuals with certain types of acute leukemia. The FDA approved revumenib for relapsed or hard-to-treat acute myeloid leukemia (AML) with a specific NPM1 mutation. This approval indicates that it has been tested in many patients and is mostly well-tolerated. In one study with 241 participants, including both adults and children, researchers carefully assessed the safety of revumenib.

Reports suggest that combining revumenib with other treatments might be safe and manageable. Although some side effects can occur, these studies indicate that revumenib can be used safely under medical supervision. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Revumenib for treating Acute Myeloid Leukemia (AML) because, unlike standard treatments that typically target the disease broadly, Revumenib specifically targets the menin-MLL1 protein interaction. This approach is believed to disrupt the cancer's growth pathway, offering a more tailored attack against the leukemia cells. Additionally, when combined with established treatments like Cytarabine and Daunorubicin, Revumenib has the potential to enhance the overall effectiveness of the treatment regimen, possibly leading to better outcomes for patients.

What evidence suggests that this trial's treatments could be effective for Acute Myeloid Leukemia?

Research has shown that revumenib, a menin inhibitor, may help treat acute myeloid leukemia (AML) with certain genetic changes. In an earlier study, 21% of patients experienced complete remission or partial improvement in their blood counts. Another study found a 40% overall response rate in patients with the NPM1 mutation. Revumenib is already approved for use in relapsed AML with specific genetic markers, demonstrating its effectiveness in difficult cases. In this trial, participants will receive revumenib alongside standard treatments, including midostaurin, which blocks FLT3, a protein that helps leukemia cells grow. Together, these treatments aim to improve outcomes for newly diagnosed AML patients with NPM1 and FLT3 mutations. ^{1 3 6 7 8}

Who Is on the Research Team?

Richard Stone, MD

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

This trial is for people newly diagnosed with a specific type of blood cancer called Acute Myeloid Leukemia (AML) that has certain genetic changes (NPM1 and FLT3 mutations). Participants should be starting their first treatment.

Inclusion Criteria

aspartate aminotransferase (AST) ≤ 2.5 × ULN*

Ability to understand and the willingness to sign a written informed consent document. (Providing consents in as many languages as possible is encouraged)

My side effects from previous treatments are mild.

Exclusion Criteria

I have hepatitis B or C, but my viral load has been undetectable in the last 3 months.

Subject has consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Star fruit within 3 days prior to the initiation of study treatment.

Subject has a significant history of various medical conditions that would adversely affect participation in the study.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Induction Treatment

Participants receive induction chemotherapy with revumenib, cytarabine, daunorubicin, and midostaurin to induce remission

4 weeks

Daily visits during treatment days

Reinduction Cycle

Participants may receive a second cycle of induction therapy if needed

4 weeks

Daily visits during treatment days

Consolidation Cycle

Participants receive consolidation chemotherapy to maintain remission

4 weeks

Daily visits during treatment days

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks

Regular follow-up visits

What Are the Treatments Tested in This Trial?

Interventions

• Cytarabine
• Daunorubicin
• Midostaurin
• Revumenib

Trial Overview The study is testing the safety and effectiveness of a new drug, Revumenib, when used with standard AML treatments Midostaurin, Cytarabine, and Daunorubicin. The goal is to find the best dose of Revumenib in this combination.

How Is the Trial Designed?

Group I: Dose-Expansion Revumenib Experimental Treatment 4 Interventions

Cycles are 28 days * Baseline visit and assessments * Induction Cycle: * Days 1-3: Predetermined dose of Daunorubicin 1x daily * Days 1-7: Predetermined dose of Cytarabine * Days 8-21: Predetermined dose of Midostaurin 2x daily * Days 8-28: Predetermined dose of Revumenib 2x daily * End of Induction visit * Follow-up * Reinduction Cycle: Therapy will be administered in the hospital * Days 1-2: Predetermined dose of Daunorubicin 1x daily * Days 1-5: Predetermined dose of Cytarabine * Days 8-21: Predetermined dose of Midostaurin 2x daily * Days 8-28: Predetermined dose of Revumenib 2x daily * End of Reinduction visit * Follow-up * Consolidation Cycle: Therapy will be administered in the hospital * Days 1, 3, and 5: Predetermined dose of Cytarabine * Days 8-21: Predetermined dose of Midostaurin 2x daily * Days 8-28: Predetermined dose of Revumenib 2x daily * End of Consolidation visit * Follow up

Group II: Dose Escalation Revumenib Experimental Treatment 4 Interventions

Standard 3+3 design for a recommended phase 2 dose of Revumenib per dose-limiting toxicity rules. Cycles are 28 days. * Baseline * Induction Cycle: * Days 1-3: Predetermined dose of Daunorubicin 1x daily * Days 1-7: Predetermined dose of Cytarabine * Days 8-21: Predetermined dose of Midostaurin 2x daily * Days 8-28: Predetermined dose of Revumenib 2x daily * End of Induction visit * Follow-up * Reinduction Cycle: Therapy will be administered in the hospital * Days 1-2: Predetermined dose of Daunorubicin 1x daily * Days 1-5: Predetermined dose of Cytarabine * Days 8-21: Predetermined dose of Midostaurin 2x daily * Days 8-28: Predetermined dose of Revumenib 2x daily * End of reinduction visit * Follow-up * Consolidation Cycle: Therapy will be administered in the hospital * Days 1, 3, and 5: Predetermined dose of Cytarabine * Days 8-21: Predetermined dose of Midostaurin 2x daily * Days 8-28: Predetermined dose of Revumenib 2x daily * End of consolidation visit * Follow up

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

Approved in United States as Cytosar-U for:

• Acute myeloid leukemia
• Acute lymphocytic leukemia
• Chronic myeloid leukemia
• Meningeal leukemia

Approved in European Union as Depocyt for:

• Lymphomatous meningitis

Approved in Canada as Cytosar-U for:

• Acute myeloid leukemia
• Acute lymphocytic leukemia
• Chronic myeloid leukemia

Who Is Running the Clinical Trial?

Maximilian Stahl, MD

Lead Sponsor

Trials

2

Recruited

130+

Richard Stone, MD

Lead Sponsor

Trials

2

Recruited

50+

Syndax Pharmaceuticals

Industry Sponsor

Trials

49

Recruited

2,700+

Published Research Related to This Trial

The VALOR study, involving 711 patients, showed that the combination of vosaroxin and cytarabine resulted in better complete remission rates and survival for older patients (≥60 years) with relapsed/refractory acute myeloid leukemia (AML) compared to placebo/cytarabine.

Vosaroxin demonstrated a safety profile similar to existing AML treatments, making it a promising option for older patients who often face poor outcomes due to comorbidities and unfavorable cytogenetics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vosaroxin in relapsed/refractory acute myeloid leukemia: efficacy and safety in the context of the current treatment landscape. Sedov, V., Stuart, RK.[2020]

Tandutinib, a FLT3 inhibitor, shows promising antileukemic activity in about half of AML patients, especially those with FLT3 ITD mutations, and does not cause common chemotherapy side effects like myelosuppression or cardiac toxicity.

Combining tandutinib with standard chemotherapy (the '3 + 7' regimen) enhances its effectiveness and may allow for lower doses of chemotherapy, reducing side effects, making it a potentially safer option for elderly or medically compromised patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The FLT3 inhibitor tandutinib (formerly MLN518) has sequence-independent synergistic effects with cytarabine and daunorubicin. Schittenhelm, MM., Kampa, KM., Yee, KW., et al.[2020]

In a study of 155 patients with relapsed or refractory acute myeloid leukemia, the Ara-C couplets regimen showed a higher overall response rate (54.4%) compared to the MEC regimen (43.7%), although this difference was not statistically significant (P = 0.10).

Patients receiving Ara-C couplets had significantly better outcomes in terms of overall survival and progression-free survival, were more likely to proceed to allogeneic stem cell transplant (54.4% vs 31%; P = 0.003), and experienced fewer severe toxicities, such as febrile neutropenia and gastrointestinal issues, indicating a safer profile for Ara-C couplets.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A multi-institutional comparison of mitoxantrone, etoposide, and cytarabine vs high-dose cytarabine and mitoxantrone therapy for patients with relapsed or refractory acute myeloid leukemia. Christian, S., Arain, S., Patel, P., et al.[2022]

In a phase II trial involving patients with acute myeloid leukemia (AML) and the FLT3-ITD mutation, quizartinib combined with high-dose cytarabine and mitoxantrone (HAM regimen) is being tested to improve complete remission rates, which are currently low with standard treatments.

The study uses a novel matched threshold crossing approach to compare outcomes with historical controls, aiming to enhance the reliability of results while assessing the efficacy and safety of quizartinib in achieving remission before potential stem cell transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Q-HAM: a multicenter upfront randomized phase II trial of quizartinib and high-dose Ara-C plus mitoxantrone in relapsed/refractory AML with FLT3-ITD. Jaramillo, S., Le Cornet, L., Kratzmann, M., et al.[2023]

Acute myeloid leukemia (AML) treatment has seen little change in 40 years, but new agents like IDH inhibitors and antibody-drug conjugates show promise in improving outcomes, either alone or with traditional chemotherapy.

A variety of novel therapies, including cytotoxic agents, epigenetic modifiers, and targeted inhibitors, are currently being tested in clinical trials, indicating a potential shift in AML management strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Emerging therapies for acute myeloid leukemia. Saygin, C., Carraway, HE.[2023]

Younger adults with acute myeloid leukemia (AML) have seen better treatment outcomes over the past 40 years, but older adults have not experienced similar improvements, with only 20% to 30% achieving long-term survival after initial treatment.

Recent advances in understanding AML's molecular mechanisms have led to the development of targeted therapies, such as FLT3 inhibitors and immunoconjugates, which represent a promising new direction for treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Drug therapy for acute myeloid leukemia. Tallman, MS., Gilliland, DG., Rowe, JM.[2022]

Recent advancements in drug approvals for acute myeloid leukemia (AML) have significantly improved treatment options, particularly for patients with specific genetic abnormalities, such as core-binding factor and FLT3.

For newly diagnosed patients who are considered 'unfit' for traditional chemotherapy, a combination of venetoclax and azacitidine is recommended, highlighting the need for ongoing research to better define patient fitness for treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic Advances in First-Line Management of Acute Myeloid Leukemia. Pollyea, DA.[2020]

Midostaurin, when combined with standard chemotherapy (cytarabine and daunorubicin), significantly improves event-free survival, disease-free survival, and overall survival in patients with newly diagnosed FLT3-mutated acute myeloid leukemia (AML), based on a phase III trial.

The treatment with midostaurin is considered safe, showing no significant difference in overall toxicity compared to placebo, although it was associated with a higher incidence of grade 3 to 5 anemia and rash.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Midostaurin in Combination With Standard Chemotherapy for Treatment of Newly Diagnosed FMS-Like Tyrosine Kinase 3 (FLT3) Mutation-Positive Acute Myeloid Leukemia. Kim, M., Williams, S.[2019]

In a clinical trial involving 93 patients with relapsed/refractory acute myeloid leukemia (AML), the combination of chidamide, decitabine, aclarubicin, cytarabine, and G-CSF (CDCAG) resulted in a 46.2% overall response rate, with 24 patients achieving complete remission (CR).

The treatment was well tolerated, and patients with specific epigenetic and transcription factor-related gene mutations (excluding FLT3-ITDs) had a higher response rate of 55.6%, indicating that this regimen may be particularly beneficial for this subgroup.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chidamide, decitabine, cytarabine, aclarubicin, and granulocyte colony-stimulating factor (CDCAG) in patients with relapsed/refractory acute myeloid leukemia: a single-arm, phase 1/2 study. Wang, L., Luo, J., Chen, G., et al.[2021]

Vyxeos (CPX-351) received FDA approval for treating adults with newly diagnosed therapy-related acute myeloid leukemia (t-AML) or acute myeloid leukemia with myelodysplasia-related changes (AML-MRC), based on a study involving 309 patients aged 60-75 that showed improved overall survival (9.6 months vs. 5.9 months with standard treatment).

The safety profile of Vyxeos was comparable to the standard treatment, but it was associated with longer periods of neutropenia and thrombocytopenia, highlighting the need for careful monitoring and a warning against switching between different formulations of daunorubicin and cytarabine during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: (Daunorubicin and Cytarabine) Liposome for Injection for the Treatment of Adults with High-Risk Acute Myeloid Leukemia. Krauss, AC., Gao, X., Li, L., et al.[2020]

Vyxeos, a liposomal formulation combining daunorubicin and cytarabine, significantly improves overall survival in patients aged 60-75 with untreated high-risk acute myeloid leukemia (AML), showing a median survival of 9.56 months compared to 5.95 months with standard chemotherapy.

The study demonstrated that Vyxeos not only enhances survival rates but also increases the likelihood of patients undergoing hematopoietic stem cell transplantation, which is crucial for potentially curing AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

EMA Review of Daunorubicin and Cytarabine Encapsulated in Liposomes (Vyxeos, CPX-351) for the Treatment of Adults with Newly Diagnosed, Therapy-Related Acute Myeloid Leukemia or Acute Myeloid Leukemia with Myelodysplasia-Related Changes. Tzogani, K., Penttilä, K., Lapveteläinen, T., et al.[2022]

Intensive research is being conducted to understand and overcome resistance to chemotherapy in acute myeloid leukemia (AML), particularly focusing on the drugs daunorubicin and cytarabine, which are currently the most effective treatments.

Current studies are exploring ways to enhance the effectiveness of cytarabine by improving its delivery to leukemic cells and increasing the number of cells in the S-phase of the cell cycle, which may lead to better treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cellular and pharmacologic aspects of drug resistance in acute myeloid leukemia. Ross, DD.[2019]

Citations

1. ir.syndax.com ir.syndax.com/news-releases/news-release-details/syndax-announces-compelling-revuforjr-revumenib-and-niktimvotm

Syndax Announces Compelling Revuforj® (revumenib) and ... Two poster presentations will report preliminary results from Phase 1 trials of revumenib in combination with intensive chemotherapy in newly ...

2. fda.gov fda.gov/drugs/resources-information-approved-drugs/fda-approves-revumenib-relapsed-or-refractory-acute-myeloid-leukemia-susceptible-npm1-mutation

FDA approves revumenib for relapsed or refractory acute ... FDA approves revumenib for relapsed or refractory acute myeloid leukemia with a susceptible NPM1 mutation ... The main efficacy outcome ...

3. ir.syndax.com ir.syndax.com/news-releases/news-release-details/syndax-announces-fda-approval-revuforjr-revumenib-adult-and

Syndax Announces FDA Approval of Revuforj® (revumenib) in ... The rate of complete remission (CR) plus CR with partial hematological recovery (CRh) was 23% (15/65 pts; 95% CI: 14%, 35%). The median time to ...

4. revuforj.com revuforj.com/trial-results/

Trial Results | Revuforj® (revumenib) Official Patient Site In the clinical trial, 21% of people (22 out of 104) achieved complete remission (CR) or complete remission with a partial hematologic recovery (CRh).

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11060303/

Revumenib (SNDX-5613): a promising menin inhibitor for ... The result of the phase 1/2 clinical trial of Ziftomenib has shown an ORR of 40% and CRh of 35% in patients with NPM1 mutation AML, with a ...

6. revuforj.com revuforj.com/

Revuforj® (revumenib) | Official Patient Site Revuforj can be used in the acute leukemia types above that have come back or have not improved after previous treatment(s). Important Safety Information.

7. clinicaltrials.gov clinicaltrials.gov/study/NCT06222580

Study Details | NCT06222580 | SNDX-5613 and Gilteritinib ... Giving SNDX-5613 with gilteritinib may be safe, tolerable and/or effective in treating patients with relapsed/refractory FLT3 mutated acute myeloid leukemia.

8. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/6065/527234/Efficacy-and-Safety-of-Revumenib-in-the-Treatment

Efficacy and Safety of Revumenib in the Treatment of Acute ... Revumenib demonstrates promising efficacy in achieving high response rates and MRD negativity in adult patients with relapsed or refractory AML with KMT2A ...