SNDX-5613 for Acute Leukemia

(AUGMENT-101 Trial)

Recruiting at 54 trial locations

Overseen By Syndax Pharmaceuticals

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Syndax Pharmaceuticals

Must be taking: CYP3A4 inhibitors

Must not be taking: QT prolonging drugs

Disqualifiers: Acute promyelocytic leukemia, HIV, Hepatitis, others

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

Compensation: Varies

Number of Visits: Unknown

413 Participants Needed

Trial Summary

What is the purpose of this trial?

Phase 1 dose escalation will determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of revumenib in participants with acute leukemia. In Phase 2, participants will be enrolled in 3 indication-specific expansion cohorts to determine the efficacy, short- and long-term safety, and tolerability of revumenib.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you must stop all current medications. However, certain medications, especially those affecting the CYP3A4 enzyme, may affect eligibility. Participants in Phase 1 are grouped based on their use of specific CYP3A4 inhibitors or inducers. Additionally, there are specific washout periods for various treatments, such as 14 days for antileukemia therapy and 7 days for systemic glucocorticoids. It's best to discuss your current medications with the trial team to determine your eligibility.

What data supports the idea that SNDX-5613 for Acute Leukemia is an effective drug?

The available research shows that SNDX-5613, also known as Revumenib, is effective in treating acute leukemia. A phase II study reported a 63% response rate in patients with relapsed or refractory disease and specific genetic changes. Additionally, a phase I trial combining SNDX-5613 with three chemotherapies resulted in complete remissions in patients with acute myeloid leukemia. This suggests that SNDX-5613 is a promising option for patients with acute leukemia, especially those with certain genetic alterations. ^{1 2 3 4 5}

What safety data is available for SNDX-5613 (Revumenib, Revuforj) in treating acute leukemia?

The provided research does not contain any safety data for SNDX-5613, Revumenib, or Revuforj in the treatment of acute leukemia. The studies focus on other treatments and conditions. ^{6 7 8 9 10}

Is the drug SNDX-5613 a promising treatment for acute leukemia?

The information provided does not include specific details about SNDX-5613, so we cannot determine if it is a promising treatment for acute leukemia based on the given research articles. ^{1 2 11 12 13}

Research Team

Angela R Smith, M.D.

Principal Investigator

Syndax Pharmaceuticals

Eligibility Criteria

This trial is for individuals with relapsed/refractory acute leukemias, specifically those with MLL rearrangement or NPM1 mutation. Participants must have a white blood cell count below 25,000/microliter and resolved prior treatment toxicities to ≤Grade 1 (except neuropathy or alopecia). They should not be on certain antifungal drugs unless specified in the study arms, have no active central nervous system disease, HIV viral load, hepatitis B/C, significant cardiac issues within the last six months, severe gastrointestinal conditions affecting drug absorption or serious graft-versus-host disease.

Inclusion Criteria

My AML has relapsed or is resistant, and tests show NPM1c mutation.

I am taking strong antifungal medication like itraconazole.

I am not taking any medication that strongly affects liver enzymes.

Exclusion Criteria

My liver disease is severe, as indicated by my Child-Pugh score.

Detectable human immunodeficiency virus (HIV) viral load within the previous 6 months. Participants with a known history of HIV 1/2 antibodies must have viral load testing prior to study enrollment.

Participants meeting any of the following criteria are not eligible for study participation:

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1: Dose Escalation

Oral revumenib; sequential cohorts of escalating dose levels to identify the MTD and RP2D

Approximately 1 year

Phase 2: Dose Expansion

Participants enrolled in 3 indication-specific expansion cohorts to determine efficacy, safety, and tolerability

Approximately 3 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

Approximately 1 year

Treatment Details

Interventions

• SNDX-5613

Trial Overview The trial tests SNDX-5613 alone or combined with cobicistat to determine its maximum tolerated dose and efficacy in treating specific types of leukemia. Phase 1 focuses on dosage while Phase 2 evaluates effectiveness and safety across different patient groups defined by their genetic mutations related to leukemia.

Participant Groups

Group I: Revumenib Experimental Treatment 2 Interventions

Phase 1: Oral revumenib; sequential cohorts of escalating dose levels of revumenib to identify the MTD and RP2D. Participants will be enrolled in 1 of 6 dose-escalation arms: * Arm A: Participants not receiving any strong CYP3A4 inhibitor/inducers or fluconazole * Arm B: Participants receiving any strong CYP3A4 inhibitors for antifungal prophylaxis * Arm C: Participants receiving revumenib and cobicistat * Arm D: Participants receiving fluconazole for antifungal prophylaxis * Arm E: Participants not receiving any weak, moderate, or strong CYP3A4 inhibitors/inducers * Arm F: Participants receiving isavuconazole for antifungal prophylaxis Phase 2: Oral revumenib; Following the determination of the RP2D in Phase 1, 3 indication-specific expansion cohorts will be enrolled as follows: * Cohort 2A: Participants with KMT2Ar ALL/MPAL * Cohort 2B: Participants with KMT2Ar AML * Cohort 2C: Participants with NPM1m AML

Who Is Running the Clinical Trial?

Syndax Pharmaceuticals

Lead Sponsor

Trials

49

Recruited

2,700+

Findings from Research

In a phase 1b/2 trial involving 19 patients with relapsed/refractory acute myeloid leukemia (AML), the combination of azacitidine and the anti-PD-L1 inhibitor avelumab was well tolerated but showed limited clinical activity, with an overall complete remission rate of only 10.5%.

Analysis of bone marrow blasts revealed significantly higher expression of PD-L2 compared to PD-L1, suggesting that PD-L2 may play a key role in the resistance to anti-PD-L1 therapy in AML, indicating a potential target for future treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1b/2 study of azacitidine with PD-L1 antibody avelumab in relapsed/refractory acute myeloid leukemia. Saxena, K., Herbrich, SM., Pemmaraju, N., et al.[2022]

In a phase I trial involving 37 pediatric patients with relapsed/refractory acute myeloid leukemia (R/R AML), the combination of decitabine, vorinostat, and FLAG chemotherapy showed a promising overall response rate of 54%, with 16 patients achieving complete response (CR).

The treatment was well-tolerated with no dose-limiting toxicities, and among those who responded, 90% achieved minimal residual disease (MRD) negativity, leading to a significantly higher two-year overall survival rate of 75.6% for MRD-negative patients compared to 17.9% for those with residual disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Decitabine and vorinostat with FLAG chemotherapy in pediatric relapsed/refractory AML: Report from the therapeutic advances in childhood leukemia and lymphoma (TACL) consortium. Pommert, L., Schafer, ES., Malvar, J., et al.[2023]

Revumenib, a menin inhibitor, showed a 63% response rate in a phase II study for patients with relapsed or refractory acute leukemias with KMT2A rearrangements.

In a phase I trial, combining revumenib with three chemotherapies resulted in complete remissions in patients with acute myeloid leukemia, highlighting its potential effectiveness in treatment regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Menin Inhibitors Trigger Leukemia Remissions. [2023]

Recent advancements in high-throughput sequencing have improved our understanding of acute myeloid leukemia (AML) by identifying key genetic mutations involved in the disease, paving the way for more targeted therapies.

In the last two years, the FDA has approved eight new therapies for AML, including those targeting specific mutations like FLT3 and IDH, which represent a significant shift towards personalized treatment options for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

From DNA Sequencing to Clinical Trials: Finding New Targeted Drugs for Acute Myeloid Leukemia. Yilmaz, M., Daver, N.[2020]

In a trial involving 19 adult patients with acute myelogenous leukemia (AML), all-trans retinoic acid (ATRA) was found to have mostly non-severe toxicity, with a notable incidence of headaches, but did not improve remission rates or survival outcomes compared to a control group of 29 patients not receiving ATRA.

The study showed that the complete remission rate after the first treatment cycle was 54%, and overall survival at three years was 30%, with no significant differences between ATRA-treated and untreated patients, leading to the conclusion that ATRA does not significantly enhance standard AML treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prolonged administration of all-trans retinoic acid in combination with intensive chemotherapy and G-CSF for adult acute myelogenous leukemia: single-centre pilot study in different risk groups. Bassan, R., Chiodini, B., Lerede, T., et al.[2016]

The combination of emactuzumab and selicrelumab showed a manageable safety profile, with infusion-related reactions being the most common adverse event observed in 75.7% of patients, but the maximum tolerated doses were not reached.

Despite demonstrating pharmacodynamic activity, such as increased activated CD8+ T cells, the treatment did not result in significant objective clinical responses, with only 40.5% of patients achieving stable disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase Ib study of anti-CSF-1R antibody emactuzumab in combination with CD40 agonist selicrelumab in advanced solid tumor patients. Machiels, JP., Gomez-Roca, C., Michot, JM., et al.[2021]

Ramucirumab effectively inhibited endothelial cord formation in vitro across various pediatric cancer cell lines, highlighting its potential as a treatment targeting VEGFR2 in solid tumors.

In preclinical mouse models, the anti-VEGFR2 antibody DC101 showed significant tumor growth delay and partial regressions in several pediatric cancers when combined with chemotherapy, although it was less effective in osteosarcoma models.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-VEGFR2 therapy delays growth of preclinical pediatric tumor models and enhances anti-tumor activity of chemotherapy. Lowery, CD., Blosser, W., Dowless, M., et al.[2019]

Demcizumab, a humanized monoclonal antibody targeting the Notch ligand DLL4, was generally well tolerated in a phase I trial with 55 patients, showing disease stabilization and some tumor size reduction at doses up to 5 mg weekly.

The most common treatment-related adverse event was hypertension (47%), and prolonged use at higher doses raised concerns about congestive heart failure, indicating the need for careful monitoring in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I dose escalation and expansion study of the anticancer stem cell agent demcizumab (anti-DLL4) in patients with previously treated solid tumors. Smith, DC., Eisenberg, PD., Manikhas, G., et al.[2018]

In a phase I trial involving 60 patients with HER2-expressing or HER2-mutant solid tumors, trastuzumab deruxtecan (T-DXd) showed a confirmed objective response rate of 28.3%, with particularly high efficacy in HER2-mutant non-small cell lung cancer (NSCLC) at 72.7%.

The treatment was generally well-tolerated, although common side effects included nausea and decreased appetite, and there were two fatal adverse events related to the drug, highlighting the need for careful monitoring for severe side effects like interstitial lung disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting HER2 with Trastuzumab Deruxtecan: A Dose-Expansion, Phase I Study in Multiple Advanced Solid Tumors. Tsurutani, J., Iwata, H., Krop, I., et al.[2021]

Ramucirumab is a monoclonal antibody that effectively targets VEGFR-2, showing promising clinical activity in advanced gastric and colorectal cancers, leading to its approval as a second-line therapy.

While it has demonstrated efficacy in certain cancers, ramucirumab did not significantly improve survival in patients with advanced hepatocellular carcinoma, highlighting the need for careful patient selection in treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ramucirumab Clinical Development: an Emerging Role in Gastrointestinal Tumors. Sanchez-Gastaldo, A., Gonzalez-Exposito, R., Garcia-Carbonero, R.[2023]

In a phase II trial involving 65 patients aged 60 and older with acute myeloid leukemia or myelodysplastic syndrome, the combination of vosaroxin and decitabine showed a high overall response rate of 74%, with 48% achieving complete remission.

Reducing the vosaroxin dose to 70 mg/m2 significantly decreased the incidence of severe mucositis and improved median overall survival to 14.6 months, compared to 5.5 months with the higher dose, indicating a better safety profile while maintaining efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vosaroxin in combination with decitabine in newly diagnosed older patients with acute myeloid leukemia or high-risk myelodysplastic syndrome. Daver, N., Kantarjian, H., Garcia-Manero, G., et al.[2019]

Acute myeloid leukemia (AML) treatment remains difficult, especially for older patients over 60, who experience high toxicity and low response rates, while younger patients can achieve a 70% response rate with standard therapies.

New targeted therapies, such as oral farnesyltransferase inhibitors, are showing promise in treating refractory AML and are currently in phase II testing, potentially offering better efficacy and safety profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of acute myeloid leukemia: state-of-the-art and future directions. Stone, RM.[2019]

In a phase I study involving 10 patients with relapsed/refractory acute myeloid leukemia (AML), the combination of midostaurin, all-trans retinoic acid (ATRA), and CLAG chemotherapy showed promising results with no dose-limiting toxicities observed.

The treatment led to a 22% complete remission rate and a 11% rate of complete remission with incomplete count recovery, indicating potential efficacy, especially in specific genetic subtypes of AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of cladribine, cytarabine, granulocyte colony stimulating factor (CLAG regimen) and midostaurin and all-trans retinoic acid in relapsed/refractory AML. Ramsingh, G., Westervelt, P., McBride, A., et al.[2022]

References

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

A phase 1b/2 study of azacitidine with PD-L1 antibody avelumab in relapsed/refractory acute myeloid leukemia. [2022]

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

Decitabine and vorinostat with FLAG chemotherapy in pediatric relapsed/refractory AML: Report from the therapeutic advances in childhood leukemia and lymphoma (TACL) consortium. [2023]

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

Menin Inhibitors Trigger Leukemia Remissions. [2023]

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

From DNA Sequencing to Clinical Trials: Finding New Targeted Drugs for Acute Myeloid Leukemia. [2020]

5. England pubmed.ncbi.nlm.nih.gov

Prolonged administration of all-trans retinoic acid in combination with intensive chemotherapy and G-CSF for adult acute myelogenous leukemia: single-centre pilot study in different risk groups. [2016]

6. England pubmed.ncbi.nlm.nih.gov

Phase Ib study of anti-CSF-1R antibody emactuzumab in combination with CD40 agonist selicrelumab in advanced solid tumor patients. [2021]

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

Anti-VEGFR2 therapy delays growth of preclinical pediatric tumor models and enhances anti-tumor activity of chemotherapy. [2019]

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

A phase I dose escalation and expansion study of the anticancer stem cell agent demcizumab (anti-DLL4) in patients with previously treated solid tumors. [2018]

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

Targeting HER2 with Trastuzumab Deruxtecan: A Dose-Expansion, Phase I Study in Multiple Advanced Solid Tumors. [2021]

10. France pubmed.ncbi.nlm.nih.gov

Ramucirumab Clinical Development: an Emerging Role in Gastrointestinal Tumors. [2023]

11. Italy pubmed.ncbi.nlm.nih.gov

Vosaroxin in combination with decitabine in newly diagnosed older patients with acute myeloid leukemia or high-risk myelodysplastic syndrome. [2019]

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

Treatment of acute myeloid leukemia: state-of-the-art and future directions. [2019]

13. Japan pubmed.ncbi.nlm.nih.gov

Phase I study of cladribine, cytarabine, granulocyte colony stimulating factor (CLAG regimen) and midostaurin and all-trans retinoic acid in relapsed/refractory AML. [2022]