SNDX-5613 Demonstrates Robust Clinical Activity in MLL-Rearranged and NPM1c-Mutant R/R Acute Leukemia

In the phase 1/2 AUGMENT-101 clinical trial, treatment with the novel menin-MLL small molecule inhibitor SNDX-5613 led to robust clinical responses in patients with mixed lineage leukemia rearranged and NPM1c-mutant relapsed or refractory acute leukemias.

In the phase 1/2 AUGMENT-101 clinical trial (NCT04065399), treatment with the novel menin-MLL small molecule inhibitor SNDX-5613 led to robust clinical responses in patients with mixed lineage leukemia rearranged (MLLr; KMT2A) and NPM1c-mutant relapsed or refractory (R/R) acute leukemias, announced Syndax Pharmaceuticals, Inc., in a press release.1

The efficacy finding was from the dose-escalation portion of the study, during which the recommended phase 2 dose (RP2D) of SNDX-5613 was also identified.

"Genetically-defined acute leukemias, including those harboring MLLr and NPM1c mutations, represent a disease area with a particularly poor prognosis and few effective treatment options," said Eytan M. Stein, MD, assistant attending physician and director, Program for Drug Development in Leukemia, Department of Medicine at Memorial Sloan Kettering Cancer Center, and the trial's principal investigator, in a statement. "With 5-year survival rates in MLLr and NPM1c-mutant acute leukemias of 50% or less, novel treatments that can offer clinically-meaningful benefit are desperately needed. I am excited to present evidence that underscores previous observations that SNDX-5613 has the potential to disrupt the treatment paradigm for this disease."

In the dose-escalation phase of AUGMENT-101, 43 patients who had received a median of 3 prior therapies—such as prior stem cell transplant, venetoclax (Venclexta), and chemotherapy—were evaluated on treatment with SNDX-5613. The patients were dosed with the agent without strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducers, and with strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducers in arm B for antifungal prophylaxis. In phase 2, the study will explore treatment of SNDX-5613 in 3 cohorts comprised of patients with MLLr acute lymphoblastic leukemia or mixed phenotype acute leukemia in cohort 2A, MLLr acute myeloid leukemia (AML) in cohort 2B, and with NPM1c-mutant AML in cohort 2C.

The key phase 1 coprimary end points included dose-limiting toxicities and the frequency, duration, and severity of treatment-related adverse events (AEs). In phase 2, the key primary end points will be the complete remission rate, and the frequency and severity of AEs. The secondary end points explored in phase 2 will include relapse-free survival, time to relapse, duration of response, and overall survival.

At the time of data cutoff on March 12, 2021, 31 patients in phase 1 were evaluable for efficacy. The objective response rate (ORR) observed in these patients was 48%, and 67% of those who responded achieved minimal residual disease negativity. Four of the patients who responded went onto to stem cell transplant. In the subgroup of patients who harbored an MLL rearrangement (n = 24), the ORR was 54%, and for those who harbored a NPM1c mutation (n = 7), the ORR was 29%.

The RP2D of SNDX-5613, according to the study, is 226 mg every 12 hours for patients not receiving a concomitant strong CYP3A4 inhibitor, and 113 mg every 12 hours for patients on a concomitant strong CYP3A4 inhibitor treatment. Thus far, 18 patients have been treated with the RP2D, and response rates observed in these patients were consistent with those in the overall population.

In terms of safety, the novel agent appeared to be well tolerated across the cohorts. There was no treatment discontinuation observed related to treatment-related AEs. QT prolongation, anemia, and differentiation syndrome were among the AEs observed in the study in 5% of the population. In addition, 9% of patients experienced grade 3 QT prolongation.

In earlier preclinical studies, SNDX-5613 demonstrated an event-free survival of over a year and 7 out of 8 models benefitted from a single treatment of the agent.2

The agent SNDX-5613 has also received an orphan drug designation from the FDA for the treatment of adult and pediatric patients with AML.


1. Syndax announces positive interim data demonstrating robust clinical activity in phase 1 portion of the AUGMENT-101 trial of SNDX-5613 in patients with genetically-defined acute leukemias. News release. Syndax Pharmaceuticals. April 20, 2021. Accessed April 20, 2021.

2. McGeehan J. A first-in-class Menin-MLL1 antagonist for the treatment of MLL-r and NPM1 mutant leukemias. Presented at: the 2020 AACR Virtual Annual Meeting I; April 27-28, 2020. Abstract DDT01-01.