SNDX-5613 Shows Early Promise in Acute Leukemias

Michael J. Thirman, MD

The menin-MLL1 inhibitor SNDX-5613 is a novel targeted therapy for patients with acute leukemias that harbor MLL rearrangements and NPM1 mutations, and ongoing research with the compound is aimed at identifying a recommended phase 2 dose, according to Michael J. Thirman, MD.¹

The phase 1/2 AUGMENT-101 trial (NCT04065399) is evaluating SNDX-5613 in patients with relapsed/refractory leukemias, including those with an MLL/KMT2Aa gene rearrangement. The phase 1 dose-escalation portion of the trial will determine the maximum-tolerated dose and recommended phase 2 dose of the compound in patients with acute leukemias, starting at a dose of 113 mg twice daily. In the phase 2 portion, patients will be enrolled in 3 indication-specific expansion cohorts to determine efficacy, short- and long-term safety, and tolerability of SNDX-5613.²

SNDX-5613 was recently granted an orphan drug designation by the FDA for the treatment of adult and pediatric AML.³

Results from the phase 1 portion of the study were presented at the 2020 AACR Virtual Annual Meeting I. One patient with MLL rearrangements, t(10;11) mutation, and FLT3 ITD who was receiving 226 mg of the compound every 12 hours experienced a complete response (CR) with incomplete blood count recovery after 28 days of therapy. When the dose was reduced to 113 mg every 12 hours, the patient achieved a CR. Another patient with MLL rearrangements and t(9;11) mutations who was receiving the drug at 113 mg every 12 hours achieved a partial response with incomplete blood count recovery after 28 days of therapy. Both patients were also on a strong CYP3A4 inhibitor.

“The dosing appears to depend on what other drugs patients are receiving,” said Thirman. “In particular, a certain category of drugs seems to affect the metabolism of this drug. It is being looked at in terms of whether or not people are on that category of drugs. It is still early days, but progress is being made on determining the pharmacokinetics with the goal of identifying the correct dose for phase 2 trials.”

In an interview with Onclive, Thirman, an associate professor of medicine at the University of Chicago Medicine, further discussed the novel compound and shed light on the next steps for this research.

OncLive: What was the rationale for this study of SNDX-5613?

Thirman: A great deal of studies have been done [in this area]. I have been involved in a study of MLL rearrangements in acute leukemia for a long time. Several labs around the world have identified the interaction of MLL with menin as a key mediator of these leukemias. Many groups have worked to identify compounds that would block the interaction of MLL and menin. Syndax Pharmaceuticals was able to develop a compound that is highly specific and blocks the MLL/menin interaction. Investigators tested [this agent] in preclinical models and showed that it did, in fact, work to block that interaction. Additionally, it was demonstrated in cell lines, as well as in animal models, that the compound was capable of eliminating leukemia cells that harbored these MLL rearrangements. Investigators have brought that compound to the clinic now and they are currently in phase 1 testing.

What is the prevalence and prognosis of these rare molecular subtypes in acute myeloid leukemia (AML)?

MLL is rearranged in about 5% to 10% of both AML and acute lymphoblastic leukemia (ALL). MLL rearrangements are particularly common in acute leukemias in infants, as well as in those who develop therapy-related leukemias who had previously received other chemotherapies for other cancers. In addition, [the Syndax] drug may work in patients with NPM1-mutated leukemia, which is present in about 20% to 30% of [all cases of] AML. Historically, patients who have MLL gene rearrangements have had a very poor prognosis, both in ALL and AML. Patients with NPM1-mutated AML have had an intermediate prognosis.

Could you talk about the mechanism of action with this agent and why it is being investigated in this patient population?

MLL normally interacts with menin and that interaction allows it to regulate the expression of its gene targets. In the fusion genes, the MLL fusion also binds menin and regulates a series of targets. When the interaction of MLL and menin is blocked, it allows the normal transcription to occur and it blocks the effects on the targets that the MLL fusions normally regulate.

How was the study designed?

Right now, it is a phase 1 trial. In this research, investigators are trying to identify the recommended phase 2 dose of the compound. An expansion will be done once that recommended dose is determined.

What has been learned so far through the phase 1 trial?

It is important to obtain a lot of pharmacokinetic data to pursue this phase 1 trial, which is being conducted at several sites around the country. Right now, a lot of work is being done to determine the optimal dosing. We have seen some promising early results in a patient that I am involved in taking care of.

Were any safety signals noted with this agent that are interesting or of concern?

Nothing that was unexpected. There were some initial close monitoring related to the QTc intervals on electrocardiograms. Other than that, there really have not been any safety signals.

What are the potential clinical implications of this drug moving into future clinical trials?

For these patients with MLL gene rearrangements, there have not been any good therapies identified. Studies from our group, as well as others, have shown that stem cell transplants do not tend to work well in this group. Even CAR T-cell therapy in patients with ALL is not particularly effective in this group because of lineage switch that can occur. We are hoping that we can identify a new way of treating these patients with this drug.

Is there anything else you would like to highlight?

It would be very important to go to phase 2 and then establish the compound’s efficacy in MLL-rearranged leukemia as well as in NPM1-mutated leukemia.We are continuing to work to develop targeted therapies [for these patients] and this [research] is a beautiful example of how that can be accomplished.

References

1. 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. bit.ly/2Z3Y4MX.
2. A Study of SNDX-5613 in R/R Leukemias Including Those With an MLLr/KMT2A Gene Rearrangement or NPM1 Mutation (AUGMENT-101). www.clinicaltrials.gov/ct2/show/NCT04065399. Updated April 13, 2020. Accessed May 12, 2020.
3. Syndax Pharmaceuticals announces preclinical profile and initial phase 1 data demonstrating clinical activity of Menin inhibitor SNDX-5613 in adults with relapsed/refractory acute leukemias. News release. Syndax Pharmaceuticals; April 27, 2020. bit.ly/2T1Sxmx. Accessed May 12, 2020.