AACR 2020 | Preliminary phase I results of the AUGMENT-101 trial demonstrate clinical activity of SNDX-5613 in adults with relapsed/refractory acute leukemias

Mixed lineage leukemia rearranged (MLL-r) is caused by rearrangements of the MLL gene that produce MLL-fusion proteins. MLL-r acute leukemias (acute lymphoblastic leukemia [ALL] or acute myeloid leukemia [AML]) have a poor prognosis and occur in   ̴80% of infant acute leukemias and up to 10% of all acute leukemias. The interaction of MLL-fusion proteins with the chromatin-associated menin protein is critical in maintaining leukemic state by epigenetic activation of stem cell-like processes, including HOX gene expression. Disruption of this interaction blocks leukemic cell growth.^1,2

NPM1c⁺ AML, caused by point mutations in the nucleophosmin 1 (NPM1) gene, altering the C-terminus of the NPM1 protein, represents   ̴30% of all adult AML cases. Similar to MLL-r leukemias, the inhibition of the menin-MLL interaction in NPM1c⁺ AML blocks leukemic cell proliferation. Currently, there are no approved therapies for both MLL-r and NPM1c⁺ AML.^1,2

SNDX-5613 is a potent, highly selective, oral inhibitor of the menin-MLL binding interaction that recently received orphan drug designation from the U.S. Food and Drug Administration for the treatment of adult and pediatric AML.¹

Preclinical and initial clinical data for SNDX-5613 have been presented at the 2020 American Association for Cancer Research (AACR) Virtual Annual Meeting I by Jerry McGeehan.²

Preclinical data²

• In eight MLL-r patient derived xenograft (PDX) models, the SNDX-50469 menin inhibitor demonstrated single-agent activity with marked survival benefits in seven PDXs after a single round of 28-day treatment
• In NPM1c⁺ PDX models, after   ̴90 days of treatment with the menin inhibitor SNDX-50469, single-agent survival benefits have been observed
• The clinical candidate SNDX-5613 is specific for menin-MLL inhibition:
  • It is almost exclusively metabolized via CYP4A4, and since many patients receive antifungal prophylaxis with CYP3A4 inhibitors, this could influence the clearance of SNDX-5613
  • SNDX-5613 provided survival benefits and leukemic control in aggressive MOLM-13 disseminated xenografts after 28 days of treatment, in a dose-dependent manner
  • A pharmacokinetic analysis revealed the drug exposures required for leukemic control

These results indicated that the inhibition of the menin-MLL interaction may provide benefits for both NPM1 mutant AML and MLL-r acute leukemias.

Clinical data

Study design^1,2

SNDX-5613 is currently being evaluated in the AUGMENT-101 phase I/II (NCT04065399) clinical trial for the treatment of relapsed/refractory (R/R) acute leukemias. Here, we report a summary of the phase I preliminary results.

• The phase I (N = 6) dose escalation portion of the study is designed to identify the maximum tolerated dose and the recommended phase II dose (RP2D) of orally administered SNDX-5613. Patient characteristics and SNDX-5613 doses are reported in Table 1

Table 1. Patient characteristics and SNDX-5613 doses²          

MLL-r, mixed lineage leukemia rearranged; NPM1, nucleophosmin 1; PO, per os; PTD, partial tandem duplication; QD, once daily
Patient #	Age, years	Mutational status	Prior lines of therapy	SNDX-5613 doses
1	60	No MLL-r or NPM1 mutation	3	113 mg PO q12 h
2	69	MLL-TET1 fusion; FLT3-ITD	2	226 mg PO q12 h to 113 mg q12 h
3	32	MLL-r t(5;11)	8	226 mg PO q12 h
4	30	No MLL-r or NPM1 mutation	˃ 3	226 mg PO q12 h
5	79	MLL PTD	2	226 mg PO q12 h
6	61	MLL-r t(9;11)	3	113 mg PO q12 h to 113 mg QD

• Based on concomitant treatment with a strong CYP3A4 inhibitor (antifungal therapy), the phase I dose escalation portion was separated into two arms:
  • Arm A: patients not receiving a strong CYP3A4 inhibitor
  • Arm B: patients receiving a strong CYP3A4 inhibitor
• The phase II portion will evaluate efficacy across three expansion cohorts: MLL-r ALL, MLL-r AML, and NPM1 mutant AML

Results²

• Responses were observed in two out of three patients with MLL-r:
  • One patient (#2), had a complete response with incomplete blood count recovery (CRi) after 28 days of therapy that then improved to a complete response (CR)
  • The second patient (#6) achieved a partial response with incomplete blood count recovery (PRi) after 28 days of therapy
• Treatment with SNDX-5613 was well tolerated, with no dose-limiting toxicities (DLTs) reported
• A response summary is reported in Table 2

Table 2. Response summary²

CR, complete response; CRi, complete response with incomplete blood count recovery; DLT, dose-limiting toxicity; PD, progressive disease; PRi, partial response with incomplete blood count recovery
Patient #	DLT	Response
Arm A 1   3	No DLTs   No DLTs	PD/off study   No response/on study
Arm B 2        4   5   6	No DLTs Grade 2 QTc prolongation resolved with dose reduction   Inevaluable   No DLTs   No DLTs Grade 1 QTc prolongation resolved with dose reduction	CRi improved to CR        PD/off study   No response/on study   PRi

Conclusion²

Preclinical data showed that SNDX-5613 had single-agent activity in xenograft models. Preliminary phase I data indicated that SNDX-5613 can induce response in patients with MLL-r rapidly, after a single 28-day cycle. All together, these preliminary results demonstrated that the disruption of the menin-MLL1 interaction with the selective inhibitor SNDX-5613 could induce durable response in a select population of patients with MLL-r acute leukemias. The clinical investigation of SNDX-5613 is ongoing.