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2020-05-01T08:54:33.000Z

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

May 1, 2020
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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 design1,2

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.

  1. PR Newswire. 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. https://www.prnewswire.com/news-releases/syndax-pharmaceuticals-announces-preclinical-profile-and-initial-phase-1-data-demonstrating-clinical-activity-of-menin-inhibitor-sndx-5613-in-adults-with-relapsedrefractory-acute-leukemias-301047764.html. Published Apr 27, 2020. Accessed Apr 28, 2020.
  2. McGeehan J. A first-in-class Menin-MLL1 antagonist for the treatment of MLL-r and NPM1 mutant leukemias. Oral abstract DDT01-01. 2020 American Association for Cancer Research Virtual Annual Meeting I; Apr 27, 2020.

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