Asparec (PEGylated recombinant Erwinia chrysantemi-derived L-asparaginase)

Our previous studies have demonstrated that pegcrisantaspase (PegC), a long-acting Erwinia asparaginase, synergizes with the BCL-2 inhibitor Venetoclax (Ven) in vitro and in vivo; however, the anti-leukemic activity of E. coli-derived asparaginases in combination with BCL-2 inhibition, and potential synergy with inhibitors of MCL-1, a key resistance factor of BCL-2 inhibition, has yet to be determined. Using a combination of human AML cells lines, primary samples, and in vivo xenograft mouse models, we established the anti-leukemic activity of the BCL-2 inhibitor S55746 and the MCL-1 inhibitor S63845, alone and in combination with the long-acting E. coli asparaginase calaspargase pegol-mknl (CalPegA)...The S55746-CalPegA combination inhibited protein synthesis and increased eIF4E/4EBP1 interaction, suggesting an inhibition of translational complex formation. These results support the clinical evaluation of CalPegA in combination with BCL-2 inhibition for AML.

P1, N=19, Terminated, M.D. Anderson Cancer Center | Active, not recruiting --> Terminated; Administratively Complete

P2, N=300, Suspended, National Cancer Institute (NCI) | N=550 --> 300

Response correlated with alterations in proteins involved in mRNA translation. In patients with RUNX1 mutations, the composite complete rate was 100%.

P1, N=19, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting | N=62 --> 19

In this high-risk, heavily treated population, the combination of fludarabine, cytarabine, and PegC is feasible. Responding patients included 2 AML and 1 ALL. Further exploratory analysis about the relation between response and asparagine depletion as well as specific sensitive subsets could clarify which patients might benefit the most from this combination.

Our previous studies have shown that pegcrisantaspase (PegC), a long-acting pegylated crisantaspase, synergizes with the BCL2 inhibitor, Venetoclax (Ven), to kill several AML cell lines and patient-derived primary AML cells with complex karyotype in vitro and in vivo in a xenograft mouse model... Using a panel of 4 human AML cell lines (MOLM14, MV411, MonoMac6, HL60) as well as primary AML patient samples, weestablished the anti-leukemic activity of the BCL2 inhibitor S55746 and the MCL1 inhibitor S63845 alone and in combination with the long-acting E. coli asparaginase, calaspargase pegol-mknl (CalPegA)... We report that the E. coli asparaginase, CalPegA, enhances the anti-leukemic effect of the BCL2 inhibitor, S55746, but does not impact the activity of the MCL1 inhibitor, S63845, in AML cell lines, patient derived primary AML samples, and in an AML xenograft mouse model. Ongoing studies are further investigating the anti-leukemic mechanism of S55476/S63845 + CalPegA and examining the efficacy and pharmacodynamic/pharmacokinetic effects of these agents in a patient derived xenograft model of AML.

We reported in vitro and in vivo depletion of Gln induced by long-acting Erwinia asparaginase, PegC, inhibited proliferation of complex karyotype (CK) AML and synergistically enhanced the antiapoptotic activity of Ven-mediated antagonism of Bcl-2 by decreasing the expression of proteins such as Mcl-1, whose translation is cap-dependent...Pt 31 (post-alloHSCT relapsed AML with FLT3-ITD) who had persistent disease after gilteritinib achieved an MRD-negative CRi, pending 2nd alloHSCT... VenPegC is a novel regimen that can induce complete remission in some heavily pretreated R/R AML patients, even with previous exposure to Ven. Pts with RUNX1 mutation, whose translation depends on pheIF4E, may benefit further from this regimen.

P1, N=27, Active, not recruiting, University of Maryland, Baltimore | Recruiting --> Active, not recruiting

P1, N=62, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2022 --> Dec 2024 | Trial primary completion date: Dec 2022 --> Dec 2024

Ven-PegC is a well-tolerated regimen with a novel metabolically-targeted mechanism of action. Early efficacy results in patients with poor prognosis R/R AML, a population with very limited treatment options, has been very promising. A clear correlation between the dose of PegC administered and the reduction in plasma Gln was observed.

P1, N=30, Recruiting, University of Maryland, Baltimore | Trial completion date: Jul 2023 --> Sep 2025 | Trial primary completion date: Apr 2023 --> Sep 2024

The Ven-PegC combination at the lowest dose of PegC administered, produced an MRD negative CRh in one patient and a transient substantial reduction in bone marrow blast count in another, both associated with decreases in plasma Gln levels. The study is ongoing.

We validated the observed changes in gene/protein expression in vitro and confirmed our cell line-based studies in the bone marrow of an AML PDX model after Ven-PegC treatment. These results support examining alterations in the translatome post-chemotherapy to offer insight into drug mechanism of action and to inform future therapeutic decisions.

The study is currently open at the University of Maryland Greenebaum Comprehensive Cancer Center. ClinicalTrials.gov Identifier is NCT04666649.

P1, N=30, Recruiting, University of Maryland, Baltimore | Not yet recruiting --> Recruiting | Trial completion date: Jul 2022 --> Jul 2023 | Trial primary completion date: Apr 2022 --> Apr 2023

P1, N=30, Not yet recruiting, University of Maryland, Baltimore