P527: PHASE 1 TRIAL OF PEGCRISANTASPASE IN COMBINATION WITH VENETOCLAX IN ADULTS WITH RELAPSED OR REFRACTORY ACUTE MYELOID LEUKEMIA (R/R AML) - SAFETY, EFFICACY AND PK/PD IN THE FIRST TWO COHORTS

Abstract

Background: Glutamine depletion induced by Erwinia asparaginases including pegcrisantaspase (PegC) downregulates the mTOR/p70S6K pathway and inhibits 4EBP1 phosphorylation. We recently found that the combination of PegC with the Bcl-2 inhibitor venetoclax (Ven) has strong in vitro and in vivo activity in poor-prognosis AML, mediated by enhancement of eIF4E-4EBP1 interaction on the cap-binding complex and decreasing protein synthesis. We hypothesized that Ven-PegC treatment will be safe and effective in the treatment of R/R AML. Here we report the results from the first two cohorts of a phase 1 trial of Ven-PegC in adults with R/R AML. Aims: The primary objective is to estimate the maximum tolerated dose and to determine the regimen-limiting toxicities (RLT) of Ven-PegC. The exploratory endpoints include plasma amino acids levels 1- and 2-weeks post-PegC administration. Methods: This is an open-label phase 1b clinical trial (NCT04666649) of daily oral Ven in combination with biweekly out-patient IV PegC in 28-day cycles that will be administered to 4 cohorts (Table 1A) based on a standard 3 + 3 design. Results: Eight patients (pts) were enrolled into the first two cohorts; 7 received ≥ 1 dose of PegC and one dropped out before receiving study drugs. Pts’ characteristics are shown in Table 1B. Median age was 66 (59-76) years; two (29%) were female; six (86%) had adverse-risk AML by ELN classification; and four (57%) had complex karyotypes. Pharmacokinetic (PK) and pharmacodynamic (PD) data are available for 5 pts; all pts achieved a nadir plasma asparaginase activity > 0.1 IU/mL during cycle 1 (3/3 in cohort 1 within 3 weeks and 2/2 in cohort 2 within 10 days). Mean plasma amino acid levels (µmol/L) at baseline were: asparagine (Asn) 29 (17-38), glutamine (Gln) 421 (384-465), glutamate (Glu) 59 (22-103), serine (Ser) 66 (49-80) and glycine (Gly) 203 (166-207). All pts achieved an Asn level of 0 by day 7; Asn remained undetectable throughout the study. Plasma Gln (µmol/L) reduction from baseline occurred in 4/5 (80%) pts within cycle 1: pt4 423→273 (Day15), pt5 446→86 (Day28), pt6 467→216 (Day22), pt7 388→156 (Day8), pt10 420→395 (Day10). Plasma Glu levels increased in all pts, indicating conversion of Gln to Glu by PegC. Interestingly, plasma levels of Ser increased 1.5-2-fold at the nadir of plasma Gln (Figure 1A-C, maximum amino acid changes after Ven-PegC). Seven pts from cohorts 1 (4 pts) and 2 (3 pts) who received at least one dose of Ven-PegC were included in analysis of toxicity and efficacy, with data cutoff February 26, 2022 (Table 1B). No RLT has been observed. In cohort 1, pt2 died before completing cycle 1 due to septic shock and delay in seeking medical care, pt4 died of AML progression. In cohort 2, pt7 had progressive disease after cycle 1, pt9 opted for comfort care before evaluation of response, and pt10 died of AML progression, In cohort 1, pt6 achieved measurable residual disease (MRD)-negative complete remission with partial hematologic recovery (CRh) and proceeded to allogeneic hematopoietic stem cell transplant (allo-HSCT) after 3 cycles of Ven-PegC, and bone marrow blasts in pt5 decreased from 78% to 9% after cycle 1. These two pts had the lowest plasma Gln levels (103 [pt6, cycle2 day29] and 86 [pt5, cycle1 day28]). Image:Summary/Conclusion: No RLT has been observed following Ven-PegC in cohorts 1 or 2. 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.