Abstract 1654P
Background
ALRN-6924 is a cell-permeating, stabilized alpha-helical peptide that binds with high affinity to endogenous p53 inhibitors MDM2 and MDMX. In cancer patients with tumors harboring p53 mutations, ALRN-6924 can selectively induce transient cell cycle arrest in normal cells with wildtype p53, thus allowing chemotherapy to preferentially target cancer cells.
Methods
A phase Ib/II study was conducted in ED SCLC patients with ECOG PS 0-2 receiving treatment with five daily doses of topotecan (topo). ALRN-6924 was given either 24 hr or 6 hr prior to each 1.5 mg/m2 topo infusion. The objective was to evaluate ALRN-6924 at different dose levels and two treatment schedules for the mitigation of chemotherapy-induced myelosuppression. Hematology assessments occurred on treatment days 1-5 and on day 12 of each 21-day therapy cycle, with laboratory values coded as AEs based on NCI CTC v5.0.
Results
39 (38 evaluable) patients with ED SCLC were enrolled. 31 patients were treated on the 24 hr schedule: 0.2 mg/kg (N=4), 0.3 mg/kg (N=16), 0.6 mg/kg (N=5) and 1.2 mg/kg (N=6). 7 patients were treated with 0.3 mg/kg of ALRN-6924 at 6h prior to topo. Median patient age was 67 years, 74% males, ECOG PS 0 58%, baseline LDH ≥ULN 55%, chemosensitive population 50%. Median number of completed topo treatment cycles was 3. 13% of patients required topo dose reduction. No patients reported NCI CTC Grade ≥3 events of nausea, vomiting, diarrhea; 5% had Grade 3 fatigue. The 0.3 mg/kg ALRN 6924 dose level 24 hr prior to topo showed the most favorable chemoprotection results, with NCI CTC Grade 3/4 anemia and thrombocytopenia limited to 19% and 50% of patients, respectively, and a 44% rate of Grade 4 neutropenia. Those results compare favorably to recent historical results of 63%, 70% and 76%, respectively (Hart et al., Adv Ther 2020). None of the patients treated at the 0.3 mg/kg ALRN 6924 dose level had a related SAE; 6% required RBC and platelet transfusions (historical result: 41% and 36%, respectively).
Conclusions
ALRN-6924 showed encouraging evidence of chemoprotection in SCLC patients treated with topotecan. No significant differences between two schedules were observed. The RP2D for ALRN-6924 is 0.3 mg/kg.
Clinical trial identification
2019-001848-21.
Editorial acknowledgement
Legal entity responsible for the study
Aileron Therapeutics Inc.
Funding
Aileron Therapeutics Inc.
Disclosure
C. Caldwell: Financial Interests, Personal, Full or part-time Employment: Aileron Therapeutics. D. Ferrari: Financial Interests, Personal, Full or part-time Employment: Aileron Therapeutics. A. Annis: Financial Interests, Personal, Full or part-time Employment: Aileron Therapeutics. V. Vukovic: Financial Interests, Personal, Full or part-time Employment: Aileron Therapeutics. All other authors have declared no conflicts of interest.