On June 29, 2022, Aileron Therapeutics, Inc. (“Aileron” or the “Company”) announced interim data from its Phase 1b randomized, double-blind, placebo-controlled clinical trial evaluating ALRN-6924 as a chemoprotective agent in patients with p53-mutated non-small cell lung cancer, or NSCLC, undergoing treatment with first-line carboplatin plus pemetrexed with or without immune checkpoint inhibitors, and announced plans to stop further enrollment in the NSCLC trial. Aileron plans to apply key learnings from the interim analysis to strengthen its Phase 1b clinical trial to evaluate ALRN-6924 as a chemoprotective agent in patients with p53-mutated ER+/HER2- neoadjuvant breast cancer undergoing treatment with doxorubicin plus cyclophosphamide and docetaxel.
The interim analysis consisted of the first 20 patients randomized to ALRN-6924 0.3 mg/kg plus carboplatin/pemetrexed (n=11) or placebo plus carboplatin/pemetrexed (n=9).1,2 ALRN-6924-treated patients were able to stay on chemotherapy treatment longer, completing 93% of the first 4 cycles of carboplatin/pemetrexed administered compared to 78% on placebo.2,3 This imbalance of completed cycles between the treatment arms may have introduced a bias against ALRN-6924 on the composite primary endpoint. The imbalance increases further when looking at percentages of patients completing 6 cycles of treatment (79% on ALRN-6924 versus 57% on placebo). This is reflected in the progression free survival, which was 4.6 months in the ALRN-6924 arm versus 3.2 months in the placebo arm.
The composite primary endpoint consisted of the proportion of treatment cycles free of Grade ≥3 neutropenia, Grade ≥3 thrombocytopenia, Grade ≥3 anemia, blood transfusions, and the use of growth factors, as well as dose reductions or dose delays within the first 4 cycles of treatment. ALRN-6924-treated patients demonstrated 56% of cycles free from these Grade ≥3 hematologic toxicities and related events compared to 50% on placebo.
While the ALRN-6924 0.3 mg/kg dose previously demonstrated protection against topotecan-induced hematologic toxicities in Aileron’s small cell lung cancer trial, Aileron believes that a higher dose level could provide more durable cell cycle arrest and, thus more chemoprotection against certain chemotherapies, including carboplatin/pemetrexed. This is supported by the recently generated data from the company’s healthy volunteer study. In that study, serum MIC-1 levels were measured as an indicator of the duration of effect of ALRN-6924, including the duration of cell cycle arrest. Increasing dose levels of ALRN-6924 elicited more durable p53 activation, which correlates with cell cycle arrest in the bone marrow. Cell cycle arrest is a basis for protecting cells from chemotherapy.
The learnings from the NSCLC interim analysis create an opportunity for Aileron to take several steps to strengthen the Phase 1b breast cancer trial, including revising the primary endpoint to duration of severe neutropenia in cycle 1 and changing the chemotherapy regimen to a simultaneous administration of doxorubicin plus cyclophosphamide and docetaxel, referred to as TAC. Additionally, the Company plans to modify the dosing strategy for the breast cancer trial and will not further enroll additional patients in the ongoing 0.3 mg/kg and 0.6 mg/kg dose cohorts.
| 1 | One patient was randomized to the placebo arm, but treatment was initiated with ALRN-6924 due to a dispensing error, and the decision was made to maintain that patient on ALRN-6924. |
| 2 | The composite primary endpoint was designed to evaluate the first 4 cycles of chemotherapy, which is standard of care for patients receiving checkpoint inhibitors (CPI). Given that none of the 20 patients in the interim analysis received a CPI, the interim analysis also included results for all 6 cycles of chemotherapy, which is standard of care for patients not receiving CPI. |
| 3 | As of the interim analysis data cut-off of June 16, 2022, 3 patients on each arm included in this interim analysis remained on treatment. |
