NEW YORK – Aileron Therapeutics revealed changes in the protocol for its Phase Ib trial of ALRN-6924 as a chemoprotective agent in patients with p53-mutated breast cancer that will become the primary development path for the drug following disappointing interim results in non-small cell lung cancer.
Aileron stopped enrolling patients in that NSCLC trial in June when an interim analysis showed that the drug was not performing better than placebo on the exploratory composite primary endpoint, which was the proportion of treatment cycles free of certain adverse events grade three or higher. The trial was intended to evaluate whether ALRN-6924 can protect patients with p53-mutated NSCLC from severe toxicities associated with carboplatin or pemetrexed compared to placebo.
The Boston-based company believes the endpoint miss might be a paradoxical result of the drug's efficacy, as patients in the ALRN-6924 arm stayed on treatment longer, completing 93 percent of the first four cycles of carboplatin and pemetrexed compared to 78 percent of those on placebo. As well, patients on ALRN-6924 had improved progression-free survival compared to patients on placebo — 4.6 months versus 3.2 months.
The drug has previously shown protection against hematologic toxicities in NSCLC patients treated with topotecan. Aileron is confident that a breast cancer trial will demonstrate that the drug is effective at preventing chemotherapy-induced side effects. The Phase Ib, open-label, single-arm trial will assess safety, tolerability, and the chemoprotective effects of ALRN-6924 in up to 24 patients with p53-mutated breast cancer who are receiving adjuvant or neoadjuvant therapy with docetaxel, doxorubicin, and cyclophosphamide. The primary endpoints are changes in the duration and incidence of severe neutropenia in the first cycle, which is frequent in this setting. The researchers will also observe the effect of ALRN-6924 on chemotherapy-induced alopecia, which occurs in more than 90 percent of breast cancer patients on neoadjuvant chemotherapy compared to less than 10 percent of patients receiving carboplatin and pemetrexed.
Some of the changes from the previous trial design include the use of a single, well-established endpoint instead of an exploratory composite endpoint, an increased dose of ALRN-6924, and expanded eligibility for patients with p53-mutated breast cancer who are receiving adjuvant or neoadjuvant chemotherapy.
ALRN-6924 activates p53 in normal cells, temporarily arresting their cell cycle. The adverse effects of chemotherapy drugs are related to cell cycle activities, so arresting the cell cycle protects those healthy cells. At the same time, in p53-mutated cancers, the cell cycle is not arrested, so tumor cells would still be vulnerable to the effects of the drugs. While the company is attempting to find the optimal trial design to show a benefit in breast cancer, it believes that ALRN-6924 could have potential as a supportive therapy for all p53-mutated cancers.
In a statement, Aileron CEO and President Manuel Aivado said that the company will be making cuts to extend its cash, and that its resources will now support operations through the end of the first quarter of 2024, long enough to get top-line results from the breast cancer trial and prepare for a potential pivotal trial.