On August 1, 2022 Aileron Therapeutics (Nasdaq: ALRN), a chemoprotection oncology company that aspires to make chemotherapy safer and thereby more effective to save more patients’ lives, reported its strategy to strengthen the company’s Phase 1b chemoprotection trial of ALRN-6924 in patients with p53-mutated breast cancer (Press release, Aileron Therapeutics, AUG 1, 2022, View Source [SID1234617204]).
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The Phase 1b, open-label, single-armi, multicenter trial is designed to evaluate the safety, tolerability and chemoprotective effect of ALRN-6924 in up to 24 patients with p53-mutated breast cancer undergoing either neoadjuvant or adjuvant treatment with docetaxel, doxorubicin and cyclophosphamide, also known as TAC. The primary endpoints are duration and incidence of severe neutropenia (Grade 4) in cycle 1. Secondary endpoints include the chemoprotective effect of ALRN-6924 on chemotherapy-induced alopecia, as well as other hematologic and non-hematologic toxicities. TAC will be administered every 3 weeks for 4 to 6 cycles based on investigators’ discretion. ALRN-6924 will be administered at 1.2 mg/kg on 3 consecutive days in each treatment cycle, Days 0, 1 and 2, while chemotherapy will be administered on Day 1.
"Our team has worked methodically and expeditiously to modify the Phase 1b breast cancer trial in order to enhance our opportunity to demonstrate a robust chemoprotective effect of ALRN-6924 in patients with p53-mutated breast cancer. The evidence-based modifications we are implementing reflect key, collective learnings from our healthy volunteer study, as well as our non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) clinical trials. We are also expanding the eligibility criteria and plan to activate additional sites in additional countries, which we believe will help ensure we are able to recruit the targeted number of patients in a timely and cost-efficient manner," said Manuel Aivado, M.D., Ph.D., President and Chief Executive Officer at Aileron.
Dr. Aivado continued, "We have been closely evaluating operations and have successfully identified cost efficiencies that we’ve already begun to implement. With our decision to cease enrollment in our NSCLC trial last month, and the cash preservation measures we have identified, we believe that our cash resources will now fund our continued operations through the end of the first quarter of 2024. We expect that this will allow us to get to topline readouts for the breast cancer trial next year and if warranted by the trial results, to initiate preparation for a potential pivotal trial."
Nashat Gabrail, M.D., founder of the Gabrail Cancer Center in Canton, Ohio, President of Innovative Community Oncology Practices (ICOP), and the U.S. lead investigator in the ALRN-6924 breast cancer trial commented, "We are excited to continue our participation in this important clinical trial of ALRN-6924 in patients with p53-mutated breast cancer, and we fully support the protocol enhancements. Protecting cancer patients from chemotherapy-induced toxicities remains a critical unmet need. For bone marrow toxicities, such as neutropenia, existing treatments are often not effective and are associated with significant drawbacks. For other side effects, such as alopecia, there currently are no pharmacological options. We look forward to the continued clinical investigation of this potentially transformative therapy to prevent multiple chemotherapy-induced side effects and help patients fight cancer more effectively."
The Gabrail Cancer Center is part of the Sargon Research network, comprising community oncology practices throughout the U.S., whose goal is to drive critical oncology research in the community oncology setting. Five of the Sargon Research network sites, in addition to the Gabrail Cancer Center, will participate in the Aileron breast cancer trial.
Key Enhancements to ALRN-6924 Breast Cancer Trial Design and Study Conduct
Increase the ALRN-6924 dose from the previous 0.3 mg/kg and 0.6 mg/kg dose levels to 1.2 mg/kg with the goal of extending duration of cell cycle arrest. In recently generated data from Aileron’s Phase 1 pharmacology study of ALRN-6924 in healthy human volunteers, higher ALRN-6924 dose levels yielded longer-lasting pharmacodynamic (PD) effects. Specifically, the PD data demonstrated that serum levels of MIC-1 were correlated with bone marrow p21, which is a marker for cell cycle arrest. Based on these findings, Aileron believes that prolonged elevation of serum levels of MIC-1 at higher ALRN-6924 dose levels may result in more durable cell cycle arrest.
Andres Brainsky, M.D., Vice President of Clinical Development at Aileron, commented, "While the ALRN-6924 0.3 mg/kg dose demonstrated protection against topotecan-induced hematologic toxicities in patients enrolled in our SCLC trial, based on the data we now have in hand, we believe a higher dose level should provide more durable cell cycle arrest and, therefore, more durable chemoprotection against certain chemotherapies, including TAC. Moreover, the ALRN-6924 1.2 mg/kg dose was well tolerated and demonstrated a robust chemoprotective effect on hematologic toxicities when co-administered with topotecan to SCLC patients daily for 5 consecutive daysii, giving us confidence in the tolerability of this dose level for the breast cancer trial."
Change from an exploratory primary composite endpoint across cycles to an established primary endpoint in cycle 1. In a recent interim analysis of Aileron’s NSCLC trial, ALRN-6924-treated patients completed more cycles of chemotherapy than placebo-treated patients. 45% (5/11) of patients on ALRN-6924 completed 6 planned cycles of chemotherapy versus only 11% (1/9) of patients on placebo. With each cycle of chemotherapy, patients are at risk of experiencing toxicities. The higher number of cycles in the ALRN-6924 arm introduced an imbalance between the ALRN-6924 and placebo arms that resulted in a bias against ALRN-6924 on the composite primary endpoint in the NSCLC trial, which evaluated toxicities in up to 6 cycles. Limiting the primary endpoint to an evaluation of severe neutropenia exclusively in cycle 1 eliminates a confounding factor that may result from assessing toxicities across multiple treatment cycles.
Utilize a chemotherapy regimen that enables the evaluation of protection against severe hematologic toxicities in cycle 1. Previous data has shown that, despite prophylactic administration of G-CSF products (filgrastim or pegfilgrastim), up to 75% of breast cancer patients receiving TAC still experience severe neutropenia (Grade 4) in cycle 1.iii Patients in the ALRN-6924 breast cancer trial will not be administered prophylactic G-CSF products in cycle 1, which we expect would increase the likelihood that these patients would experience severe neutropenia in cycle 1 if they were not receiving ALRN-6924.
In addition to a high rate of severe neutropenia, TAC chemotherapy, specifically docetaxel, is also associated with a high rate of alopecia – approximately 90% of patients treated with this chemotherapy experience hair loss. (The exact rate of chemotherapy-induced alopecia specific to cycle 1 is unknown.) Thus, the breast cancer trial will also enable the evaluation, across treatment cycles, of ALRN-6924’s ability to prevent chemotherapy-induced alopecia.
Align the trial design with clinical and regulatory precedents. The use of TAC and a primary endpoint of duration of severe neutropenia in cycle 1 have been used in pivotal trials supporting the approval of multiple supportive care drugs indicated to prevent neutropenia; all of these trials were conducted in breast cancer. Each of these drugs was approved for all cancers outside of myeloid malignancies on the basis of these pivotal trials in breast cancer.iv
Expand eligibility to patients with p53-mutated breast cancer receiving adjuvant or neoadjuvant chemotherapy. The expanded eligibility criteria is intended to enable a larger number of patients with p53-mutated breast cancer to be considered for inclusion in the trial. Several of the clinical and regulatory precedents also included both neoadjuvant and adjuvant treatment settings.v
Expand number of sites. Aileron plans to expand the number of sites in the trial, including opening sites in additional countries. Targeted sites will include those that have enrolled breast cancer patients in previously conducted studies evaluating TAC.