On June 29, 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 interim data from its Phase 1b chemoprotection trial of patients with advanced p53-mutated NSCLC undergoing treatment with first-line carboplatin plus pemetrexed with or without immune checkpoint inhibitors (Press release, Aileron Therapeutics, JUN 29, 2022, View Source [SID1234616359]). Aileron plans to stop further enrollment in the NSCLC trial and to apply key learnings from the interim analysis to strengthen the Phase 1b breast cancer trial in accordance with clinical and regulatory precedents.

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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.

"We remain passionate about advancing ALRN-6924 for patients with p53-mutated cancer, and these interim NSCLC findings have significantly helped to clarify our development path toward that goal. We are very encouraged by the finding that ALRN-6924-treated patients were able to complete more cycles of chemotherapy in the NSCLC trial, but unfortunately it also appears that this may have worked against us given the nature of the exploratory composite primary endpoint. The more cycles patients completed the more opportunity they had to experience toxicities. This introduced an imbalance of toxicities between the active and placebo arms and, may have resulted in a bias against ALRN-6924 on the composite primary endpoint," said Manuel Aivado, M.D., Ph.D., President and CEO of Aileron.

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.

Dr. Aivado continued, "By stopping the NSCLC trial, we plan to fully focus our resources on our Phase 1b breast cancer trial to continue our development of ALRN-6924 to protect p53-mutated cancer patients from chemotherapy-induced side effects. Neoadjuvant chemotherapy for breast cancer is associated with frequent severe neutropenia in cycle 1, and we believe this offers a well-established endpoint, which has been used to secure FDA approval of multiple supportive care drugs. This endpoint also obviates any potential imbalance in the number of cycles completed on ALRN-6924 versus placebo. The breast cancer trial also gives us the ability to evaluate protection against alopecia, which occurs in more than 90% of breast cancer patients on neoadjuvant chemotherapy compared to less than 10% of patients receiving carboplatin/pemetrexed."

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 trial and will not further enroll additional patients in the ongoing 0.3 mg/kg and 0.6 mg/kg dose cohorts.

Additional NSCLC Trial highlights (Cycles 1-6)

Of the 83 cycles of carboplatin/pemetrexed administered, Grade ≥3 hematologic toxicities were observed in 25 cycles (30%): 18 cycles with 28 instances4 of hematologic toxicities on ALRN-6924, and 7 cycles with 10 instances of hematologic toxicities on placebo.
One patient receiving ALRN-6924 accounted for 15 of the total 28 Grade ≥3 hematologic instances observed on that arm, or 53%.
Grade 4 events5 were infrequent, occurring in 1 patient on ALRN-6924 and 2 patients on placebo.
5 of 11 patients treated with ALRN-6924 completed 6 planned cycles (45%) versus 1 out of 9 placebo patients (11%).
Frequency of patients experiencing Grade ≥3 hematologic events:
Treatment
(n of patients) Patients with grade≥3
neutropenia
n (%) Patients with grade ≥3
thrombocytopenia
n (%) Patients with grade ≥3
anemia
n (%)
ALRN-6924 (n=11) 5 (45%) 5 (45%) 1 (9%)
Placebo (n=9) 2 (22%) 4 (44%) 2 (22%)

Investor Webcast Details

Aileron will host a conference call and webcast today at 8:00 am ET to discuss these data and the company’s planned strategic prioritization of its breast cancer trial. The conference call can be accessed by dialing 844-838-0770 (United States) or 213-320-2558 (International) with the conference code 3218779. A live webcast may be accessed using the link here, or by visiting the "Events and Presentations" page in the investors section of the Aileron website at www.aileronrx.com. After the live webcast, the event will be archived on the Company’s website for approximately 30 days after the call.