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Drug manufacturer Aileron plans to stop further enrollment into a phase 1b trial (NCT04022876) after the chemoprotective agent ALRN-6924 missed its composite primary end point for patients with advanced p53-mutant non–small cell lung cancer.
Drug manufacturer Aileron plans to stop further enrollment into a phase 1b trial (NCT04022876) after the chemoprotective agent ALRN-6924 missed its composite primary end point for patients with advanced p53-mutant non–small cell lung cancer (NSCLC).1
Treatment with ALRN-6924 allowed those receiving first-line carboplatin plus pemetrexed (Alimta) with or without checkpoint inhibitors to stay on treatment longer. However, the drug did not reduce the rate of grade 3 or greater adverse effects compared with 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,” Manuel Aivado, MD, PhD, president and chief executive officer of Aileron, said in a news release.
The interim analysis consisted of the first 20 patients randomized to 0.3 mg/kg of ALRN-6924 plus carboplatin/pemetrexed (n = 11) or placebo plus carboplatin/pemetrexed (n = 9). ALRN-6924-treated patients completed 93% of the first 4 cycles of carboplatin/pemetrexed administered vs 78% on placebo.
The percentage of patients completing 6 cycles of treatment was 79% on ALRN-6924 vs 57% on placebo. Progression-free survival was 4.6 months and 3.2 months, respectively.
The composite primary end point consisted of the proportion of treatment cycles free of grade 3 or greater neutropenia, thrombocytopenia, and 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 or greater hematologic toxicities and related events vs 50% on placebo.
“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,” Aivado said. “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 end point.”
ALRN-6924 is a first-in-class MDM2/MDMX dual inhibitor designed to activate p53, leading to upregulation of p21, a known inhibitor of the cell replication cycle. ALRN-6924 is the only reported biomarker-driven, chemoprotective agent in clinical development.
“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,” Aivado added.
Based on the interim analysis findings, the company has decided to revise the primary end point of the ongoing phase 1b breast cancer trial to the duration of severe neutropenia in cycle 1. The company also changed the chemotherapy regimen to concurrent administration of doxorubicin plus cyclophosphamide and docetaxel. Additionally, the company plans to adjust the dosing strategy for the trial and will stop further enrollment in the ongoing 0.3 mg/kg and 0.6 mg/kg dose cohorts.
“Neoadjuvant chemotherapy for breast cancer is associated with frequent severe neutropenia in cycle 1, and we believe this offers a well-established end point which has been used to secure FDA approval of multiple supportive care drugs. This end point 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,” Aivado concluded.