A phase Ib study of the combination of alisertib (Aurora A kinase inhibitor) and MLN0128 (dual TORC1/2 Inhibitor) in patients with advanced solid tumors, final expansion cohort data.
Authors: Davis S. Lindsey , Leal Alexis Diane , Messersmith Wells A. , Lieu Christopher Hanyoung , Lam Elaine T. , Corr Bradley , O'Bryant Cindy L. , Serkova Natalie Julie , Pitts Todd , Diamond Jennifer Robinson 
Published: June 2022

3112 Background: In prior work, senescence and up-regulation of genes in the PI3K/AKT/mTor pathway were observed in patient-derived xenograft models treated with alisertib to resistance, and tumor growth inhibition was observed when MLN0128 (sapanisertib) was added to alisertib. In a previously reported dose escalation cohort of patients with advanced solid tumors treated with the combination of alisertib and MLN0128, the maximum tolerated dose (MTD) was alisertib 30mg BID days 1-7 of a 21-day cycle and MLN0128 2mg daily on a continuous schedule. Presented here are final results from the dose expansion portion of this clinical trial. Methods: Three cohorts of patients were treated with the combination at the MTD. Patients with advanced solid tumors, refractory to standard therapy, were assigned to either single-agent treatment with alisertib (Group 1) or MLN0128 (Group 2) on days 1-7 of Cycle 1. For the remainder of the study, patients received combination treatment. Group 3 enrolled patients with refractory pancreatic adenocarcinoma who were treated with standard dosing of the combination. Biopsies were performed in Groups 1 and 2 prior to treatment initiation and after both the single-agent lead-in and 7 days of combination treatment, with assessment of pharmacodynamic markers. Functional imaging was performed pre-treatment and after Cycle 1. Results: A total of 31 patients with refractory cancers were treated. Group 1 included patients with breast (5), colorectal (2), ovarian (2), and pancreatic (1) cancers. Group 2 included patients with breast (4), colorectal (2), pancreatic (2), uterine (1), and kidney (1) cancers. Eleven patients with refractory pancreatic cancer were treated in Group 3. Median time on study was 11.6 weeks in Group 1, 6 weeks in Group 2, and 9 weeks in Group 3. One partial response was documented in Group 1. One patient with pancreatic cancer in Group 1 continued on study for 47 weeks, and another pancreatic cancer patient in Group 3 continued on study for 28 weeks. Toxicity was similar across cohorts, with mucositis, fatigue, hyperglycemia and neutropenia reported as most common. Biopsy results were significant for increased apoptosis and tumor-infiltrating immune cells noted in tissues from 4 patients treated with the MLN0128 lead-in. Decreased F18-FDG uptake on PET/CT, often with increased ADC values in diffusion MRI, was observed in metastatic liver lesions in 4 patients after Cycle 1. Conclusions: In an expansion cohort of 31 patients treated with the combination of MLN0128 and alisertib at the previously defined MTD, treatment was tolerable with an expected toxicity profile. Prolonged stable disease was observed in 2 patients with pancreatic cancer. Increased apoptosis and tumor-infiltrating immune cells were noted in tissues from patients treated with a lead-in of MLN0128. Clinical trial information: NCT02719691.