A phase Ib trial of alpelisib and weekly cisplatin in patients with solid tumor malignancies.
Authors: Tsang Erica S. , Aggarwal Rahul Raj , Dhawan Mallika Sachdev , Pacaud Romain , Fattah Delaire , Thomas Scott , Grabowsky Jennifer A. , Munster Pamela N. 
Published: June 2021

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Background: The PI3K pathway may represent a mechanism to overcome cisplatin resistance, particularly in human papilloma virus (HPV)-associated tumors. We conducted a phase Ib trial of alpelisib and cisplatin for patients with solid tumor malignancies and HPV-associated tumors in the dose expansion cohort. Methods: Patients with advanced solid tumors were enrolled in this phase Ib open label study (NCT02620839). Dose escalation followed standard 3+3 design. Two different weekly doses of cisplatin (30 and 35 mg/m2) were evaluated with escalating doses of alpelisib, administered daily during a 21-day cycle. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase II dose. Secondary objectives included determining the objective response rate (ORR), median progression-free survival (PFS), and characterizing the safety profile. Results: 23 patients were enrolled in this study between September 2016-August 2018. Median age was 57 years (range 37-83), and 57% of patients were female. Tumor sites included prostate (22%), cervical (13%), endometrial (13%), breast (9%), anal (9%), penile (9%), and other (26%). 91% of patients had > 3 lines of prior therapy, with 74% who previously received a platinum. Median duration of treatment was 8.7 weeks (range 1-57.5). The MTD was alpelisib 250 mg daily with weekly cisplatin 30 mg/m2. 9 patients discontinued the study during cycle 1 due to an adverse event without progression. There were 3 DLTs, all of which were grade 4 hyperglycemia: 2 at alpelisib 250 mg and 1 at alpelisib 300 mg. Treatment-related grade 3-4 toxicities included hyperglycemia (13%), rash (13%), neutropenia (9%), anemia (4%), thrombocytopenia (4%), neuropathy (4%), and diarrhea (4%). Any grade nephropathy occurred in 17%. Dose reductions and/or interruptions were required in 61% of patients. There was a significant decrease in administered cisplatin dose intensity (33.8%) with a planned weekly cisplatin dose of 35 mg/m2 and alpelisib 250 mg. In contrast, dose intensity ranged from 55-85% for other dose levels with an intended cisplatin dose of 30 mg/m2. Dose expansion was not conducted due to significant early and cumulative toxicity. Of the 14 patients with post-baseline assessment available, ORR was 29%, with all 4 patients demonstrating partial response and 7 patients (50%) with stable disease. Of the 4 responders, tumor sites included 2 endometrial cancers, cervical neuroendocrine carcinoma, and penile SCC, and 3 were platinum-refractory. Median PFS measured 3.1 months (95% CI 1.3-4.1). 5 of 21 patients had PIK3CA mutations, with no difference in PFS ( p= 0.76). Conclusions: While alpelisib and cisplatin demonstrated responses among patients with solid tumor malignancies, the combined adverse event profile presented significant dose intensity limitations. Future prospective studies are planned using carboplatin and alpelisib to improve the toxicity and tolerability. Clinical trial information: NCT02620839.