Abstract B021: A phase 1 dose escalation study of lapatinib and paclitaxel in recurrent ovarian cancer

Abstract Objectives: Paclitaxel is a commonly used chemotherapy agent for women with recurrent ovarian cancer; however, its efficacy is limited by the development of ABCB1-mediated drug resistance. Lapatinib is an EGFR and HER2 inhibitor approved for treating breast cancer but without single agent activity in ovarian cancer. Lapatinib is also an ABCB1 inhibitor, and we hypothesize that lapatinib overcomes ABCB1-mediated paclitaxel resistance in previously treated ovarian cancer patients. Methods: This phase 1 dose escalation study used a Bayesian optimal interval (BOIN) design to determine the recommended phase 2 dose of the combination of paclitaxel and lapatinib. Secondary endpoints were to assess adverse effects, determine the objective response rate, and assess pharmacokinetics. Eligible patients had ovarian, peritoneal, or fallopian tube cancer and had recurred within 12 months of platinum-based chemotherapy. Patients received three weekly paclitaxel doses of 80 mg/m2 in 28-day cycles. Patients were pretreated with escalating doses of lapatinib twice daily in the 48 hours preceding paclitaxel for up to 3 cycles starting with the second paclitaxel dose of cycle 1. Three lapatinib doses were evaluated, escalating from 750 to 2000 mg orally twice daily. Results: Fifteen of nineteen patients were eligible and evaluable for toxicity and 12 have completed study therapy and are evaluable for response. All were female, the median age was 66, and the median number of prior therapies was 3. Three patients were treated at dose level 1, six at dose level 2, and seven at dose level 3. One patient treated at dose level 3 was not evaluable for dose-limiting toxicity (DLT). There was one DLT in dose level 2 (diarrhea) and another in dose level 3 (elevated liver function tests), with a posterior DLT estimate of 0. 17, 95% Credible Interval of (0. 01, 0. 53) for dose level 3. The most common grade 1-2 adverse effects were diarrhea (75%) and neutropenia (43. 8%). Among the 12 patients evaluable for efficacy, there were two partial responses and one stable disease for an objective response rate of 16% and a disease control rate of 25% in this heavily pretreated population. Conclusion: The combination of paclitaxel and lapatinib is safe and with an efficacy signal. The recommended phase 2 dose of the combination is 80 mg/m2 of weekly paclitaxel combined with 2000 mg bid of lapatinib two days before the paclitaxel dose. Citation Format: Connie D. Cao, Joseph R. McCorkle, Donglin Yan, Rani Jayswal, Rachel W. Miller, Charles S. Dietrich, Frederick R. Ueland, Jill M Kolesar. A phase 1 dose escalation study of lapatinib and paclitaxel in recurrent ovarian cancer abstract. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84 (5 Suppl₂): Abstract nr B021.