A Phase 1 Dose Escalation of Lapatinib and Paclitaxel in Recurrent Ovarian Cancer

Objective: The development of ABCB1-mediated resistance limits the clinical efficacy of paclitaxel. Lapatinib is a small-molecule reversible tyrosine kinase and ABCB1 inhibitor that could prevent resistance. Our objective was to de-termine a recommended phase 2 dose (RP2D) of the combination of paclitax-el and lapatinib. Methods: A phase 1 dose-escalation study utilizing a Bayesian optimal interval (BOIN) design in recurrent ovarian cancer patients. Patients were pretreated with pulsed lapatinib in the 48 hours preceding weekly paclitaxel (80 mg/m2) in 28-day cycles for up to 3 cycles. We evaluated three lapatinib doses, escalating from 750 to 2,000 mg orally twice daily. Results: Sixteen patients were eligible and evaluable for efficacy and toxicity. Patients received a median of three prior therapies. Three patients were treated at dose level 1, six at dose level 2, and seven at dose level 3. There was one dose-limiting toxicity (DLT) in dose level 2 (diarrhea) and another in dose level 3 (neutropenia), with a posterior DLT estimate of 0.17, 95% credible in-terval of (0.01, 0.53) for dose level 3 based on isotonic regression. The most common grade 1-2 adverse effects were diarrhea (87.5%), leukopenia (56.3%), and anemia (50%). One (6.25%) patient had a complete response, and 7 (43.75%) patients had partial responses for an overall response rate (ORR) of 50%. The clinical responses are supported by a significant decreasing trend in CA 125 over six cycles (p=0.0001). Among the seven patients treated at the RP2D, the ORR was 71.4%. Conclusions: The combination of paclitaxel and lapatinib is safe and with an efficacy signal. The RP2D is weekly paclitaxel 80 mg/m2 combined with lapatinib 2,000 mg twice daily two days before the paclitaxel dose. This trial was registered at ClinicalTrials.gov ID: NCT04608409.