Phase 2 evaluation of the nilotinib-paclitaxel combination in patients with rare solid tumors: Rapid analysis and response evaluation of combination anti-neoplastic agents in rare tumors trial 1 (RARE CANCER 1).

3015 Background: Rare tumors constitute a heterogeneous group of cancers with limited treatment options and poor outcomes. To address the need for novel therapeutic options in this challenging population, patient-derived xenograft models of rare cancers were developed to screen combinations of anticancer agents. Based on these preclinical data, the NCI Developmental Therapeutics Clinic designed a series of phase 2 clinical trials to assess promising novel combination therapies in patients (pts) with rare tumors. RARE1—the first trial in this series—evaluates the nilotinib-paclitaxel combination, for which a preceding phase 1 study (NCT02379416) recently identified the recommended phase 2 dose (RP2D) and promising clinical activity, including confirmed partial responses (PR) in 3 pts (2 adult granulosa cell ovarian tumors [AGCOT], 1 endometrial cancer) and 1 unconfirmed PR (anal cancer). Given this clinical experience and preclinical activity in rare tumor models, RARE1 (NCT04449549) aims to evaluate the response and mechanism of action of the nilotinib and paclitaxel combination in rare, refractory solid tumors. Methods: Pts with rare tumors meeting the RARECARE definition were treated at the RP2D: nilotinib 300 mg orally twice a day and paclitaxel 80 mg/m 2 IV on days 1, 8, and 15 in 28-day cycles. Response was assessed by RECIST v1.1. Tissue biopsies and research blood were collected at multiple timepoints for pharmacodynamic and genomic analyses. Results: This study enrolled 31 pts of diverse rare cancers as of the data cut-off. Of the 30 evaluable pts, 2 (7%) had confirmed PRs: 1 Ewing sarcoma and 1 ovarian clear cell cancer, completing 12 and 11 cycles (C) on study, respectively. Stable disease (SD) was the best response in 15 pts (50%), of which 5 pts (17%) had prolonged SD: 1 AGCOT (23+ C), 1 testicular embryonal rhabdomyosarcoma (22 C), 1 non-uterine leiomyosarcoma (21 C), 1 salivary gland (12 C), and 1 ampullary adenocarcinoma (6 C). Overall, the median number of cycles completed is 2 (range 0 - 23) and the median progression free survival is 3.8 months. No unexpected treatment-related adverse events have occurred. No grade 3-4 peripheral neuropathy has been observed. Conclusions: Preliminary clinical outcomes for the nilotinib-paclitaxel combination in patients with rare tumors showed encouraging signals of activity. To facilitate further evaluation of response and the underlying mechanism of action for this combination, enrollment now focuses on the 4 tumor types that have previously demonstrated response: Ewing sarcoma, ovarian clear cell carcinoma, AGCOT, and anal cancers. Pharmacodynamic and genomic analyses are also ongoing. This project has been funded in whole or in part with federal funds from the NCI, NIH, under contract HHSN261201500003I. Clinical trial information: NCT04449549 .