CCTG IND.231: A phase 1 trial evaluating CX-5461 in patients with advanced solid tumors

Abstract

Background: G-quadruplexes are secondary DNA structures that reversibly form in guanine-rich regions that can lead to replication fork collapse and double-stranded DNA breaks. Preclinical work by our group has demonstrated that CX-5461 can stabilize G-quadruplexes, resulting in synthetic lethality in BRCA1/2 deficient cell lines and xenograft models. Methods: We conducted a phase I study of 7 dose levels of CX-5461 (DLs: 50, 100, 150, 200, 250, 325, 475 mg/m2) administered intravenously on days 1 and 8 of a 4-week cycle in patients with advanced solid tumors with a PS 0-2 and adequate organ function using a 3+3 design. Patients were treated until disease progression. The primary objective was the determination of RP2D. The DLT evaluation period was cycle 1 and AEs needed to be maximally managed (i.e diarrhea, phototoxicity, nausea/vomiting) to be considered a DLT. Secondary objectives include ORR (RECIST 1.1), PK, and toxicity (CTCAEv4.0). Results: As of December 18th 2017, 24 patients have been treated (DL 0-3: 4 per cohort; DL 4-5: 3 per cohort; DL6: 2 enrolled). Twenty-four patients are evaluable for toxicity and PK while 20 patients are evaluable for response. Of the evaluable patients (n=24), the median age is 56 with 16 patients having 3 or more prior regimens for their disease. There have been no DLTs observed to date. There were two treatment-related non- DLT grade 3 photosensitivity events (DL0, DL4) that were reversible and were secondary to lack of photo-protective measures. Treatment-related grade 1-2 AEs >10% were mucositis, nausea, dry eyes and hand-foot syndrome. Early PK results have shown nonproportional increases for Cmax and AUC24,1. In terms of best response, one BRCA2 patient at DL2 obtained a PR with a 67% reduction in disease burden for a duration of 9.6 months. Five patients (4 BRCA1/2, 1 Li Fraumeni) obtained SD as best response. Conclusions: CX-5461 is tolerable with preventable photosensitivity being the main toxicity observed. The RP2D has not yet been reached. Preliminary activity for CX- 5461 has been observed in patients with HR-deficient tumors. Alternative dosing schedules are being evaluated. A phase II study for breast cancer patients with germline HR deficiency or tumor HRD aberrations is planned.