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44O - CCTG IND.231: A phase 1 trial evaluating CX-5461 in patients with advanced solid tumors
- John Hilton (Ottawa, CA)
- John Hilton (Ottawa, CA)
- David W. Cescon (Toronto, CA)
- Philippe Bedard (Toronto, CA)
- Heather Ritter (Kingston, CA)
- Dongsheng Tu (Kingston, CA)
- John Soong (New Taipei City, TW)
- Karen Gelmon (Vancouver, CA)
- Samuel Aparicio (Vancouver, CA)
- Lesley Seymour (Kingston, CA)
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 non-proportional increases for Cmax and AUC24,∞. 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.
Clinical trial identification
NCT02719977
Legal entity responsible for the study
Canadian Cancer Trials Group
Funding
Stand up to Cancer Senhwa Pharmaceuticals
Disclosure
J. Soong: Medical lead at Senhwa Biosciences for CX-5461. Employed by Senhwa Biosciences. S. Aparicio: Consultant with Senwha Biosciences. All other authors have declared no conflicts of interest.