In recent years, significant advances have been made in the management of metastatic colorectal cancer. Traditionally, an improvement in overall survival has been considered the “gold standard”—the most convincing measure of efficacy. However, overall survival requires larger patient numbers and longer follow-up and may often be confounded by other factors, including subsequent therapies and crossover. Given the number of active therapies for potential investigation, demand for rapid evaluation and early availability of new therapies is growing. Progression-free survival is regarded as an important measure of treatment benefit and, compared with overall survival, can be evaluated earlier, with fewer patients and no confounding by subsequent lines of therapy. The present paper reviews the advantages, limitations, and relevance of progression-free survival as a primary endpoint in randomized trials of metastatic colorectal cancer.

Background: G-quadruplexes are secondary DNA structures that reversibly form in guanine-rich regions within DNA. Our group has demonstrated that CX-5461 selectively binds and stabilizes G-quadruplex structures, causing replication fork collapse and double-stranded DNA breaks. In BRCA1/2 deficient cell lines and xenograft models, synthetic lethality was observed. We are conducting a phase I study of CX-5461, a first-in-class G-quadruplex stabilizer, in patients with advanced solid tumors enriching for patients with DNA-repair deficiencies. Methods: We conducted a phase I study of 10 dose levels of CX-5461. The initial 7 dose levels (50, 100, 150, 200, 250, 325, 475 mg/m2) were administered intravenously on days 1 and 8 of a 4-week cycle, while the final 3 dose levels (325, 475 and 650 mg/m2) were administered intravenously on days 1, 8 and 15 of a 4-week cycle. Escalation was performed using a 3+3 design. Eligible patients must have advanced disease, a PS 0-2 and adequate organ function. 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 to be considered a DLT. Secondary objectives include ORR (RECIST 1.1), PK, and toxicity (CTCAEv4.0). Results: As of March 28th, 2019, 40 patients were registered on protocol with 39 patients evaluable for toxicity and 35 patients evaluable for response. 18 of the participants were diagnosed with metastatic breast cancer. Of the evaluable patients, the median age is 53 with 24 patients having 3 or more prior regimens for their disease. There have been no DLTs observed to date. There were 5 treatment-related non-DLT grade 3 photosensitivity events (DL0, DL4, DL7, DL8, DL9) that were reversible and were secondary to lack of photo-protective measures. 3 SAEs were considered related to CX-5461 (photosensitivity of the skin (n=2); photosensitivity of the eyes (n=1). Treatment-related AEs ≥10% were photosensitivity of the skin (59%), photosensitivity of the eyes (21%), mucositis (15%), nausea (44%), hand-foot syndrome (23%), headache (10%) and rash (10%). The RP2D was determined to be 475 mg/m2 on days, 1, 8 and 15 of a 4-week cycle. PK appears dose-proportional for Cmax and AUC24,∞. Of the 40 patients treated on protocol, 34 have discontinued from the study either due to objective progressive disease (n=29), symptomatic progression of disease (n=4) or withdrawal of consent (n=1). In terms of best response, 4 patients, including 3 with breast cancer, have a confirmed PR (2 germline BRCA2, 1 germline BRCA2 VUS, germline PALB2) with an additional 6 patients, including 2 with breast cancer, (4 germline BRCA2, 2 somatic BRCA1/2) with SD as best response for >=4 cycles. Conclusion: CX-5461 is tolerable with preventable photosensitivity being the main toxicity. The RP2D is now identified at 475 mg/m2 on days 1, 8 and 15 of a 4-week cycle. Preliminary activity for CX-5461 has been observed in patients with HR-deficient tumors for both breast cancer and other tumor types. An expansion cohort, with mandatory tumor and skin biopsies, for patients with metastatic breast cancer with confirmed HR deficiency is currently open. Further updates will be provided. Citation Format: John Hilton, Karen Gelmon, David Cescon, Anna Tinker, Derek Jonker, Rachel Goodwin, Scott Laurie, Aaron Hansen, Samuel Aparicio, John Soong, Linda Hagerman, Hongbo Lui, Philippe Bedard, Kathleen Pritchard, Dongsheng Tu, Lesley Seymour. Canadian cancer trials group trial IND.231: A phase 1 trial evaluating CX-5461, a novel first-in-class G-quadruplex stabilizer in patients with advanced solid tumors enriched for DNA-repair deficiencies [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD4-02.

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The MTD of intercalated BMS-609514 combined with PC was 150 mg/day. This approach was tolerable with manageable toxicities and antitumor activity in a variety of solid tumor types.