Abstract CT066: First-in-human phase I trial of the oral PLK4 inhibitor CFI-400945 in patients with advanced solid tumors
Bibliographic record
Abstract
Abstract Background: CFI-400945 is a first-in-class, potent, selective, orally active inhibitor of Polo-like kinase 4 (PLK4) (Ki = 0.26 nM), a conserved master regulator of centriole duplication that is important for maintenance of genomic integrity. In preclinical studies, CFI-400945 demonstrated robust anti-tumor activity, including durable complete tumor regression, in a large number of patient-derived xenograft models from multiple tumor types (breast, ovarian, pancreas, prostate carcinomas; some derived from heavily pre-treated patients). The objectives of this first-in-human phase I trial are to establish safety, tolerability, pharmacokinetics, and recommended phase II dose (RP2D) of CFI-400945. Methods: Patients with advanced solid tumors age >18 years, with ECOG performance status of 0-1, adequate organ function and RECIST-measurable disease progressing on standard treatments are eligible. Dose escalation follows a standard 3+3 design, with a starting dose of 3mg once daily continuous oral dosing based upon preclinical data and a severely toxic dose to 10 percent (STD10) in rats of 3 mg/kg. The primary endpoint is the incidence of dose limiting toxicities (DLTs) during the first cycle. Safety assessments using CTCAE version 4.03 criteria are performed weekly during the first three cycles and then every two weeks. Response assessments are performed every two cycles. Results: From April/14 to December/15, 31 patients were enrolled across eight pre-defined dose levels (3, 6, 11, 16, 24, 32, 48 and 72 mg). No DLT events have been observed. Dose escalation at 96mg is currently ongoing. The most frequent treatment-related adverse events (trAEs) include fatigue (24%), diarrhea (17.2%), nausea (17.2%), decreased appetite (13.8%) and vomiting (6.9%). All trAEs were grade 1 or grade 2. Fifteen serious adverse events (SAEs) have occurred in 9 patients, all considered unrelated to CFI-400945 treatment. Preliminary PK results estimate a half-life of about 10 hours, with Cmax and AUC showing dose proportionality. Two patients enrolled at the 48 mg dose level have completed >6 cycles, including a patient with KRAS mutant colorectal cancer who achieved 24% reduction in target lesions and >50% reduction in serum CEA levels. Conclusions: CFI-400945 is well tolerated at doses up to 72mg with a favorable PK profile. Preliminary evidence of anti-tumor activity has been observed. Exploration of 96mg daily dosing is ongoing and once the RP2D has been established exploration of anti-tumor activity in biomarker-driven expansion arms of CFI-400945 in indications including advanced breast cancer is planned. Updated results of this ongoing trial will be presented at the meeting. Citation Format: Philippe L. Bedard, David W. Cescon, Graham Fletcher, Trish Denny, Richard Brokx, Peter Sampson, Mark R. Bray, Dennis J. Slamon, Tak W. Mak, Zev A. Wainberg. First-in-human phase I trial of the oral PLK4 inhibitor CFI-400945 in patients with advanced solid tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT066.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.002 | 0.005 |
| Insufficient payload (model declined to judge) | 0.011 | 0.003 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".