A phase I/II first-in-human trial of oral SRA737 (a Chk1 inhibitor) given in combination with low-dose gemcitabine in subjects with advanced cancer.
Bibliographic record
Abstract
3095 Background: SRA737 is a potent, highly selective and orally-bioavailable inhibitor of checkpoint kinase 1 (Chk1). SRA737-02 was designed to investigate the safety, tolerability and preliminary activity of SRA737 in a novel combination with sub-therapeutic doses of gemcitabine (low dose gemcitabine; LDG) utilized to potentiate SRA737’s activity by induction of replication stress in subjects with advanced solid tumors. Methods: Phase 1 dose escalation investigated cohorts of 3 to 6 subjects receiving escalating doses of SRA737 for 2 days after LDG administration on days 1, 8, 15 of 28-day cycles. Phase 2 expansion cohorts explored the hypothesis that LDG strongly synergizes with SRA737 in subjects with genetically-defined tumors hypothesized to be sensitive to Chk1 inhibition: urothelial, high grade serous ovarian, small cell lung, soft tissue sarcoma, and cervical or anogenital cancers. Results: A total of 55 subjects received SRA737 in 13 dose escalation cohorts at doses of 40 to 600 mg SRA737 combined with LDG doses of 50 to 300 mg/m 2 . No protocol-defined dose limiting toxicities (DLTs) have been observed. The pharmacokinetic profile of SRA737 revealed an AUC 0-24 and C max of 3550 ng∙h/mL and 548 ng/mL at 150 mg SRA737. At this dose, the C min (52 ng/mL) exceeded that determined in preclinical models to be effective. Enrollment into expansion cohorts was initiated at 500 mg SRA737 plus 100 mg/m 2 LDG with intra-patient dose escalation permitted to 250 mg/m 2 LDG. Approximately 80 subjects were planned and 82 have been treated. Median treatment duration was 51 days (range 1 to 358). The most common treatment-emergent adverse events were nausea (53%), vomiting (45%), fatigue (40%), diarrhea (38%), and anemia (28%); the majority were of mild to moderate severity. Proof-of-concept clinical activity has been seen in tumor types such as anal, cervical, and rectal. Conclusions: The combination of LDG and SRA737 has been well tolerated. This first-in-human clinical study provides proof-of-concept that sub-therapeutic LDG effectively potentiates SRA737. This novel replication stress-targeted therapy warrants further evaluation in genetically pre-defined solid tumors. Clinical trial information: NCT02797977.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
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 teacher head, 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".