Preclinical and early clinical activity of the oral selective inhibitor of nuclear export (SINE) exportin 1 (XPO1) antagonist KPT-330 (Selinexor) in patients (pts) with platinum-resistant/refractory ovarian cancer (OvCa).
Bibliographic record
Abstract
5522 Background: Increased XPO1 expression has been linked to progression of OvCa and is an independent poor prognostic for survival. Most tumor suppressor proteins (TSP) are transported out of the nucleus exclusively by XPO1 and thereby rendered non-functional. KPT-330 is a slowly reversible inhibitor of XPO1, and forces the nuclear retention and activation of over 10 TSP resulting in OvCa cell death while sparing normal cells. Methods: SINE compounds were tested for their ability to localize OvCa-relevant TSP to the nucleus and induce apoptosis in platinum sensitive and resistant cell lines in vitro. Combination with cisplatin was assessed in vitro and in patient-derived xenograft models (30 mg/m2 po, 3 times/week). As part of an on-going Phase 1 (KCP-330-002) in pts with solid tumors, oral KPT-330 (8-10 doses/4-weeks cycle) was administered to pts with heavily pre-treated OvCa that were progressing on study entry. Pharmacokinetic (PK) analyses were performed. Response was evaluated every 2 cycles (RECIST 1.1). Results: SINE potently induced OvCa cell death in platinum sensitive and resistant cell lines (IC50s < 0.12 µM). Nuclear accumulation and functional activation of p53 and other TSP was demonstrated. Synergy between SINE and cisplatin was shown in vitro and in vivo in OvCa models with diverse genetic backgrounds, and increased overall survival. Seven OvCa pts resistant/refractory to platinums and other agents (median age 55 yrs; ECOG PS 0/1: 3/4; median number of prior therapies 5) were treated with 30-35 mg/m2 oral KPT-330 (300 mg/cycle or 280 mg/cycle). No grade 4 AEs were reported. The most common AEs were fatigue, nausea, diarrhea, and vomiting; manageable with supportive care. PK analysis showed Cmax of 0.5-1 mM and AUC0-inf 2800-4000 ng*h/mL, which exceed levels in vitro and in animal models. RECIST response was evaluable in 5 pts: 1 PR (5 months), 2 SD (4 and 7+ months) and 2 PD. Conclusions: KPT-330 treatment is generally well tolerated and shows preliminary antitumor activity in pts with platinum resistant or refractory OvCa. Additional single agent and combination studies are planned. Clinical trial information: NCT01607905.
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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 | 0.003 | 0.003 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 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".