A phase 1b study with selinexor, a first in class selective inhibitor of nuclear export (SINE) in patients with advanced sarcomas: An efficacy analysis.
Bibliographic record
Abstract
10569 Background: Sarcomas are a heterogeneous group of malignancies with diverse genetic abnormalities. Selinexor is a first-in-class, oral, inhibitor of XPO1, (nuclear exportin protein 1) with potent anti-tumor activity in multiple sarcoma cell lines and in murine liposarcoma xenografts. Here we report results from a Phase 1b dose expansion trial of selinexor in sarcoma patients (NCT01896505). Methods: Patients (pts) with advanced, refractory sarcomas with radiographic progression received oral selinexor at 50 mg/m2 twice weekly per 28 day cycle. Pharmacokinetics (PK, n = 12) was assessed in the fasted and fed state. Pharmacodynamic studies were performed on fresh tumor biopsies. Response was evaluated every 2 cycles (RECIST 1.1). Results: 36 pts (14 M / 22 F, ECOG 0/1: 19/17, median age 57.5 years [range 18–86], median lines of previous treatments: 3 [range 1–9]). Disease subtypes include liposarcoma (LPS; N = 12), leiomyosarcoma (LMS; N = 8) and other sarcomas (N = 16). Grade 3 drug related adverse events (AEs) occurring in ≥ 2pts included: fatigue (17%), leucopenia (17%), anemia (11%), hyponatremia (8%) and vomiting (6%). One pt had reversible, grade 3 sensory and autonomic neuropathy and two pts had grade 4 thrombocytopenia (6%). Of the 33 evaluable patients, stable disease was seen in 21/33 (64%) of pts along with decrease of tumor burden (ranging from 5 – 23%) in 7 patients. There were 12 pts (36%) that progressed. In pts with progressive LPS and LMS, the median progression free survival (mPFS) on selinexor was 4.2 months (mo) and 3.7 mo, respectively. PK was similar to previously published results and there was better absorption in the fed state compared to fasting and fat content did not affect bioavailability. Matched pre- and post-tumor biopsies (N = 6) showed target inhibition of XPO1 by nuclear localization of p53, apoptosis by increased cleaved caspase, marked reduction in cellularity and Ki-67 and increase in stroma. Conclusions: Oral selinexor administered twice weekly was well tolerated with manageable toxicities. Selinexor demonstrated durable stable disease in various soft tissue and bone sarcomas. Based on promising results a larger study is planned. Clinical trial information: NCT01896505.
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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 | 0.001 | 0.001 |
| 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 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| 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".