A phase 1 dose-escalation study of the oral selective inhibitor of nuclear export (SINE) KPT-330 (selinexor) in patients (pts) with heavily pretreated non-Hodgkin lymphoma (NHL).
Bibliographic record
Abstract
8518 Background: KPT-330 (Selinexor) is a SINE XPO1 antagonist that forces nuclear retention and activation of >10 tumor suppressor proteins (TSP) and associated with reduction in c-myc and Bcl-XL. Anti-NHL activity was observed in murine models and in spontaneous canine aggressive lymphomas. Methods: Oral KPT-330 was given at 8-10 doses / 28-day cycle. XPO1 inhibition leads to rapid elevations in XPO1 mRNA, representing a pharmacodynamic (PDn) marker for KPT-330. Tumor biopsies were performed. Response evaluation was done in cycles 1, 2, and every 2 cycles. All pts had heavily pretreated NHL with progressive disease (PD) on study entry. Results: Thirty-two pts (18 M, 14 F; median age 68 yrs; ECOG PS 0/1: 9/23; median prior regimens: 3 range 1-11) received KPT-330 across 8 dose levels (3 to 60 mg/m2). Dosing at 60 mg/m2 twice weekly (BIW) is ongoing and MTD has not been reached. Cycle 1 (DLT period) Grade 3/4 events in >1 pt included thrombocytopenia (20%) and neutropenia (20%). The most common grade 1/2 AEs in cycle 1: anorexia (53%), nausea (50%), fatigue (50%), and vomiting (43%). Supportive care with appetite stimulants and anti-emetics diminished constitutional symptoms. Increases in XPO1 mRNA levels were observed at 4-48 hours, supporting BIW dosing. Tumor biopsies confirmed TSP nuclear localization, c-myc reduction, and apoptosis. Objective responses were observed in all histologies of NHL (Table). 5/16 pts have remained on therapy for an average of 9 months (>5-17) months without clinically significant toxicities. Conclusions: KPT-330 is generally well tolerated and can be administered over prolonged periods. The recommended phase 2 dose is ≥45 mg/m2BIW. Durable single agent activity was observed in heavily pretreated NHL pts, and phase 2 studies in DLBCL and Richter’s Syndrome are planned. Clinical trial information: NCT01607892.Response in 28 evaluable pts. NHL N PR+SD (%) PR (%) SD (%) [%Change in LN Size] PD Follicular (FL) 6 6 (100%) 1 (17%) 5 (83%) [-17% to -44%] – Mantle Cell 2 2 (100%) 1 (50%) 1 (50%) [-36%] – DLBCL 14 9 (64%) 3 (21%) 6 (43%) [-12% to -19%] 5 (36%) Transformed FL 3 1 (33%) 1 (33%) – 2 (67%) Richter's 3 3 (100%) 1 (33%) 2 (67%) [-22%] – Total 28 21 (75%) 7 (25%) 14 (50%) 7 (25%)
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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".