A phase I/II study of TKM-080301, a <i>PLK1</i>-targeted RNAi in patients with adrenocortical cancer (ACC).
Why this work is in the frame
A frame that forgets how it found something cannot be audited. These are the routes that admitted this work.
Bibliographic record
Abstract
2547 Background: Polo-like kinase 1 (PLK1) regulates critical aspects of tumor progression. High expression levels correlate with poor survival in ACC. TKM-080301 is a lipid nanoparticle formulation of a siRNA against PLK1. Methods: TKM-080301 was evaluated in an open-label study with dose escalation and expansion phases in patients with refractory ACC. TKM-080301 was infused IV over 30 minutes on days 1, 8, and 15 of a 28-day cycle. Primary study objectives included assessment of safety and anti-tumor activity by RECIST 1.1 after every 2 cycles. Results: Sixteen patients were treated at 0.6 or 0.75 mg/kg/week for up to 18 cycles. Eight received at least 2 cycles of study treatment and were evaluable for tumor response. Four had a best response of stable disease including one with a 13% reduction of target tumor diameter. One 51 yo man with metastatic intraperitoneal non-functional ACC had a partial response (target tumor reduction of 19% after cycle 2 and 49% after cycle 14). Residual tumor was resected and histopathology showed near-complete necrosis. Paired tumor/normal whole exome sequencing of this tumor revealed key somatic alterations including a missense mutation (Q331H) in TP53’s DNA binding domain, an NF1 nonsense mutation (S365*), and a missense ARID1A mutation (A438V). RNA sequencing showed elevated expression of PLK1 (FPKM = 13.5) in this tumor compared to a normal adrenal RNA control (FPKM = 0.95). Two subjects completed at least 6 cycles. Subjects were discontinued for progressive disease (7); infusion reactions (2); acute respiratory failure (1); elevated LFTs (1); or bowel obstruction (1). Most common AEs related to TKM-080301 were pyrexia (56%); chills (50%); back pain (31%); infusion reaction (31%); and nausea (25%). Serious AEs related to TKM-080301 were ECG T-wave inversion and musculoskeletal pain (1) and infusion reaction (1). Conclusions: TKM-080301 has been tolerated at a dose of 0.6 - 0.75 mg/kg for up to 18 cycles. Preliminary anti-tumor efficacy has been observed. A potential molecular therapeutic context of increased PLK1 expression with inactivation of p53 or NF1 was observed in a remarkable responder. Further evaluation of PLK1 as a therapeutic target of TKM-080301 in ACC is warranted. Clinical trial information: NCT01262235.
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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 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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 it