Abstract LB-289: A phase I dose escalation study of TKM-080301, a RNAi therapeutic directed against PLK1, in patients with advanced solid tumors.
Bibliographic record
Abstract
Abstract Background: Polo-like kinase 1 (PLK1) is a serine/threonine kinase that regulates multiple critical aspects of cell progression. PLK1 is over-expressed in many human tumor types and its over-expression is a negative prognostic indicator of patient outcome in a variety of cancers. TKM-080301 is a lipid nanoparticle formulation of a small interfering RNA (siRNA) directed against PLK1 that has been shown to effect highly selective reductions in PLK1 mRNA in vitro and in tumor xenograft models in mice. Methods: A phase I multi-center, open-label, non-randomized, dose-escalation study of TKM-080301 is ongoing in patients with advanced solid tumors or lymphoma. Sequential cohorts of 3 to 6 patients receive TKM-080301 as a 30-minute IV infusion on Days 1, 8, and 15 of a 28-day cycle. Primary objectives include determination of safety, maximum tolerated dose (MTD) and dose limiting toxicities (DLTs). Secondary objectives include characterization of pharmacokinetics (PK) and preliminary assessment of anti-tumor activity and pharmacodynamic effects. Pre-and post-dose biopsy samples are being collected from patients treated after DLT has been established. Results: Twenty-three (23) patients, receiving a cumulative total of 128 doses, have been treated with TKM-080301 at doses ranging from 0.15 to 0.9 mg/kg/week. The most common drug-related adverse events have been mild-to-moderate infusion related reactions with delayed onset, pyrexia, chills, nausea, vomiting, and fatigue. Mild, transient increases in certain cytokines (e.g., IL-6, IL-8, MCP-1) have been observed at dose levels ≤0.75 mg/kg/week and generally correlated with the timing of delayed infusion reactions. DLTs were observed at 0.9 mg/kg/week and included hypoxia/dyspnea in one patient (with a previous history of asthma) and thrombocytopenia in another patient. The dose level was subsequently reduced to 0.75 mg/kg/week. Pharmacokinetic parameters determined after the first dose in Cycles 1 and 2 demonstrated dose proportional Cmax and AUC and no obvious accumulation. Two patients have received TKM-080301 for at least 6 months (6 cycles) with no evidence of cumulative toxicity, including one patient with stable disease (colon) and one patient with a durable confirmed partial response (carcinoid tumor) who has received 8+ cycles of treatment. Conclusions: Preliminary results from this first-in-human trial indicate TKM-080301 was generally well-tolerated by the majority of patients. Preliminary antitumor efficacy has been observed, supporting PLK1 as a therapeutic target. As two DLTs were observed at the dose of 0.9 mg/kg/week, patient accrual is continuing at the 0.75 mg/kg/week dose level. Citation Format: Ramesh K. Ramanathan, Solomon I. Hamburg, Mitesh J. Borad, Mahesh Seetharam, Madappa N. Kundranda, Peter Lee, Paul Fredlund, Mark Gilbert, Cathy Mast, Sean C. Semple, Adam D. Judge, Brynne Crowell, Linda Vocila, Ian MacLachlan, Donald W. Northfelt. A phase I dose escalation study of TKM-080301, a RNAi therapeutic directed against PLK1, in patients with advanced solid tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-289. doi:10.1158/1538-7445.AM2013-LB-289
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.004 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".