Abstract P035: A phase 1 pharmacokinetic trial of single agent trametinib a MEK inhibitor in advanced cancer patients with hepatic dysfunction: An NCI Organ Dysfunction Working Group (ODWG) study (NCI 9591)
Bibliographic record
Abstract
Abstract Background Trametinib (Mekinist ®) is an oral bioavailable MEK 1/2 inhibitor that is FDA approved in combination with BRAF inhibitor Dabrafenib for BRAFV600 mutant solid tumors. The single agent recommended phase 2 dose (RP2D) is 2 mg daily (QD). No clinical data is available on recommendation of trametinib dosing in various degrees of hepatic dysfunction (HD). This study was designed to evaluate RP2D, maximum tolerated dose (MTD), and pharmacokinetic (PK) profile of trametinib as primary endpoints in patients (pts) with genomically unselected advanced solid tumors with various degrees of HD. Methods Advanced cancer pts with ECOG ≤2, adequate renal and bone marrow functions, were stratified (NCI ODWG Criteria) into 4 HD groups: normal (NO), mild (ML), moderate (MD), severe (SV). NO group was enrolled as control subjects and was not evaluable for dose limiting toxicity (DLT). Trametinib was given QD on a 28-days cycle, with dose escalation based on a “3+3” design within each HD group (starting dose: NO, ML: 2mg; MD: 1.5 mg; SV: 1mg). Due to the long half-life of trametinib, PK samples were collected at days 15-16 in cycle 1. Differences in PK parameters among liver function groups were evaluated using analysis of variance (ANOVA). Results Out of 46 pts enrolled (2 pts ineligible), 44 (NO=17, ML=7, MD (1.5mg)=4, MD (2mg)=5, SV (1mg)=9, SV (1.5mg)=2) were evaluable for safety and 22 for PK analysis. The most common cancer type was GI-non CRC cancer (n=16, 36%). The most common all-grade treatment related adverse events (TRAEs) were acneiform rash (NO=53%, HD=48% of pts), nausea (NO=65%, HD=22%), diarrhea (NO=53%, HD=26%) and fatigue (NO=59%, HD=15%). Grade 3/4 TRAEs occurred in 27% (n=12) of pts (NO=8, 47%; HD=4, 15%). No treatment related deaths occurred. DLT was evaluable in 15 pts (ML=6, MD (1.5mg)=3, MD (2mg)=2, SV (1mg)=3 and SV (1.5mg)=1). One DLT (grade 3 acneiform rash) was observed in an SV pt (1.5mg). Dose interruptions or reductions due to TRAEs occurred in 15 pts (34%) [NO=9, 53%; ML=2, 29%; MD (1.5mg)=1, 33%; MD (2mg)=2, 33%; SV (1mg)=1, 11%; SV (1.5mg)=1; 50%]. Best response was stable disease in all HD groups (33 to 75%) and 54% in NO group. There were no significant differences for PK parameters of Cmax (p=0.18), Cmin (p=0.16), Cavg (p=0.62), or AUC0-24 (p=0.11) (NO vs ML, NO vs MD, NO vs SV, ML vs MD, ML vs SV, MD vs SV), when trametinib was normalized to 2 mg dose. However, only limited PK data were available for the MD (n=3) and SV (n=3) groups compared to NO (n=10) and ML (n=6) groups. Trametinib is heavily protein bound, with no correlation between serum albumin level and unbound trametinib fraction (p=0.26). Conclusion RP2D for trametinib in ML pts is 2 mg QD. There are insufficient number of evaluable pts to declare RP2D for MD and SV HD groups. No DLTs were noted in the highest dose cohorts that reached 3 evaluable pts: 1.5 mg QD in MD group, and 1 mg QD in SV group. It may be appropriate for pts with MD and SV HD to start trametinib at 1.5 mg QD and 1 mg QD respectively, and monitored closely for toxicity. Citation Format: Pei Jye Voon, Eric X. Chen, Helen X. Chen, Albert C. Lockhart, Solmaz Sahebjam, Karen Kelly, Ulka N. Vaishampayan, Vivek Subbiah, Albiruni R. Razak, Daniel J. Renouf, Sebastien J. Hotte, Arti Singh, Philippe L. Bedard, Aaron R. Hansen, Ivy S. Percy, Lisa Wang, Lee-Anne Stayner, Lillian L. Siu, Anna Spreafico. A phase 1 pharmacokinetic trial of single agent trametinib a MEK inhibitor in advanced cancer patients with hepatic dysfunction: An NCI Organ Dysfunction Working Group (ODWG) study (NCI 9591) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P035.
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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 | 0.003 |
| Insufficient payload (model declined to judge) | 0.004 | 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".