MGCD265, a multitargeted oral tyrosine kinase receptor inhibitor of Met and VEGFR: Dose-escalation phase I study.
Bibliographic record
Abstract
3039 Background: MGCD265 is a multikinase inhibitor, with nanomolar IC50 against Met, VEGFR 1, 2, and 3, Tie-2, and Ron. This spectrum may confer greater anti-tumor activity than inhibiting either target alone. MGCD265 has broad anti-tumor effects in preclinical models. Methods: Patients (pts) with advanced malignancies were enrolled in this Phase I, open-label, dose escalating study using the classic 3+3 study design. MGCD265 was administered every day over a 21-day cycle. The aim of this study is to determine the safety profile including the maximum tolerated dose and the dose limiting toxicities (DLTs) of MGCD265. The pharmacokinetic (PK), pharmacodynamic (PD) profiles and the anti-tumor activity of MGCD265 were also evaluated. Results: As of January 10, 2012, 56 patients were enrolled (M/F: 37/19; ECOG 0/1/2: 16/38/2; median age: 61 years old). MGCD265 was dose escalated from 24 mg/m2 QD to 235 mg/m2 BID with a favorable safety profile. The DLTs (n=1 for each event) captured were: grade 2 hypertension (per protocol’s definition), grade 3 lipase elevation, grade 3 fatigue and grade 3 pituitary hemorrhage, all occurring at daily doses ≥ 250 mg/m2. Additional ≥ grade 3 drug-related adverse events (observed beyond Cycle 1) were diarrhea, fatigue, elevated lipase and elevated alkaline phosphatase (n=1 for each event). Two schedules of MGCD265 were tested sequentially: once (QD) and twice daily (BID), respectively. Increasing the dose frequency to BID increased the exposure of MGCD265 by ~ 2 fold at steady state. To date, the exposure (Cmax) attained at steady state with the BID schedule was ~20 fold higher than the IC50 for Met and VEGFR inhibition and was also above the plasma exposures associated with efficacy in the Met-sensitive xenograft model (MKN45). Six patients achieved SD for 6 cycles or more (up to 12 cycles). Conclusions: The safety profile of MGCD265 continues to be favorable in this Phase I dose escalating study. While no evidence of objective responses have been noted to date, several pts have had prolonged SD. Dose escalation is ongoing.
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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 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.002 | 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".