MGCD265, a multitargeted oral tyrosine kinase receptor inhibitor of Met and VEGFR, in combination with erlotinib in patients with advanced solid tumors.
Bibliographic record
Abstract
e13602 Background: MGCD265 is a multi-target oral tyrosine kinase receptor inhibitor that targets Met (wild type and clinically-relevant Met mutants), VEGFRs 1, 2, 3, Tie and Ron. Combining Met and EGFR inhibitors has been shown to be synergistic and can overcome resistance to EGFR inhibitors. MGCD265 in combination with erlotinib is being evaluated clinically for safety and efficacy. Methods: This is a phase I dose escalation trial of patients (pts) with advanced solid tumors, using the classic 3+3 design. MGCD265 and erlotinib were administered every day over a 21-day cycle. Safety evaluation included determination of dose limiting toxicities (DLTs) and the maximum tolerated dose of the combination. The pharmacokinetic (PK), pharmacodynamic (PD) profiles as well as anti-tumor activity, using RECIST 1.1, were also evaluated. Results: As ofJanuary 11, 2012, 45 pts were enrolled (median age: 58 years old; M/F: 27/18; ECOG 0/1: 20/25). MGCD265 was dose escalated from 96 mg/m2 QD to 162 mg/m2 BID, in combination with erlotinib (initially at 100 mg then at 150 mg QD). Diarrhea (n=6) was the only treatment-related ≥ grade 3 adverse event observed in ≥ 2 pts. The observed DLTs (all grade 3) were (n=1): diarrhea (96 mg/m2 QD MGCD265+100 mg erlotinib), rash and fatigue (144 mg/m2 QD MGCD265+150 mg erlotinib) and rhabdomyolysis (162 mg/m2 BID MGCD265+150 mg erlotinib). One out of 3 pts with NSCLC, who was positive for activating EGFR mutation, experienced a partial response (duration of response of 8 cycles). Seven pts with a variety of tumors experienced stable disease for 6 cycles or more. Three out of 8 pts with gastroesophageal cancer remained on study for ~12-26 cycles. The PD profile indicated a decrease in the plasma level of HGF at Cycle 1 Day 8 compared to baseline in some patients. Conclusions: MGCD265, at the doses tested, was well tolerated in combination with full-dose erlotinib. The activity of MGCD265 combined with erlotinib supports phase II development of the combination.
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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 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 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 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".