Phase I dose-escalation, open-label study of HSP990 administered orally in adult patients with advanced solid malignancies.
Bibliographic record
Abstract
2561^ Background: NVP-HSP990 is a synthetic small molecule that potently and selectively inhibits heat-shock protein 90. HSP990 leads to degradation of client proteins, offering potential simultaneous blockade of multiple oncogenic signaling pathways. The primary objective of this Phase l first-in-man study (NCT00879905) was to determine the single-agent MTD of HSP990 administered once (qw) or twice (biw) weekly to patients (pts) with advanced solid malignancies (preselected CYP2C9 genotypes only). Secondary objectives included safety, efficacy, PK, and biomarkers. Methods: HSP990 was administered orally qw or biw in 28-day cycles. Dose escalation was guided by a Bayesian logistic regression model. The MTD was determined by assessing DLTs in Cycle 1. Eligible pts included those with histologically confirmed advanced solid tumors that had progressed on standard therapy or for whom no standard therapy exists. Results: 64 pts (median age 57 yr: 44% male; 37.5% Stage IV; WHO PS 0/1) received HSP990. 53 pts received HSP990 qw at 2.5, 5, 10, 20, 30, 50 or 60 mg; and 11 pts received HSP990 biw at 25 mg. Median duration of exposure was 8 wks; 12 pts remained on treatment for >16 wks. DLTs occurred in 7 pts: 4/22 at 50 mg qw (including G3 diarrhea, G3 QTc prolongation, G4 ALT/AST elevations); 2/5 at 60 mg qw (including G3 tremors); and 1/11 at 25 mg biw (including G2 ataxia, G2 confusion, G2 visual hallucination). The 50-mg qw dose was declared as the MTD. Further dose escalation was not possible due to neurologic toxicity. Most common reported CTCAE G3/4 AEs were diarrhea (12.5%), increased ALT/AST (11% each), anemia, or cholestasis (6% each). HSP990 had Tmax of 3 h and T½ of ~20 h. Large inter-patient variability in PK exposures was observed. For qw dosing, approximate dose-dependent HSP70 induction was observed from 5−30 mg qw, which plateaued after 20 mg qw. There were no objective responses; however, 25 pts (39%) had SD. (RECIST v1.0). No pt showed a complete metabolic response (MR; by FDG-PET) and 11 pts (17%) showed a partial MR. All pts discontinued treatment, primarily due to disease progression (84%). Conclusions: The single-agent MTD of HSP990 in pts with advanced solid tumors was 50 mg qw. SD was observed in 39% of pts. Clinical trial information: NCT00879905.
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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 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 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) | 0.003 | 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".