Abstract P3-14-07: A Phase 1 Study To Assess the Safety, Tolerability and PK of ARRY-380 — An Oral HER2 Inhibitor
Bibliographic record
Abstract
Abstract Background: ARRY-380 is a potent, orally active small molecule that selectively inhibits HER2 signaling in vitro and in vivo. Methods: Patients (pts) with HER2+ MBC or other tumor types with published evidence of HER2 expression were treated with ARRY-380 as a single oral dose on C1 D1 followed by continuous dosing on C1 D3, in a BID schedule. Dose escalation was performed using standard DLT rules after all pts within a cohort completed the first cycle. Serial PK assessments were performed on D 1, 2, 3 and on D 15 of C1. Preliminary Results: As of 1 June, 2010, 30 pts have been treated at doses ranging from 25 mg to 800 mg BID. Pts had a median age of 57 years (range: 31-77 years). Cancer types included HER2+ MBC (n=23), CRC (n=6), and salivary gland (n=1). All HER2+ MBC pts had received prior trastuzumab and most (78%) had received prior lapatinib. The MTD (600 mg BID) has been determined in the dose escalation study. ARRY-380 was generally well-tolerated. One DLT of reversible grade 3 AST and one DLT of reversible grade 3 AST/ALT were noted at the 800 mg BID dose level. Other related AEs have been predominantly mild and include Grade 1 nausea, rash, and fatigue and Grade 2 fatigue. No treatment-related cardiac events have been reported. PK analyses indicate a trend for increasing Cmax and AUC with increasing dose, a median Tmax of 2 hours, and a mean t1/2 of 5.3 hours across doses. Of the 15 HER2+ MBC pts evaluable for response at doses ≥200 mg BID, 1 (7%) pt had a confirmed PR and 8 (53%) had SD accompanied by regression of tumor lesions. Of the 8 pts with SD, 5 pts demonstrated SD for ≥4 months. The rate of PR + SD ≥4 months was 43%. The HER2+ MBC pt with a PR had complete regression of all target and non-target lesions and a change in CEA from 71.1 to 3.5 ng/mL [NR = 0.0-3.0 ng/mL]. This pt is currently in Cycle 5 and has received 6 prior lines of therapy for advanced disease with a best response of PD on lapatinib. Conclusions: ARRY-380 has demonstrated a generally well-tolerated safety profile with a low incidence and severity of rash and diarrhea. ARRY-380 has shown promising signs of antitumor activity in a heavily pretreated HER2+ MBC population (43% of pts with PR or SD ≥4 months). These safety and preliminary efficacy data compare favorably to historical data of other HER2-targeted agents. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-14-07.
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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 | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.005 |
| Insufficient payload (model declined to judge) | 0.004 | 0.002 |
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".