A Phase 1 Study To Assess the Safety, Tolerability and Pharmacokinetics of ARRY-380 – An Oral Inhibitor of HER2.
Bibliographic record
Abstract
Abstract Background: ARRY-380 is a potent, orally active small molecule that selectively inhibits HER2 signaling in vitro and in vivo and significantly inhibits tumor growth in a variety of HER2-dependent tumor xenograft models. Based on its preclinical activity, tolerability and pharmacokinetic (PK) profile, a Phase 1 study was initiated to evaluate the safety, tolerability and PK profile of ARRY-380 as a single agent in patients with solid tumors and to establish the maximum tolerated dose (MTD).Methods: Patients with HER2 positive breast cancer or other tumor types for which published evidence of HER2 expression exists were treated with ARRY-380 as a single oral dose on Cycle 1 Day 1, followed by continuous twice-daily (BID) oral dosing starting on Cycle 1 Day 3. ARRY-380 was escalated in cohorts of 3 to 4 patients, using standard dose-limiting toxicity (DLT) criteria during Cycle 1 to determine dose escalation. Serial PK assessments were made during Cycle 1 on Days 1, 2, 3 and at steady-state on Day 15.Preliminary Results: As of June 1, 2009, 15 patients have been treated in 5 dosing cohorts at doses of 25 to 300 mg BID. Patients had a median age of 61 years (range, 37-77 years) and ECOG PS of 0 to 2. Cancer types included HER2+ breast cancer (8), colorectal (6) and salivary gland (1). No DLTs have been observed and drug-related adverse events have included Grade 1 nausea, rash and fatigue and Grade 2 fatigue in 2 patients at the 200 mg BID dose level. Preliminary 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 4.6 hours across all cohorts. Two patients with HER2+ breast cancer have had stable disease for ≥ 4 months with no significant toxicity. One of these two patients had a notable reduction in liver metastases (28%) after 2 cycles of ARRY-380 and is currently on study.Conclusions: ARRY-380 has demonstrated an acceptable safety and PK profile and preliminary signs of clinical benefit. Dose escalation continues to determine the MTD. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5111.
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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) | 0.001 | 0.001 |
| 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) | 0.005 | 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".