Abstract CT055: A randomized, double-blinded, controlled study of tucatinib (ONT-380) vs. placebo in combination with capecitabine (C) and trastuzumab (Tz) in patients with pretreated HER2+ unresectable locally advanced or metastatic breast carcinoma (MBC) (HER2CLIMB)
Bibliographic record
Abstract
Abstract Background: Tucatinib (ONT-380) is a highly selective small molecule inhibitor of HER2 kinase with nanomolar potency. Unlike dual HER2/EGFR agents, it does not inhibit EGFR at clinically relevant concentrations, decreasing the potential for EGFR-related toxicities (severe skin rash and diarrhea). In preclinical studies, tucatinib demonstrated synergistic activity with Tz, and was active in HER2+ models of brain metastases (mets). In a Phase 1b study, tucatinib was combined with C and Tz in pts with HER2+ MBC previously treated with trastuzumab emtansine (T-DM1) and Tz. Objective responses were seen, including in pts with brain mets. The combination was well tolerated, with low rates of Gr 3 diarrhea at the recommended dose (300 mg PO BID, equivalent to the single agent MTD). Based on these data, tucatinib is now being evaluated in a study in combination with C and Tz (HER2CLIMB). Trial Design: The primary study objective is to assess the effect of tucatinib vs. placebo given with C + Tz on progression-free survival (PFS) based on independent central review. Additional objectives include PFS in patients with brain mets, overall survival, ORR, duration of response, clinical benefit rate, and safety. The study population includes adult pts with progressive HER2+ locally advanced or MBC who have had prior treatment with a taxane, Tz, pertuzumab and T-DM1. Pts with brain mets, including untreated or progressive mets, may be enrolled. 480 pts will be enrolled in North America, Europe, and Australia. Pts are receiving C (1000 mg/mg2 PO BID for 14 days of a 21-day cycle) and Tz (6 mg/kg IV once every 21 days), and are being randomized in a 2:1 ratio to tucatinib 300 mg PO BID or placebo. Pts with isolated CNS progression may continue on study treatment after undergoing local CNS therapy. An independent Data Monitoring Committee is monitoring pt safety. Citation Format: Carey Anders, Rashmi Murthy, Erika Hamilton, Virginia Borges, David Cameron, Lisa Carey, Volkmar Müller, Giuseppe Curigliano, Karen Gelmon, Gabriel Hortobagyi, Ian Krop, Sibylle Loibl, Xavier Pivot, Mark Pegram, Dennis Slamon, Sara Hurvitz, Michaela Tsai, Eric Winer. A randomized, double-blinded, controlled study of tucatinib (ONT-380) vs. placebo in combination with capecitabine (C) and trastuzumab (Tz) in patients with pretreated HER2+ unresectable locally advanced or metastatic breast carcinoma (MBC) (HER2CLIMB) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT055. doi:10.1158/1538-7445.AM2017-CT055
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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 | 0.003 | 0.002 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.004 | 0.002 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.002 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.002 | 0.003 |
| Insufficient payload (model declined to judge) | 0.010 | 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".