Abstract P6-11-06: A phase Ib study of LCL161, an oral inhibitor of apoptosis (IAP) antagonist, in combination with weekly paclitaxel in patients with advanced solid tumors
Bibliographic record
Abstract
Abstract Background: Impaired apoptosis is a common feature of cancer cells and may contribute to chemoresistance. LCL161 is an oral small molecule antagonist of Inhibitor of Apoptosis Proteins (IAPs) that sensitizes a subset of tumors from diverse lineages to treatment with cytotoxic therapies, including paclitaxel. Multiple breast cancer models are sensitive to LCL161 as a single agent and LCL161 acts synergistically with paclitaxel in these models. A phase I study established an LCL161 dose of 1800 mg once weekly as well tolerated, with strong evidence of pharmacodynamic activity at doses ≥320 mg. This ongoing phase Ib study defines the dose limiting toxicities (DLTs), maximum tolerated dose (MTD), safety, and pharmacokinetics (PK) of LCL161 in combination with weekly paclitaxel. Methods: Patients with advanced/metastatic solid tumors were treated with paclitaxel 80 mg/m2 each week followed by escalating doses of LCL161 administered once weekly immediately following paclitaxel. PK and biomarker sampling was performed. Results: Thirty-two patients have received LCL161 doses of 600 mg (n = 3), 1200 mg (n = 5), 1500 mg (n = 4), and 1800 mg (n = 20). The most frequent adverse events considered LCL161-related included diarrhea (n = 11; 1 Grade 3), nausea (n = 8), fatigue (n = 7; 2 Grade 3), peripheral neuropathy (n = 6; 1 Grade 3), vomiting (n = 6), decreased appetite (n = 5), alopecia (n = 4), and anemia (n = 4). The principal DLTs were neutropenia, fatigue, and neuropathy. Significant cytokine release syndrome, the DLT of single-agent LCL161, has not been observed likely due to the use of dexamethasone as a premedication. No PK interaction between LCL161 and paclitaxel was observed. RECIST partial responses have been observed in 4 patients with diverse tumor types, including breast cancer. Preliminary antitumor activity in the expansion cohort with breast cancer patients will be presented. Discussion: LCL161 and paclitaxel combination therapy is well tolerated, with manageable toxicities and no evidence of a PK interaction that might interfere with the activity of either agent. Enrollment of additional patients with breast and ovarian cancer into an expansion cohort is ongoing, utilizing an approach to identify those more likely to respond to treatment with IAP antagonists. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-11-06.
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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) | 0.002 | 0.001 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.004 |
| 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".