Abstract P3-12-04: A phase 2, multi-center, open label study evaluating the efficacy and safety of GRN1005 alone or in combination with trastuzumab in patients with brain metastases from breast cancer
Bibliographic record
Abstract
Abstract Rationale: Treatment of brain metastasis (BM) remains an unmet medical need due to the inability of most anti-cancer agents to effectively cross the blood-brain barrier (BBB). GRN1005 is a peptide-drug conjugate (PDC) consisting of 3 molecules of paclitaxel conjugated to a 19-amino acid peptide, Angiopep-2. GRN1005 effectively penetrates the BBB by targeting the low-density lipoprotein receptor-related protein 1 (LRP1), which is expressed on the surface of the BBB and on certain neoplastic cells. In a phase 1 study, GRN1005 demonstrated encouraging anti-tumor activity in breast cancer (BC) patients with BM. Methods: Up to 157 patients (pts) with measurable BM from BC, with or without extra-cranial disease, are currently being enrolled in an ongoing open label study. Prior cranial irradiation is allowed but lesions previously treated with stereotactic radiosurgery (SRS) are excluded from the efficacy analysis. All currently enrolled pts received GRN1005 at a starting dose of either 650 or 550 mg/m2 IV every three weeks, until intra-cranial disease progression (iPD), unacceptable toxicity, or initiation of non-protocol systemic therapy. HER2 positive pts received concomitant trastuzumab. The primary endpoint is intra-cranial objective response rate (iORR), as assessed by independent review using CNS RECIST 1.1. Additional endpoints include safety, duration of intra-cranial response, 3-month intra-cranial progression free survival (iPFS3), extra-cranial ORR, and neurocognitive function. Results: As of 4 June 2012, 24 pts (13 at 650 mg/m2 and 11 at 550 mg/m2) have been treated with a median of 2 cycles of GRN1005 (range 1–5). Median age was 51.5 years (34–68) and 14 (58%) pts have HER2-positive disease. Pts received a median of 6 (3–14) prior systemic regimens; 19 had received prior whole brain radiation therapy (WBRT) ± SRS and 2 had received prior SRS only (data pending on 3 pts). Six (25%) pts have discontinued treatment with GRN1005, including 2 due to iPD and 2 due to adverse events (AE). One additional pt had clinical progression and discontinued GRN1005. The AEs observed at 650 mg/m2 are qualitatively consistent with conventional paclitaxel but are more frequent and more severe than observed with q3 week paclitaxel which led to a protocol amendment and dose reduction to 550 mg/m2 for all subsequent pts. Among all treated pts, the most frequent AEs were neutropenia (75%), fatigue (50%), mucositis (33%), neuropathy (29%), and diarrhea (25%). Notable Grade 3–4 AEs were neutropenia in 12 pts (including 1 case of febrile), and arthralgia, fatigue, and rash in 3 pts each. Preliminary anti-tumor activity has been observed in both intra-cranial and extra-cranial lesions. Conclusions: GRN1005 is a promising treatment for BM associated with breast cancer and demonstrates a safety profile qualitatively similar to paclitaxel dosed every 3 weeks. Due to tolerability concerns at the 650 mg/m2 dose, the 550 mg/m2 dose is currently being evaluated in these heavily pretreated BC pts. Updated efficacy and safety data will be presented at the meeting. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-12-04.
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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 | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.002 | 0.005 |
| Insufficient payload (model declined to judge) | 0.005 | 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".