A phase II trial of perifosine as second line therapy for advanced pancreatic cancer. A study of the Princess Margaret Hospital [PMH] Phase II Consortium
Bibliographic record
Abstract
4166 Background: Perifosine is a synthetic, substituted heterocyclic alkylphospholipid, structurally related to miltefosine, with a unique spectrum of activity across the NCI 60 cell line screen. Phase I testing identified a recommended phase 2 dose (RP2D) of 150 mg/dy on a 21/28 day schedule with anorexia, fatigue, dehydration, nausea/vomiting as the predominant toxicities. Methods: Patients had advanced pancreatic adenocarcinoma and were allowed to have one prior systemic therapy. Perifosine [50mg tablets] was given on a 28 day cycle: Cycle 1 -loading dose 1050 mg over 2 days followed by 150mg daily on days 3–21; Cycle 2 and greater -day 1 dose of 300mg followed by 150mg days 2–21. A 2 stage design was employed with continuation to stage 2 only if 4/15 survive 6 months from study entry. In parallel with stage 1 of the clinical study, Panc-1 and MiaPaCa-2 xenografts were treated with perifosine at the MTD of 200mg/kg on Day 1 followed by 20mg/kg daily by oral gavage. Animals were sacrificed at 0, 24, 48, and 96hr, and tumor tissue analyzed by immunohistochemistry for effects on p21, p27, and cleaved caspase 3, and by immunohistochemistry and western blot for pAkt, pERK, pSAPK/JNK, pp38MAPkinase. If the clinical study proceeded to stage 2, then biopsies to identify effects on identified drug targets in vivo would be undertaken. Results: 19 patients were entered on study and received a total of 36 cycles of therapy. The response was stable disease in 2 [duration 3 & 8 months], progressive disease in 15 and 2 were inevaluable. The median survival time was 3.1 months, the median time to progression was 1.6 months and 5 survived 6 months or greater. The most frequent adverse events were fatigue, anorexia and abdominal pain. In the xenograft studies no significant alterations were detected in any of the biomarkers over the 96 hour experiments. Conclusions: Although 5/17 patients were alive at 6 months, the high rate of early progression and the short median time to progression indicate that single agent perifosine on this schedule is not sufficiently active to warrant study continuation. No significant financial relationships to disclose.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.003 | 0.008 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.003 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
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 teacher head, 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".