A phase I dose-finding study of combined treatment with an antisense Bcl-2 oligonucleotide (Genasense) and mitoxantrone in patients with metastatic hormone-refractory prostate cancer.
Bibliographic record
Abstract
PURPOSE: Bcl-2 is a negative prognostic indicator in prostate cancer, implicated in the development of androgen independence and treatment resistance, and is overexpressed in hormone-refractory prostate cancer (HRPC). Genasense is a phosphorothioate antisense oligonucleotide complementary to the bcl-2 mRNA open reading frame that in preclinical studies has shown significant activity in inhibiting expression of Bcl-2, delaying androgen independence, and improving chemosensitivity in prostate and other cancer models. In this dose escalation study, we evaluated the combination of Genasense and mitoxantrone, a standard chemotherapy for patients with HRPC. DESIGN: Twenty-six patients with HRPC were treated at seven dose levels receiving Genasense at a dose ranging from 0.6 to 5.0 mg/kg/day and mitoxantrone from 4 mg/m(2) to 12 mg/m(2). Genasense was administered as a 14-day i.v. continuous infusion every 28 days with mitoxantrone given as an i.v. bolus on day 8. RESULTS: No dose-limiting toxicities were observed. Hematological toxicities were transient and included neutropenia, thrombocytopenia, and lymphopenia. Nonhematological toxicities included fatigue, fever, nausea, arthralgias, myalgias, and transient elevations in serum creatinine, none of which were severe. Two patients had >50% reductions in prostate-specific antigen. One patient, who received six cycles of Genasense at 1.2 mg/kg/day and a low dose (4 mg/m(2)) of mitoxantrone, also had symptomatic improvement in bone pain. Peripheral blood lymphocyte Bcl-2 protein expression decreased in five of five patients given Genasense at 5mg/kg/day (mean change from baseline, -12.8%; SD, 16.4%) as assessed by flow cytometry. Serum concentrations of Genasense given at doses of 3 mg/kg/day and greater, exceeded 1 microg/ml. CONCLUSIONS: Genasense and mitoxantrone are well tolerated in combination, and mitoxantrone can be delivered at a standard dose with biologically active doses of Genasense without significant additional toxicity. This observation allays concerns about trials that combine Genasense with full doses of other cytotoxic agents seeking greater evidence of activity.
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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) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.003 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.002 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.003 |
| 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".