A phase I study of the combination of intravenous Reolysin (REO) and gemcitabine (GEM) in patients (pts) with advanced cancer
Bibliographic record
Abstract
3584 Background: REO (reovirus serotype 3) is a Dearing strain, naturally occurring, non-enveloped virus with limited pathogenecity in humans. REO replicates specifically in transformed Ras-activated cells due to inhibition of the dsRNA-activated protein kinase, resulting in cell-lysis. GEM has shown efficacy in a wide range of tumors commonly driven by activated Ras, and causes cell cycle arrest in S phase. Results from isobologram analysis suggest potential synergies of REO and GEM. Methods: This open-label, dose-escalating, two-centre phase-I trial studied the combination of iv REO, d1–5 and iv GEM, d1 and 8, qw3. The REO starting dose was 3x109 TCID50 over 1-hour, increasing in successive cohorts and GEM was given at a fixed dose of 1,000 mg/m2 over 30-min. Endpoints were the maximum tolerated dose (MTD), dose limiting toxicity (DLT), and safety profile of REOGEM and to establish a RP2D. Secondary endpoints were to evaluate the immune response, to evaluate pharmacokinetics of REOGEM and to describe any antitumor activity. Results: Since July 2007, 15 heavily pre-treated pts with disease progression prior to trial entry (9M/6F, median age 56 years, ECOG 0/1: 3/12) were entered into this trial. After 2 pts had Grade >3 toxicities during the first cycle (1 pt: GGT and Trop-I increase and PD; 1 pt: Trop-I increase and unspecific ST-changes) considered probably related to both agents the protocol was amended and the dose of REO was adjusted to 1x109 TCID50, d1 of each cycle (C-1) and increased in subsequent cohorts to 3x109, 1x1010, and 3x1010 TCID50. In total 45 cycles were administered (median 3) resulting in mild and expected toxicities including fever, headaches, rhinorrhea, fatigue and myelosupression. The MTD was not reached. Of the 10 pts evaluable for response, 2 pts (breast and nasopharyngeal) had PR and/or clinical response and 5 pts had SD for 4–8 cycles, amounting for a total disease control rate (CR+PR+SD) of 70%. Conclusions: The combination of REOGEM was well tolerated and resulted in disease control for a majority of pts. A RP2D, of REO 3x1010, d1 and GEM 1000mg/m2, d1 and 8, qw3, was recommended and phase-2 trials are underway. [Table: see text]
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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) | 0.002 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 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".