Phase 1 study of CPX-1, a fixed ratio formulation of irinotecan (IRI) and floxuridine (FLOX), in patients with advanced solid tumors
Bibliographic record
Abstract
2014 Background: In vitro studies have shown that varying the ratio of individual agents in drug combinations can result in synergistic, additive or antagonistic activity against tumor cells. CPX-1 is a liposomal formulation of IRI and FLOX in a fixed 1:1 molar ratio which was selected as optimal in vitro and confirmed to be synergistic in vivo in preclinical tumor models. CPX-1 overcomes the dissimilar pharmacokinetics (PK) of the individual drugs, enables sustained maintenance of this ratio after IV administration, and was evaluated in a Phase I open-label, dose-escalation study. Methods: Starting dose was 30 U/m2 (1 Unit of CPX-1 contains 1 mg IRI + 0.36 mg FLOX) given on day 1 and 15 of each 28-day cycle. Dose escalation was by modified Fibonacci with 4 subjects/cohort. Eligibility included: ≥ 18 yo; advanced solid tumor; ECOG PS ≤ 2; adequate bone marrow/liver/renal function. PK analysis was done on day 1 and 15 of the first cycle. Results: 26 subjects (16M:10F), median age 54.5 y (21–72), all with prior therapy, enrolled in 6 cohorts with the 5th cohort expanded to 6 subjects. Diagnoses: 8 colorectal, 3 pancreatic, 3 ovarian, 2 breast, 2 gastric, 2 esophageal, 2 sarcomas, 1 renal cell, 1 prostate, 1 NSCLC and 1 sphenoid sinus. Response: 20 subjects evaluable: 2 confirmed PRs (NSCLC 8+ wks; Colon 13+ wks, in a patient with prior IRI exposure) and 13 with SD (8–24+wks). Safety: DLTs were observed at the 6th dose level: 4 subjects with DLTs: 3 diarrhea (one resulting in death due to dehydration/ARF) and one neutropenia. Other possibly related grade 3 and 4 events included one each of: grade 3 diarrhea, grade 3 vomiting, grade 3 neutropenia, grade 3 fatigue, grade 3 compression fracture and arthralgia and pulmonary embolism grade 4. PK: In all 14 subjects analyzed to date the 1:1 molar ratio of IRI to FLOX was maintained for 24 hours and metabolites 5-FU and SN-38 were present in the plasma. Conclusions: CPX-1 represents a new approach to developing drug combinations in which drug ratios are pre-selected in vitro based on optimal antitumor activity and maintained systemically through pharmacokinetic control. Phase 2 studies are planned with a recommended dose of 210U/m2 of CPX-1. [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) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.001 | 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) | 0.004 | 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".