A phase I and pharmacokinetic (PK) study of vinorelbine liposomes injection in patients with advanced solid tumors, non-Hodgkin’s lymphoma, and Hodgkin’s disease
Bibliographic record
Abstract
A150 Introduction: Vinorelbine tartrate injection (VLB) is a cell-cycle specific, lipophilic anti-cancer drug that inhibits mitosis at metaphase through its disruption of microtubule assembly. Alocrest TM (vinorelbine liposomes injection) is a sphingomyelin/cholesterol liposomal (OPTISOME TM ) formulation of VLB (55/45, mol%) that efficiently transports large quantities of drug and prolongs drug release properties in vivo . In a preliminary pharmacokinetic (PK) profile study in ICR mice, Alocrest demonstrated a 68-fold increase in plasma AUC, 29-fold reduction in drug clearance and 265-fold reduction in volume of distribution compared to conventional VLB. The improved PK profile of Alocrest was associated with enhanced anti-tumor activity and therapeutic index in several xenograft models (MX-1, breast; HT-29 colon). This report describes a phase 1 and PK profile study of Alocrest administered to humans as a 60-minute IV infusion on days 1 and 8 every 21 days. Methods: Adult subjects with confirmed solid tumors refractory to standard therapy or for which no standard therapy was known to exist, or relapsed and/or refractory non-Hodgkin’s lymphoma or Hodgkin’s disease and an ECOG PS 0-2 were eligible for enrollment. Safety assessments were described using standard laboratory and clinical dose limiting toxicity (DLT) definitions. Responses were based on RECIST and the Non-Hodgkin’s Lymphoma International Workshop Criteria. PK analyses of total (encapsulated + released) and free (released non-protein bound) VLB were performed on days 1 and 8 and analyzed by LC-MS/MS. Area under the concentration versus time curves from 0 to last (AUC last ) was calculated by noncompartmental analysis. Results: At the time of this report, 13 subjects (M/F: 9/4) with refractory solid tumors (n=11) and non-Hodgkin’s lymphoma (n=2) have been enrolled and received a total of 35 cycles of Alocrest (median 2, range, 1-15) at 4 dose levels (2, 4, 8, and 16 mg/m 2 /dose). The MTD has not yet been reached. The study is currently dosing subjects at 32 mg/m 2 /dose which approximates the approved dose of conventional VLB (30 mg/m 2 /dose). Stable disease was observed in 3 refractory solid tumor subjects (1 each at the 2, 4, and 16 mg/m 2 /dose level) having received a median number of 11 (range, 7-15) cycles of therapy. No DLTs were observed at these dose levels. The mean ± SD total VLB AUC last (ng*h /mL) for Day 1 and 8, respectively, were as follows: 2 mg/m 2 : 7,810 ± 6,030, 4,930 ± 2,740; 4 mg/m 2 : 26,600 ± 9,090, 27,300 ± 12,300; 8 mg/m 2 : 35,400 ± 15,700, 39,600 ± 21,000; 16 mg/m 2 : 68,500 ± 35,200, 65,500 ± 29,800. For free VLB, the mean ± SD AUC last (ng*h /mL) for Day 1 and 8, respectively, were as follows : 2 mg/m 2 : 65.1 ± 31.5, 97.9 ± 66.9; 4 mg/m 2 : 1,140 ± 905, 458 ± 157; 8 mg/m 2 : 378 ± 465, 125 ± 32.3; 16 mg/m 2 : data pending. Conclusions: Alocrest demonstrated acceptable tolerability with encouraging activity in refractory solid tumors over multiple cycles of therapy. There is relatively high inter- and low intra-patient variability in the PK profile of total and free VLB. In plasma, free VLB accounts for a small percentage of the total VLB concentration. It is the extended circulation time of OPTISOME encapsulated VLB that contributes to the hypothesis that Alocrest has the potential to increase tumor drug delivery and improve anti-tumor activity compared to conventional VLB.
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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) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.002 | 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".