Mathematical modeling for Phase I cancer trials: A study of metronomic vinorelbine for advanced non-small cell lung cancer (NSCLC) and mesothelioma patients

Our plain-English summary of Mathematical modeling for Phase I cancer trials: A study of metronomic vinorelbine for advanced non-small cell lung cancer (NSCLC) and mesothelioma patients, by F. Barlesi, D.C. Imbs, P. Tomasini, et al (Oncotarget, 2017).

The study

• Authors: F. Barlesi, D.C. Imbs, P. Tomasini, L. Greillier, M. Galloux, A. Testot-Ferry, M. Garcia, X. Elharrar, A. Pelletier, N. André, C. Mascaux, B. Lacarelle, R.E. Cheikh, R. Serre, J. Ciccolini, D. Barbolosi
• Journal: Oncotarget
• Published: 2017;8(29):47161-47166
• Cited by: 19 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Introduction: Using mathematical modelling allows to select a treatment's regimen across infinite possibilities. Here, we report the phase I assessment of a new schedule for metronomic vinorelbine in treating refractory advanced NSCLC and mesothelioma patients.

Results: Overall, 13 patients were screened and 12 were treated (50% male, median age: 68yrs), including 9 NSCLC patients. All patients received at least one week (3 doses) of treatment. At data cut-off, the median length of treatment was 6.5 weeks (1-32+). All the patients presented with at least one adverse event (AE) and six patients with a severe AE (SAE). One partial response and 5 stable diseases were observed. The median OS was 6.4 months (95% CI, 4.8 to 12 months). The median and mean vinorelbine's AUC were 122 ng/ml*h and 159 ng/ml*h, respectively, with the higher plasmatic vinorelbine exposure associated with the best ORR (difference of AUC comparison between responders and non-responders, p-value 0.017).

Materials And Methods: The mathematical modelling determined the administration of vinorelbine, 60 mg on Day 1, 30 mg on Day 2 and 60 mg on Day 4 weekly until progression, as the best schedule. Advanced NSCLC or mesothelioma patients progressing after standard treatment were eligible for the trial. NCT02555007.

Conclusions: Responses with acceptable safety profile were observed in heavily pretreated NSCLC and mesothelioma patients using oral vinorelbine at this metronomic dosage based on a mathematic modeling. This study demonstrates the feasibility of this new type of approach, as mathematical modeling may help to rationally decide the better regimen to be clinically tested across infinite possibilities.

In plain English

This article reported the first stage of a phase I drug trial in Marseille, France; it did not study asbestos exposure. Using a mathematical model, the authors chose a weekly schedule of oral vinorelbine, a chemotherapy drug: 60 mg on Day 1, 30 mg on Day 2 and 60 mg on Day 4. Between August 2015 and February 2016, 12 patients whose disease was progressing after standard treatment were treated: 9 with advanced non-small cell lung cancer (NSCLC) and 3 with mesothelioma. Every patient had at least one adverse event (a health problem during treatment, not necessarily caused by the drug), and six had a severe adverse event. One patient died of a lung infection reported as unrelated to the drug. One NSCLC patient had a partial response, and five patients (three NSCLC, two mesothelioma) had stable disease. Median overall survival was 6.4 months (95% CI 4.8 to 12 months). Responders had higher blood levels of the drug (p = 0.017), though levels varied widely between patients. The authors concluded that responses with acceptable safety were seen and the approach was feasible. They noted that the small number of patients did not support a different schedule.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Phase I clinical trial (first stage of a two-stage design) testing a vinorelbine schedule chosen by mathematical modeling
• Who was studied: 13 patients were screened and 12 treated, from August 26, 2015 to February 18, 2016, in Marseille, France. Of the 12, 9 had advanced NSCLC and 3 had mesothelioma, all progressing after standard treatment. There were 6 men and 6 women, with a median age of 68 years (range 44 to 78) and a median of 4 previous lines of therapy.
• Exposure: Not an asbestos exposure study. The exposure studied was the drug oral vinorelbine: 60 mg on Day 1, 30 mg on Day 2 and 60 mg on Day 4 each week, continued until disease progression or unacceptable toxicity.
• Main results:
  • Among the 12 treated patients, the median length of treatment was 6.5 weeks (range 1 to 32 weeks). One patient was still on treatment at the September 1, 2016 data cut-off.
  • All 12 patients had at least one adverse event, and six had a severe adverse event. One patient died of a drug-unrelated severe adverse event (pulmonary infection).
  • Two patients were not evaluable for response. Among evaluable patients there was 1 partial response (NSCLC) and 5 cases of stable disease (3 NSCLC, 2 mesothelioma). Per Table 3, the disease progressed in 4 patients (3 NSCLC, 1 mesothelioma).
  • After a median follow-up of 12.1 months for patients still alive, median progression-free survival was 2.5 months (95% CI 1.2 to 7.6) and median overall survival was 6.4 months (95% CI 4.8 to 12). Three patients were still alive.
  • Median and mean vinorelbine AUC (a measure of blood drug exposure) were 122 ng/ml*h and 159 ng/ml*h (range 13 to 392). Large variations were seen across patients.
  • Patients with higher vinorelbine blood exposure had the best responses. AUC differed between responders and non-responders with p = 0.017.
  • Computer simulations using the updated model found no better schedule, so 20 additional patients will receive the same protocol.
• The authors' conclusion: The authors concluded that responses with acceptable safety were observed in heavily pretreated NSCLC and mesothelioma patients using this model-based oral vinorelbine schedule. They also concluded that the study demonstrates the feasibility of the approach.
• Limitations the authors state:
  • The small number of patients in the first part of the study did not allow the authors to propose a different schedule.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Vinorelbine, Non-Small Cell Lung Cancer, Mesothelioma, P-Value.

Related studies

• A phase Ia/Ib clinical trial of metronomic chemotherapy based on a mathematical model of oral vinorelbine in metastatic non-small cell lung cancer and malignant pleural mesothelioma: rationale and study protocol — X. Elharrar, D. Barbolosi, et al. (2016)
• A dose-finding study of gemcitabine and vinorelbine in advanced previously treated malignancies — J.P. Delord, E. Raymond, et al. (2000)
• BRCA1 is an essential mediator of vinorelbine-induced apoptosis in mesothelioma — S. Busacca, M. Sheaff, et al. (2012)
• A randomized phase II study of SRL172 (Mycobacterium vaccae) combined with chemotherapy in patients with advanced inoperable non-small-cell lung cancer and mesothelioma — M.E. O'Brien, A. Saini, et al. (2000)
• Randomised phase II study of cisplatin-etoposide versus infusional carboplatin in advanced non-small-cell lung cancer and mesothelioma — S.C. White, H. Anderson, et al. (2000)
• Gemcitabine and vinorelbine as second-line or beyond treatment in patients with malignant pleural mesothelioma pretreated with platinum plus pemetrexed chemotherapy — G. Toyokawa, M. Takenoyama, et al. (2014)

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