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.
BACKGROUND
Metronomic oral vinorelbine is effective in metastatic NSCLC and malignant pleural mesothelioma, but all the studies published thus far were based upon a variety of empirical and possibly suboptimal schedules, with inconsistent results. Mathematical modelling showed by simulation that a new metronomic protocol could lead to a better safety and efficacy profile.


METHODS
This phase Ia/Ib trial was designed to confirm safety (phase Ia) and evaluate efficacy (phase Ib) of a new metronomic oral vinorelbine schedule. Patients with metastatic NSCLC or malignant pleural mesothelioma in whom standard treatments failed and who exhibited ECOG performance status 0-2 and adequate organ function will be eligible. Our mathematical PK-PD model suggested an alternative weekly D1, D2 and D4 schedule (named Vinorelbine Theoretical Protocol) with a respective dose of 60, 30 and 60 mg. Trial recruitment will be two-staged, as 12 patients are planned to participate in phase Ia to confirm safety and consolidate the calibration of the model parameters. Depending on the phase Ia results and after a favourable decision from a consultative committee, the extension phase (phase Ib) will be an efficacy study including 20 patients who will receive the Optimal Vinorelbine Theoretical Protocol. The primary endpoint is the tolerance (assessed by CTC v4.0) for the phase Ia and the objective response according to RECIST 1.1 for phase Ib. An ancillary study on circulating angiogenesis biomarkers will be a subproject of the trial.


CONCLUSIONS
This ongoing trial is the first to prospectively test a mathematically optimized schedule in metronomic chemotherapy. As such, this trial can be considered as a proof-of-concept study demonstrating the feasibility to run a computational-driven protocol to ensure an optimal efficacy/toxicity balance in patients with cancer.


BACKGROUND
EudraCT N°: 2015-000138-31.
Multidisciplinary Oncology and Therapeutic Innovations department, Assistance Publique Hôpitaux de Marseille, Aix Marseille University, Marseille, France. xavier.elharrar@ap-hm.fr.|SMARTc Pharmacokinetics Unit, Aix Marseille University, Inserm S_911 CRO2, Marseille, France. xavier.elharrar@ap-hm.fr.
Xavier
X
Elharrar
SMARTc Pharmacokinetics Unit, Aix Marseille University, Inserm S_911 CRO2, Marseille, France.
Dominique
D
Barbolosi
SMARTc Pharmacokinetics Unit, Aix Marseille University, Inserm S_911 CRO2, Marseille, France.
Joseph
J
Ciccolini
SMARTc Pharmacokinetics Unit, Aix Marseille University, Inserm S_911 CRO2, Marseille, France.
Christophe
C
Meille
SMARTc Pharmacokinetics Unit, Aix Marseille University, Inserm S_911 CRO2, Marseille, France.
Christian
C
Faivre
SMARTc Pharmacokinetics Unit, Aix Marseille University, Inserm S_911 CRO2, Marseille, France.
Bruno
B
Lacarelle
SMARTc Pharmacokinetics Unit, Aix Marseille University, Inserm S_911 CRO2, Marseille, France.|Assistance Publique Hôpitaux de Marseille, Centre d'Essais Précoces en Cancérologie de Marseille APHM CLIP2, Aix Marseille University, Marseille, France.|Paediatry Oncology Unit, Assistance Publique Hôpitaux de Marseille, Marseille, France.
Nicolas
N
André
Multidisciplinary Oncology and Therapeutic Innovations department, Assistance Publique Hôpitaux de Marseille, Aix Marseille University, Marseille, France. Fabrice.Barlesi@ap-hm.fr.|SMARTc Pharmacokinetics Unit, Aix Marseille University, Inserm S_911 CRO2, Marseille, France. Fabrice.Barlesi@ap-hm.fr.|Assistance Publique Hôpitaux de Marseille, Centre d'Essais Précoces en Cancérologie de Marseille APHM CLIP2, Aix Marseille University, Marseille, France. Fabrice.Barlesi@ap-hm.fr.
Fabrice
F
Barlesi
D059250:Administration, Metronomic; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D008875:Middle Aged; D008962:Models, Theoretical; D015996:Survival Rate; D014747:Vinblastine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000077235:Vinorelbine; D017321:Clinical Trials, Phase I as Topic
D000972:Antineoplastic Agents, Phytogenic; D014747:Vinblastine; D000077235:Vinorelbine
Computational oncology; Lung cancer; Mesothelioma; Metronomics; Modelling and simulation; Vinorelbine