Limits...
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.

Elharrar X, Barbolosi D, Ciccolini J, Meille C, Faivre C, Lacarelle B, André N, Barlesi F - BMC Cancer (2016)

Bottom Line: Mathematical modelling showed by simulation that a new metronomic protocol could lead to a better safety and efficacy profile.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.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.

View Article: PubMed Central - PubMed

Affiliation: Multidisciplinary Oncology and Therapeutic Innovations department, Assistance Publique Hôpitaux de Marseille, Aix Marseille University, Marseille, France. xavier.elharrar@ap-hm.fr.

ABSTRACT

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.

Design: 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.

Discussion: 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.

Trial registration: EudraCT N°: 2015-000138-31.

No MeSH data available.


Related in: MedlinePlus

PK and PD simulation of two metronomic protocols. Comparative model prediction for a median PK (a) profile, neutrophil count (b) and tumor weight (c) profiles with inter-individual variability, for 160 days, of two different metronomic protocols: Briasoulis et al. schedule (i.e., 50 mg on D1, D3, D5) vs the computational-based schedule Vinorelbine Theoretical Protocol (i.e.,60, 30, 60 mg on D1, D2, D4). Whereas similar tolerance is predicted between both schedules, the VTP schedule could lead to a much greater impact on tumor growth, with less variability
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC4837593&req=5

Fig1: PK and PD simulation of two metronomic protocols. Comparative model prediction for a median PK (a) profile, neutrophil count (b) and tumor weight (c) profiles with inter-individual variability, for 160 days, of two different metronomic protocols: Briasoulis et al. schedule (i.e., 50 mg on D1, D3, D5) vs the computational-based schedule Vinorelbine Theoretical Protocol (i.e.,60, 30, 60 mg on D1, D2, D4). Whereas similar tolerance is predicted between both schedules, the VTP schedule could lead to a much greater impact on tumor growth, with less variability

Mentions: With adjusted parameters, the PK-PD model described adequately the clinical data published by Briasoulis et al. (30, 40 and 50 mg, thrice a week, D1, D3, D5) both in terms of efficacy and toxicity. In a second step, the model was used to simulate, for a known average PK profile, alternate continuous metronomic schedules, achieving higher efficacy while being tolerated. A dosing regimen weekly D1, D2 and D4 with 60, 30 and 60 mg dose respectively was selected. Simulation of this protocol, named VTP (Vinorelbine Theoretical Protocol), resulted in more favourable efficacy profile and significant reduction of variability in response while maintaining a total dose per week of 150 mg (Fig. 1).Fig. 1


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.

Elharrar X, Barbolosi D, Ciccolini J, Meille C, Faivre C, Lacarelle B, André N, Barlesi F - BMC Cancer (2016)

PK and PD simulation of two metronomic protocols. Comparative model prediction for a median PK (a) profile, neutrophil count (b) and tumor weight (c) profiles with inter-individual variability, for 160 days, of two different metronomic protocols: Briasoulis et al. schedule (i.e., 50 mg on D1, D3, D5) vs the computational-based schedule Vinorelbine Theoretical Protocol (i.e.,60, 30, 60 mg on D1, D2, D4). Whereas similar tolerance is predicted between both schedules, the VTP schedule could lead to a much greater impact on tumor growth, with less variability
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4837593&req=5

Fig1: PK and PD simulation of two metronomic protocols. Comparative model prediction for a median PK (a) profile, neutrophil count (b) and tumor weight (c) profiles with inter-individual variability, for 160 days, of two different metronomic protocols: Briasoulis et al. schedule (i.e., 50 mg on D1, D3, D5) vs the computational-based schedule Vinorelbine Theoretical Protocol (i.e.,60, 30, 60 mg on D1, D2, D4). Whereas similar tolerance is predicted between both schedules, the VTP schedule could lead to a much greater impact on tumor growth, with less variability
Mentions: With adjusted parameters, the PK-PD model described adequately the clinical data published by Briasoulis et al. (30, 40 and 50 mg, thrice a week, D1, D3, D5) both in terms of efficacy and toxicity. In a second step, the model was used to simulate, for a known average PK profile, alternate continuous metronomic schedules, achieving higher efficacy while being tolerated. A dosing regimen weekly D1, D2 and D4 with 60, 30 and 60 mg dose respectively was selected. Simulation of this protocol, named VTP (Vinorelbine Theoretical Protocol), resulted in more favourable efficacy profile and significant reduction of variability in response while maintaining a total dose per week of 150 mg (Fig. 1).Fig. 1

Bottom Line: Mathematical modelling showed by simulation that a new metronomic protocol could lead to a better safety and efficacy profile.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.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.

View Article: PubMed Central - PubMed

Affiliation: Multidisciplinary Oncology and Therapeutic Innovations department, Assistance Publique Hôpitaux de Marseille, Aix Marseille University, Marseille, France. xavier.elharrar@ap-hm.fr.

ABSTRACT

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.

Design: 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.

Discussion: 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.

Trial registration: EudraCT N°: 2015-000138-31.

No MeSH data available.


Related in: MedlinePlus