Once weekly paclitaxel associated with a fixed dose of oral metronomic cyclophosphamide: a dose-finding phase 1 trial

Diane Pannier, Antoine Adenis, Emilie Bogart, Eric Dansin, Stéphanie Clisant-Delaine, Emilie Decoupigny, Anne Lesoin, Eric Amela, Sandrine Ducornet, Jean-Pierre Meurant, Marie-Cécile Le Deley, Nicolas Penel, Diane Pannier, Antoine Adenis, Emilie Bogart, Eric Dansin, Stéphanie Clisant-Delaine, Emilie Decoupigny, Anne Lesoin, Eric Amela, Sandrine Ducornet, Jean-Pierre Meurant, Marie-Cécile Le Deley, Nicolas Penel

Abstract

Background: The primary aim of this trial was to determine the recommended phase II dose (RP2D) of weekly paclitaxel (wP) administered in combination with oral metronomic cyclophosphamide (OMC).

Methods: Patients ≥ 18 years of age with refractory metastatic cancers were eligible if no standard curative measures existed. Paclitaxel was administered IV weekly (D1, D8, D15; D1 = D28) in combination with a fixed dose of OMC (50 mg twice a day). A 3 + 3 design was used for dose escalation of wP (40 to 75 mg/m2) followed by an expansion cohort at RP2D. Dose-limiting toxicity (DLT) was defined over the first 28-day cycle as grade ≥ 3 non-hematological or grade 4 hematological toxicity (NCI-CTCAE v4.0) or any toxicity leading to a dose reduction.

Results: In total, 28 pts. (18 in dose-escalation phase and 10 in expansion cohort) were included, and 16/18 pts. enrolled in the dose-escalation phase were evaluable for DLT. DLT occurred in 0/3, 1/6 (neuropathy), 0/3 and 2/4 pts. (hematological toxicity) at doses of 40, 60, 70 and 75 mg/m2 of wP, respectively. The RP2D of wP was 70 mg/m2; 1/10 patients in the expansion phase had a hematological DLT. At RP2D (n = 14), the maximal grade of drug-related adverse event was Gr1 in three patients, Gr2 in six patients, Gr3 in one patient and Gr4 in one patient (no AE in three patients). At RP2D, a partial response was observed in one patient with lung adenocarcinoma.

Conclusion: The combination of OMC and wP resulted in an acceptable safety profile, warranting further clinical evaluation.

Trial registration: TRN: NCT01374620 ; date of registration: 16 June 2011.

Keywords: Dose-finding phase 1 trial; Metronomic cyclophosphamide; Weekly paclitaxel.

Conflict of interest statement

Ethics approval and consent to participate

This study was approved by the regional Ethics Committee (“Comité de Protection des Patients Nord-Ouest III”, date of approval: 02 March 2011) and the French Health Products Safety Agency (“Agence Française de Sécurité Sanitaire et des Produits de Santé”, Date of 13 May 2011). This study was registered in the ClinicalTrial.gov Register (NCT01374620). Written informed consent was obtained from each patient.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Distribution of treatment-related adverse events during the first treatment cycle (all patients, N = 28)

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