Abstract
BackgroundThe 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).MethodsPatients ≥ 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.ResultsIn 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.ConclusionThe combination of OMC and wP resulted in an acceptable safety profile, warranting further clinical evaluation.Trial registrationTRN: NCT01374620; date of registration: 16 June 2011.
Highlights
The primary aim of this trial was to determine the recommended phase II dose (RP2D) of weekly paclitaxel administered in combination with oral metronomic cyclophosphamide (OMC)
Because of its manageable toxicity profile, weekly administration of paclitaxel remains in everyday practice a largely used as palliative chemotherapy, especially in ovarian and bladder cancer patients [8, 9, 15]
G 0: no AE; G 1: Grade 1 AE, G 2: Grade 2 AE, G 3: Grade 3 AE, G 4: Grade 4 AE, G 5: lethal AE For each category type, we considered the maximum grade per patient observed over the entire treatment duration All adverse events, classified as drug-related or not, are summarized in (Additional file 1: Table S1) *Myalgia has been pooled with peripheral sensory neuropathy because this symptom reflects more a peripheral neurotoxicity than a musculoskeletal disorder in the study setting
Summary
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). The mode of action of paclitaxel involves the stabilization of microtubules through the inhibition of the depolymerization process [4, 5]. Compared with 3-week cycles, weekly administration of paclitaxel induces a clear increase in dose-intensity without significant enhancement of toxicity for fragile or heavily pretreated patients with ovarian [8, 9], lung [10, 12] gastric cancers [11] or bladder cancer [15]. Because of its manageable toxicity profile, weekly administration of paclitaxel remains in everyday practice a largely used as palliative chemotherapy, especially in ovarian and bladder cancer patients [8, 9, 15]. In the IMVigor211 trial, atezolizumab failed to demonstrate superiority compared to classical chemotherapy, and weekly paclitaxel appears the most effective drug
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