A dose-escalating study of XRP6258 in combination with capecitabine, in patients (pts) with metastatic breast cancer (MBC) progressing after anthracycline and taxane therapy: Preliminary results

1053 Background: Cabazitaxel (X), a new taxoid showed activity in taxane resistant MBC. Capecitabine (C) is approved in MBC pts pretreated with anthracycline and taxane. Methods: A standard 3+3 escalation scheme explored doses of combined intravenous X (Day (D)1) with oral C twice daily (D1to14), every 3 weeks (q3w). The study objectives were the identification of dose limiting toxicities (DLTs), recommended dose (RD) of the combination, assessment of safety, pharmacokinetics (PK) and activity at the RD in an expanded cohort. Results: 32 MBC pts pretreated with taxane and anthracycline were enrolled and treated (15 in the dose escalation part and 17 at the RD). Data for the first 25 pts, are available so far: median age 52 [34–74], ECOG-PS 0/1: 15/10, in first or second line chemotherapy, median of 3 (1–7) organs involved (mainly: bone, liver, lymph nodes). In the escalation part, X+C were administered at 3 dose levels (DL) (Table). DL2 was defined as the RD and the expansion cohort was initiated. PK analysis did not show any drug-drug interaction with this schedule of administration. Overall, out of the 25 pts (125cy), the main Gr3–4 toxicities (N pts) were asthenia (4), hand-foot syndrome (4), neutropenia (15), febrile neutropenia (1), neutropenic infection (1), no toxic death. Efficacy was observed at each DL with a total of 1 complete response, 4 partial responses (PR) and 16 stabilizations (including 3 unconfirmed PR). Conclusions: X was safely combined to C. X at 20 mg/m2 D1 + C at 1000 mg/m2 twice a D (D1–14), q3w is the RD. Updated results for efficacy and safety will be presented. [Table: see text] [Table: see text] </jats:p

Phase I clinical and pharmacokinetic studies of the taxoid derivative RPR 109881A administered as a 1-hour or a 3-hour infusion in patients with advanced solid tumors

Purpose: To define the maximum tolerated dose (MTD), the recommended phase II dose, the optimal infusion duration and pharmacokinetics of the semisynthetic taxoid derivative RPR 109881A, given as a 1-h or 3-h infusion every 3 weeks. Patients and methods: RPR109881A was administered as a 1-h i.v. infusion to 34 patients (study 1) with oral steroids as pre-medication. In a subsequent study, 29 patients were treated at the recommended dose or at the dose immediately below (study 2); the first 14 patients received RPR 109881A as a 3-h infusion, while the subsequent 15 were randomized to receive the drug as a 1-h or 3-h infusion. The pharmacokinetics of RPR109881A was studied in plasma and urine and for selected patients in some biological fluids (cerebrospinal fluid, pleural effusion, ascitis). Results: In study 1, the dose was escalated from 15 to 105 mg/m2, at which dose two of five patients presented dose-limiting toxicities with febrile neutropenia (FN) after the first cycle, thus defining the MTD. The dose of 90 mg/m2, at which grade 3/4 neutropenia was almost universal with FN in 18%, was recommended for phase II. At 90 mg/m2 the incidence of diarrhea, fatigue and alopecia were 59, 29 and 70%, respectively. The results of study 2 were comparable to those of study 1, thus recommending the 1-h infusion duration for phase II evaluation. RPR 109881A exhibited a high total body clearance, a large distribution volume and long terminal half-life of 20 h. RPR 109881A was detected in cerebrospinal fluid shortly after the end of 1-h infusion. Three objective responses were observed in non-small-cell lung cancer (NSCLC) patients, including a patient with brain metastases. Conclusions: The antitumor activity in NSCLC, the reproducible profile of toxicity and above all the ability to cross the blood-brain barrier make RPR 109881A worthy of further disease-oriented clinical developmen

A multicentre dose-escalating study of cabazitaxel (XRP6258) in combination with capecitabine in patients with metastatic breast cancer progressing after anthracycline and taxane treatment: a phase I/II study.

Most patients with metastatic breast cancer (MBC) progress after chemotherapy. Cabazitaxel (XRP6258) is a new taxoid that is active in chemotherapy-resistant tumour cell lines. The objectives of this phase I/II study were to assess the maximum tolerated dose (MTD), safety profile, pharmacokinetics, and activity of cabazitaxel plus capecitabine in patients with MBC who had been previously treated with taxanes and anthracyclines.Clinical Trial, Phase IIClinical Trial, Phase IIIJournal ArticleMulticenter StudyResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Phase I clinical and pharmacokinetic studies of the taxoid derivative RPR 109881A administered as a 1-hour or a 3-hour infusion in patients with advanced solid tumors.

Purpose: To define the maximum tolerated dose (MTD), the recommended phase II dose, the optimal infusion duration and pharmacokinetics of the semisynthetic taxoid derivative RPR 109881 A, given as a 1-h or 3-h infusion every 3 weeks. Patients and methods: RPR109881A was administered as a 1-h i.v. infusion to 34 patients (study 1) with oral steroids as pre-medication. In a subsequent study, 29 patients were treated at the recommended dose or at the dose immediately below (study 2); the first 14 patients received RPR109881A as a 3-h infusion, while the subsequent 15 were randomized to receive the drug as a 1-h or 3-h infusion. The pharmacokinetics of RPR109881A was studied in plasma and urine and for selected patients in some biological fluids (cerebrospinal fluid, pleural effusion, ascitis). Results: In study 1, the dose was escalated from 15 to 105 mg/m(2), at which dose two of five patients presented dose-limiting toxicities with febrile neutropenia (FN) after the first cycle, thus defining the MTD. The dose of 90 mg/m(2), at which grade 3/4 neutropenia was almost universal with FN in 18%, was recommended for phase II. At 90 mg/m(2) the incidence of diarrhea, fatigue and alopecia were 59, 29 and 70%, respectively. The results of study 2 were comparable to those of study 1, thus recommending the 1-h infusion duration for phase 11 evaluation. RPR 109881 A exhibited a high total body clearance, a large distribution volume and long terminal half-life of 20 It. RPR 10988 1 A was detected in cerebrospinal fluid shortly after the end of 1-h infusion. Three objective responses were observed in non-small-cell lung cancer (NSCLC) patients, including a patient with brain metastases. Conclusions: The antitumor activity in NSCLC, the reproducible profile of toxicity and above all the ability to cross the blood-brain barrier make RPR 10988 1 A worthy of further disease-oriented clinical development