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1.
Cancer Chemother Pharmacol ; 72(3): 515-28, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23820961

ABSTRACT

PURPOSE: While first-generation taxanes are valuable treatment options for many solid tumors, they are limited by an inability to cross the blood-brain barrier (BBB) and by limited efficacy in pediatric patients. Following promising preclinical data for the next-generation taxane cabazitaxel, including activity in tumor models fully sensitive, poorly sensitive or insensitive to docetaxel, and its ability to cross the BBB, further preclinical studies of cabazitaxel relevant to these two clinical indications were performed. METHODS: Cabazitaxel brain distribution was assessed in mice, rats and dogs. Cabazitaxel antitumor activity was assessed in mice bearing intracranial human glioblastoma (SF295; U251) xenografts, and subcutaneous cell line-derived human pediatric sarcoma (rhabdomyosarcoma RH-30; Ewing's sarcoma TC-71 and SK-ES-1) or patient-derived pediatric sarcoma (osteosarcoma DM77 and DM113; Ewing's sarcoma DM101) xenografts. The activity of cabazitaxel-cisplatin combination was evaluated in BALB/C mice bearing the syngeneic murine colon adenocarcinoma, C51. RESULTS: Cabazitaxel penetrated rapidly in the brain, with a similar brain-blood radioactivity exposure relationship across different animal species. In intracranial human glioblastoma models, cabazitaxel demonstrated superior activity to docetaxel both at early (before BBB disruption) and at advanced stages, consistent with enhanced brain penetration. Compared with similar dose levels of docetaxel, cabazitaxel induced significantly greater tumor growth inhibition across six pediatric tumor models and more tumor regressions in five of the six models. Therapeutic synergism was observed between cisplatin and cabazitaxel, regardless of administration sequence. CONCLUSIONS: These preclinical data suggest that cabazitaxel could be an effective therapy in CNS and pediatric tumors, supporting ongoing clinical evaluation in these indications.


Subject(s)
Antineoplastic Agents/pharmacology , Blood-Brain Barrier/metabolism , Brain/metabolism , Neoplasms/drug therapy , Taxoids/pharmacology , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacokinetics , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Brain Neoplasms/drug therapy , Brain Neoplasms/pathology , Child, Preschool , Cisplatin/administration & dosage , Dogs , Drug Synergism , Female , Humans , Male , Mice , Mice, Inbred BALB C , Neoplasm Staging , Neoplasms/pathology , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/pathology , Rats , Rats, Sprague-Dawley , Species Specificity , Taxoids/administration & dosage , Taxoids/pharmacokinetics , Tissue Distribution , Xenograft Model Antitumor Assays , Young Adult
2.
Eur J Cancer ; 49(1): 25-34, 2013 Jan.
Article in English | MEDLINE | ID: mdl-22975213

ABSTRACT

BACKGROUND: Although the taxanes paclitaxel and docetaxel are among the most active agents for the treatment of a wide range of cancers, tumours often develop resistance to these treatments. Cabazitaxel is a novel taxane active in both preclinical models of chemotherapy-sensitive and -resistant human tumours and patients with advanced prostate cancer that progressed following docetaxel treatment. AIM: To establish the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of cabazitaxel. PATIENTS AND METHODS: Cabazitaxel was administered every 3 weeks to patients with advanced solid tumours. The design allowed intrapatient dose escalation. The primary objective was to determine the MTD. Secondary objectives were to describe the safety profile, establish an appropriate dose, determine the pharmacokinetic (PK) profile of cabazitaxel, and assess antitumour activity. RESULTS: Twenty-one patients were recruited. The MTD was reached at 30 mg/m(2), at which three of five patients experienced haematologic DLTs during the first cycle. DLTs during subsequent cycles were mainly haematologic and reported at 25 and 30 mg/m(2) dosing levels. Nail disorders and severe alopecia were not reported, and neurotoxicity, fluid retention and hypersensitivity were mild and infrequent. Cabazitaxel demonstrated linear PK, a triphasic elimination profile, with a long half-life and high clearance. Of the 19 patients evaluable for response, one unconfirmed partial response and six occurrences of stable disease were reported. CONCLUSIONS: The 25mg/m(2) dose of cabazitaxel was recommended for use in future clinical studies. In this study, cabazitaxel had an acceptable tolerability profile and activity in cervical, colorectal, endometrial and lung cancers.


Subject(s)
Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacokinetics , Neoplasms/drug therapy , Taxoids/pharmacokinetics , Taxoids/therapeutic use , Adult , Aged , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Area Under Curve , Female , Humans , Male , Maximum Tolerated Dose , Middle Aged , Taxoids/administration & dosage , Taxoids/adverse effects
3.
Eur J Cancer ; 47(7): 1037-45, 2011 May.
Article in English | MEDLINE | ID: mdl-21339064

ABSTRACT

BACKGROUND: 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. PATIENTS AND METHODS: In part I, we used a 3+3 dose-escalation scheme to assess the MTD of intravenous cabazitaxel (day 1) with oral capecitabine twice daily (days 1-14) every 3 weeks. In part II, we evaluated the objective response rate (ORR) at the MTD. RESULTS: Thirty-three patients were enrolled and treated (15 in part I; 18 in part II). Cabazitaxel 20mg/m(2) plus capecitabine 1000 mg/m(2) was the MTD. Pharmacokinetic analysis showed no apparent drug-drug interaction. In all patients, the main grade 3-4 toxicities were asthenia (n=5), hand-foot syndrome (n=5), neutropenia (n=21), neutropenic infection (n=1), and neutropenic colitis (n=1). One patient had febrile neutropenia. Antitumour activity was observed at all dose-levels with two complete responses, five partial responses (PRs), and 20 disease stabilisations (seven unconfirmed PR). At the MTD, 21 patients were evaluable for efficacy. The ORR was 23.8% (95% CI: 8.2-47.2%). The median response duration was 3.1 months (95% CI: 2.1-8.4 months), with four of five lasting for more than 3 months. Median time to progression was 4.9 months. CONCLUSIONS: Cabazitaxel combined with capecitabine is active, has a safety profile consistent with a taxane plus capecitabine combination and warrants further investigation in patients with MBC.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Deoxycytidine/analogs & derivatives , Fluorouracil/analogs & derivatives , Taxoids/administration & dosage , Adult , Aged , Area Under Curve , Capecitabine , Deoxycytidine/administration & dosage , Drug Resistance, Neoplasm , Female , Fluorouracil/administration & dosage , Humans , Maximum Tolerated Dose , Middle Aged , Neoplasm Metastasis , Treatment Outcome
4.
Ann Oncol ; 17(7): 1158-65, 2006 Jul.
Article in English | MEDLINE | ID: mdl-16600980

ABSTRACT

BACKGROUND: Oral administration of irinotecan (CPT-11) should allow sustained exposure to the drug without the inconvenience of intravenous delivery and with fewer side-effects. PATIENTS AND METHODS: The present phase I trial of CPT-11, administered orally as a powder-filled capsule for 5 consecutive days every 3 weeks at doses ranging from 30 to 90 mg/m(2)/day, was conducted in 47 patients for whom a satisfactory standard treatment option was no longer available (24 males/23 females; median age 51 years, range 26-85). Tumour types included melanoma (11), colorectal (4), urinary tract (3), lung/pleura (4), thyroid (3), liver (3), gallbladder (2), cervix/uterus (3), breast (2), pancreas (2), carcinoma and other cancer types (10). RESULTS: A total of 171 cycles were administered (median 3, range 1-11). Dose limiting toxicities (DLTs) occurred during the first cycle in five of 31 patients in the dose-escalation part of the study: one patient at the 50 mg/m(2)/day dose level (diarrhoea grade 4); one patient at the 80 mg/m(2)/day dose level (prolonged neutropenia grade 4 and diarrhoea grade 3); and three patients at the 90 mg/m(2)/day dose level (diarrhoea, vomiting and neutropenia). The 80 mg/m(2)/day dose level was expanded, as a feasibility study, to include 16 additional patients, five of whom had received extensive prior pelvic irradiation. A further three patients in this cohort experienced DLTs, two of whom had received extensive prior pelvic irradiation. One patient died on study day 15 during the first cycle of oral CPT-11 following grade 3 diarrhoea, febrile neutropenia and a necrotic enterocolitis. Overall the grade 3/4 toxicities in 47 patients were asthenia (19%), anorexia (17%), neutropenia (14.9 %), diarrhoea (13%), nausea (12.7%), vomiting (8.5%) and thrombocytopenia (8.5%). Partial responses were observed in two melanoma patients and disease stabilisation was noted in 17 (36.1%) patients. Pharmacokinetic parameters were recorded for 46 patients. CONCLUSIONS: At the maximum tolerated dose, defined as 80 mg/m(2)/day for 5 days every 3 weeks, oral CPT-11 was shown to be well tolerated and safe with few of the haematological toxicities associated with the intravenous formulation.


Subject(s)
Antineoplastic Agents, Phytogenic/administration & dosage , Camptothecin/analogs & derivatives , Neoplasms/drug therapy , Administration, Oral , Adult , Aged , Aged, 80 and over , Antineoplastic Agents, Phytogenic/adverse effects , Antineoplastic Agents, Phytogenic/pharmacokinetics , Area Under Curve , Camptothecin/administration & dosage , Camptothecin/pharmacokinetics , Camptothecin/toxicity , Female , Humans , Irinotecan , Male , Middle Aged , Topoisomerase I Inhibitors
5.
Ann Oncol ; 16(7): 1123-32, 2005 Jul.
Article in English | MEDLINE | ID: mdl-15939714

ABSTRACT

PURPOSE: The aim of this study was to determine in patients with previously untreated advanced colorectal cancer the maximum tolerated dose (MTD) and safety profile of irinotecan in combination with capecitabine, to identify a recommended dose and to determine the response rate and time to disease progression. In addition, we aimed to explore the pharmacokinetic parameters of irinotecan and capecitabine when used in different sequences of administration, with irinotecan infusion either prior to or after the first intake of capecitabine. PATIENTS AND METHODS: One hundred patients were included: 43 patients were recruited into an extended phase I trial of alternating escalation in dose of both drugs where irinotecan was administered intravenously (i.v) on day 1 after first intake of capecitabine taken from days 1-14 twice daily, with cycles repeated every 3 weeks. After the determination of recommended dose a further 57 patients were treated in a phase II evaluation with the reverse sequence of drugs on day 1. Pharmacokinetic analysis was performed in patients treated at the recommended dose in two cohorts of patients in which the sequence of the first administration of each drug was reversed. RESULTS: The MTD of the combination was determined as irinotecan 300 mg/m2, with capecitabine 2000 mg/m2/day. Dose limiting toxicities were neutropenia and diarrhoea. The recommended dose is irinotecan intravenous (i.v.) 250 mg/m2 day 1 and capecitabine 2000 mg/m2/day days 1-14, every 3 weeks. Treatment was well tolerated, with diarrhoea the most common serious toxicity. Response rate in the phase II cohort was 42% [95% confidence interval (CI) 29% to 56%]. Median duration of response was 7.7 months (95% CI 7.5-8.9). Median time to progression was 8.3 months (95% CI 5.8-10). No significant effect on irinotecan pharmacokinetics was observed whatever the intake of capecitabine before or after irinotecan infusion. An effect of irinotecan on capecitabine and some capecitabine metabolites was observed, but irinotecan did not effect 5-fluorouracil (5-FU) pharmacokinetics. CONCLUSIONS: Irinotecan in combination with capecitabine is a well tolerated regimen with an activity comparable to, but more convenient than, irinotecan-5-FU i.v. combinations in patients with previously untreated advanced colorectal cancer. The pharmacokinetic data suggest that the sequence of administration does not impact significantly on the metabolism of the two drugs.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/drug therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Area Under Curve , Camptothecin/administration & dosage , Camptothecin/analogs & derivatives , Capecitabine , Cohort Studies , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Dose-Response Relationship, Drug , Female , Fluorouracil/analogs & derivatives , Humans , Irinotecan , Male , Middle Aged
6.
Ann Oncol ; 13(7): 1140-50, 2002 Jul.
Article in English | MEDLINE | ID: mdl-12176795

ABSTRACT

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/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 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 development.


Subject(s)
Neoplasms/drug therapy , Neoplasms/pathology , Paclitaxel/analogs & derivatives , Paclitaxel/administration & dosage , Paclitaxel/pharmacokinetics , Taxoids , Adolescent , Adult , Aged , Biological Availability , Biopsy, Needle , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Humans , Infusions, Intravenous , Male , Maximum Tolerated Dose , Middle Aged , Neoplasm Staging , Neoplasms/metabolism , Neoplasms/mortality , Risk Assessment , Sensitivity and Specificity , Survival Analysis , Treatment Outcome
7.
Psychopharmacol Bull ; 34(4): 811-8, 1998.
Article in English | MEDLINE | ID: mdl-10513457

ABSTRACT

Fananserin is a potential antipsychotic compound with high affinity for both D4 and 5-HT2A receptors, and negligible affinity for D2 receptors. Because the tolerance for antipsychotic compounds often differs between schizophrenic patients and healthy subjects, this bridging study was designed to evaluate the tolerability of fananserin, to define the slow titration maximum tolerated dose in the target population, and to identify the most rapid well-tolerated rate of titration for this compound. Three rates of titration regimens were examined in a total of 26 schizophrenic patients in a parallel group design, following a 3-day placebo washout period from previous antipsychotic medication. The slow rate of titration (reaching the maximum dose of 600 mg/day in 16 days with 100-mg increases every 3 days) was well tolerated, but a rapid titration schedule (reaching 600 mg/day in 8 days with 200-mg increases every 3 days) resulted in hypotension in 3 of 6 patients and termination of the group on Day 10. An intermediate rate of titration (reaching 600 mg/day in 10 days with 100-mg increases every 2 days) was then examined and was well tolerated, with transient episodes of mild hypotension reported in 2 of 10 patients. Thus, although hypotension was identified as the dose-limiting adverse event in this study, a reduction in the titration rate was effective in reducing the incidence and severity of this side effect. In this study, schizophrenic patients administered multiple doses of fananserin tolerated doses 400 percent greater than the maximum tolerated single dose in healthy volunteers.


Subject(s)
Antipsychotic Agents/therapeutic use , Cyclic S-Oxides/therapeutic use , Naphthalenes/therapeutic use , Schizophrenia/drug therapy , Adolescent , Adult , Antipsychotic Agents/adverse effects , Antipsychotic Agents/pharmacokinetics , Cyclic S-Oxides/adverse effects , Cyclic S-Oxides/pharmacokinetics , Female , Humans , Male , Middle Aged , Naphthalenes/adverse effects , Naphthalenes/pharmacokinetics
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