Phase I study of JM-216 (an oral platinum analogue) in combination with paclitaxel in patients with advanced malignancies

This phase I study wasconducted to determine the dose limitingtoxicity, maximum tolerated doses, andrecommended phase II doses of thecombination of JM-216 and paclitaxel. Patients received paclitaxel intravenouslyover one hour on day 1 of each cycle. OralJM-216 was administered on days 1–5starting after the paclitaxel infusion. Cycles were repeated every 21 days. Patients were accrued at nine differentdosing combinations. JM-216 doses rangedfrom 10–80 mg/m²/day and werecombined with paclitaxel doses of 150, 175,or 200 mg/m². Forty-three patientswere treated with 146 cycles of therapy. Dose-limiting toxicity, consisting offebrile neutropenia and grade 3thrombocytopenia, was encountered in 2patients at the seventh dose level (JM-21680 mg/m²/day + paclitaxel175 mg/m²). Two intermediate doselevels were explored. The first level(JM-216 70 mg/m²/day + paclitaxel175 mg/m²) produced dose-limitingthrombocytopenia in 1 of 6 patients. However, two additional patients alsodemonstrated delayed recovery fromthrombocytopenia following treatment. As aresult, a second intermediate dose level(JM-216 60 mg/m²/day + paclitaxel200 mg/m²) was filled with sixpatients. No dose-limiting toxicities werereported in any patients at this doselevel. The combination of oral JM-216 andpaclitaxel is well-tolerated with minimalnon-hematologic and reversible hematologictoxicity. The recommended dose for phaseII study is JM-216 60 mg/m²/day for 5days and paclitaxel 200 mg/m² on day 1repeated every 21 days. Higher doses ofJM-216 are associated with more severethrombocytopenia and delayed hematologicrecovery resulting in subsequent dosingdelays.     

A phase I and pharmacokinetic study of paclitaxel and epirubicin in advanced cancer

The objectives of this phase I trial were to determine the maximally tolerated doses of the combination of epirubicin and paclitaxel with and without G-CSF (granulocyte colony stimulating factor) support and to investigate whether epirubicin pharmacokinetics are altered by paclitaxel. Patients with advanced cancer, performance status 0–2, and a normal left ventricular ejection fraction who had received up to 1 prior chemotherapy regimen were treated with epirubicin followed by a 3-hour infusion of paclitaxel repeated every 3 weeks. Dose levels studied were (paclitaxel/epirubicin) 155/75, 175/75, 175/90, 200/90 mg/m² without G-CSF and 175/90 mg/m² with G-CSF. Thirty-five patients were entered and all were assessable for toxicity. The dose-limiting dose level was 175 mg/m² paclitaxel and 90 mg/m² epirubicin with limiting toxicities of febrile neutropenia, diarrhea and esophagitis. The addition of G-CSF did not allow escalation of epirubicin. No significant cardiac toxicity was observed. Epirubicin pharmacokinetics were studied during the first 2 cycles in 6 patients, who were randomized to receive 1 cycle with no interval between the completion of the epirubicin and the commencement of the paclitaxel infusion and the other cycle with a 72-hour interval between the drugs. There was no substantial effect of paclitaxel on epirubicin or epirubicinol pharmacokinetics, although there was a marginal increase in glucoronidation. In conclusion, paclitaxel 175 mg/m² and epirubicin 75 mg/m² is recommended for phase II and III studies.     

Phase I trial of vinflunine and pemetrexed in refractory solid tumors

Background Vinflunine is a novel vinca alkaloid with promising single agent clinical activity. Pemetrexed has at least additive activity with other vincas. A phase I trial was undertaken to assess the safety of vinflunine and pemetrexed in patients with refractory solid tumors. Methods A standard 3-patient cohort dose escalation scheme was used to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of the vinflunine/pemetrexed combination. Pemetrexed 500 mg/m² was given with vinflunine 280 mg/m² (cohort 1), 300 mg/m² (cohort 2) or 320 mg/m² (cohort 3) on day 1 of a 21-day cycle. Results 19 patients were enrolled, median age 58 years (range 32 to 77) and had a median of 3 (range 1–6) prior therapies. DLT occured 1 of 6 pts in cohort 1 (thrombocytopenia, hyponatremia), 2 of 10 pts in cohort 2 (febrile neutropenia, hyponatremia, hyperbilirubinema; febrile neutropenia), and 2 of 3 pts in cohort 3 (febrile neutropenia, hypokalemia; febrile neutropenia). 1 pt in cohort 2 died prior to completion of cycle 1 likely from disease progression. Most common grade 3/4 adverse events were neutropenia (7), leukopenia (5). Febrile neutropenia occurred in 4 patients (21%). No objective responses were seen. Two patients (breast and lung) had prolonged stable disease for 25 and 20 cycles respectively. Conclusions Based on this experience we recommend vinflunine 300 mg/m² and pemetrexed 500 mg/m² in combination every 3 weeks for future study. At these doses, the combination of vinflunine and pemetrexed was tolerable in this heavily pretreated population. Hematologic toxicity, including febrile neutropenia, was prominent.     

A phase I study of ispinesib,a kinesin spindle protein inhibitor,administered weekly for three consecutive weeks of a 28-day cycle in patients with solid tumors

Purpose To establish the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), safety, and pharmacokinetic profile of ispinesib when administered as a 1-h intravenous infusion weekly for three consecutive weeks of a 28 day treatment period to patients with advanced solid tumors. Experimental Design Thirty patients were enrolled using an initial accelerated dose-escalation phase followed by a standard dose-escalation phase at doses ranging from 1–8 mg/m²/week. Pharmacokinetic samples, skin punch biopsies, and tumor biopsies (in patients with accessible tumor) were obtained during cycle 1 of treatment. Disease assessment was performed every two treatment cycles. Results The MTD was defined as 7 mg/m² administered as a 1-h infusion weekly for three consecutive weeks of a 28 day schedule. The MTD was exceeded at 8 mg/m² due to DLTs of grade 2 (one patient) and grade 3 neutropenia (one patient) that resulted in the inability to administer the Day 15 dose in Cycle 1. The neutrophil nadir occurred at approximately Day 8 with a 3–7 day recovery period. The most common toxicities were nausea, diarrhea, fatigue, and neutropenia. Alopecia, mucositis, and neuropathy were not observed. Stable disease was reported as the best response to treatment in nine patients. Conclusion The recommended dose of ispinesib is 7 mg/m² over 1 h weekly for three consecutive weeks of a 28 day treatment cycle.     

Phase I study of NK105, a nanomicellar paclitaxel formulation,administered on a weekly schedule in patients with solid tumors

Previous studies have established the rationale for NK105, a nanomicellar formulation of paclitaxel, administered every 3 weeks. The aim of this phase I study was to determine the recommended dose and pharmacokinetics of weekly administered NK105. NK105 was administered by a 30-min infusion once weekly for three consecutive weeks in each 4-week cycle. In the dose-escalation phase, three to seven patients with solid tumors were enrolled to each of the four dose levels (50–100 mg/m²; n = 16). At a dose level of 100 mg/m², predefined dose-limiting toxicity (DLT) manifested in only one out of six evaluable patients, whereas a dose delay due to neutropenia during the first course occurred two patients. None of the three patients given 80 mg/m² had a dose reduction, while a dose delay occurred in two. NK105 exhibited linear pharmacokinetics at doses of 50–100 mg/m², and approximately 5 % of total paclitaxel was released from micelles. Thus, the recommended dose was set at 80 mg/m², and an additional 10 advanced breast cancer (ABC) patients were given this dose in the dose-expansion phase. DLT manifested in two patients, and grade ≥ 3 neutropenia was found in eight patients. Among the nine patients who completed the first cycle, four had a dose reduction, mostly because of neutropenia. Of the 10 patients, six achieved partial response (PR), and four achieved stable disease (SD) status. Overall, weekly NK105 was well tolerated and had a desirable antitumor activity profile. Further investigations of NK105 in ABC patients are currently underway.     

A phase I dose escalation study of TTI-237 in patients with advanced malignant solid tumors

Purpose: This study was to determine the maximum tolerated dose, dose-limiting toxicities, and pharmacokinetic profile of TTI-237, a novel anti-tubulin drug, administered weekly in patients with refractory solid tumors. Patients and methods: Using an accelerated dose escalation design, patients with refractory solid tumors were enrolled in this study and treated with TTI-237 intravenously on days 1, 8 and 15 of a 28-day cycle. The starting dose was 4.5 mg/m². Pharmacokinetic studies were performed in patients at all dose levels. Result: Twenty-eight patients were enrolled and treated with TTI-237 at dose of 4.5, 9, 15, 22.5 and 31.5 mg/m². One dose-limiting toxicity neutropenia fever was observed at 31.5 mg/m², and all seven patients developed grade 3 or 4 neutropenia at that dose level. TTI-237 dosage was de-escalated to 22.5 and 18 mg/m². Six patients were treated at the 18 mg/m² dose level without dose-limiting toxicity prior to trial termination. The mean terminal-phase elimination half-life (t_1/2) for TTI-237 was 25–29 h, and the mean area under the concentration time curve at 31.5 mg/m² was 2,768 ng•h/mL. Conclusion: A protocol defined maximum tolerated dose was not determined because of early termination of the TTI-237 trial by the sponsor. 18 mg/m² may be a tolerable dose of TTI-237.     

A population pharmacokinetic model for paclitaxel in the presence of a novel P-gp modulator,Zosuquidar Trihydrochloride (LY335979)

AIMS: To develop a population pharmacokinetic model for paclitaxel in the presence of a MDR modulator, zosuquidar 3HCl. METHODS: The population approach was used (implemented with NONMEM) to analyse paclitaxel pharmacokinetic data from 43 patients who received a 3-h intravenous infusion of paclitaxel (175 mg x m(-2) or 225 mg x m(-2)) alone in cycle 2 or concomitantly with the oral administration of zosuquidar 3HCl in cycle 1. RESULTS: The structural pharmacokinetic model for paclitaxel, accounting for the Cremophor ELTM impact, was a three-compartment model with a nonlinear model for paclitaxel plasma clearance (CL), involving a linear decrease in this parameter during the infusion and a sigmoidal increase with time after the infusion. The final model described the effect of Zosuquidar 3HCl on paclitaxel CL by a categorical relationship. A 25% decrease in paclitaxel CL was observed, corresponding to an 1.3-fold increase in paclitaxel AUC (from 14829 microg x l(-1) x h to 19115 microg x l(-1) x h following paclitaxel 175 mg x m(-2)) when zosuquidar Cmax was greater than 350 microg x l(-1). This cut-off concentration closely corresponded to the IC50 of a sigmoidal Emax relationship (328 microg x l(-1)). A standard dose of 175 mg x m(-2) of paclitaxel could be safely combined with doses of zosuquidar 3HCl resulting in plasma concentrations known, from previous studies, to result in maximal P-gp inhibition. CONCLUSIONS: This analysis provides a model which accurately characterized the increase in paclitaxel exposure, which is most likely to be due to P-gp inhibition in the bile canaliculi, in the presence of zosuquidar 3HCl (Cmax > 350 microg x l(-1)) and is predictive of paclitaxel pharmacokinetics following a 3 h infusion. Hence the model could be useful in guiding therapy for paclitaxel alone and also for paclitaxel administered concomitantly with a P-gp inhibitor, and in designing further clinical trials.     

Pemetrexed combined with paclitaxel: a dose-finding study evaluating three schedules in solid tumors

Summary  The objectives of this phase I study were to determine the maximum tolerated dose (MTD), recommended phase II dose (RD), antitumor activity, safety, and pharmacokinetics of pemetrexed–paclitaxel combination. Patients (N = 95) with advanced solid tumors were assigned to three schedules (21-day cycles [q21d]). Starting doses for each schedule of pemetrexed and paclitaxel, respectively, were: (S1) 400 and 135 mg/m² on d1; (S2) 400 mg/m² d1 and 40 mg/m² d1 and d8; S3) 400 mg/m² d8 and 30 mg/m² d1 and d8. MTD was 500/135 mg/m² (S1), 400/40 mg/m² (S2), and 500/120 mg/m² (S3). Most common dose limiting toxicities were febrile neutropenia, fatigue, and neuromotor toxicities. Most common toxicity was grade 3/4 lymphopenia. Four patients had partial response, 43 patients had stable disease. The RD determined was pemetrexed 500 mg/m² (d8) and paclitaxel 90 mg/m² (d1 and d8), q21d. The combination was well tolerated and showed efficacy in thyroid carcinoma and mesothelioma.     

Phase I study of pemetrexed and pegylated liposomal doxorubicin in patients with refractory breast,ovarian, primary peritoneal,or fallopian tube cancer

Purpose: Pemetrexed and pegylated liposomal doxorubicin (PLD) are clinically active as single agents and preclinically synergistic. This phase I, open-label trial evaluated the maximum tolerated dose (MTD) and safety of pemetrexed followed by PLD in patients with breast or gynecologic cancers. Patients: Using 3 + 3 dose escalation, cohorts of 3–9 patients received escalating doses of pemetrexed 400–500 mg/m² on days 1 and 15 and PLD 30–45 mg/m² on day 1 of a 28-day cycle. All patients received folic acid and vitamin B₁₂ until 21 days after last pemetrexed dose. Patients continued until dose-limiting toxicity (DLT) or progression (PD). Results: From 11/05 to 2/08, 29 patients entered treatment; median age: 60.6 years (range, 47.5–80.1); ECOG PS 0/1: 27.6%/72.4%; primary disease site: ovarian (55.2%), breast (34.5%), peritoneum (10.3%); prior therapies: chemotherapy (100.0%), surgery (72.4%), hormones/biologics (35%), and radiation (20.7%). Pemetrexed/PLD dose levels: L1 = 400/30 (n = 4), L2 = 400/35 (n = 6), L3 = 500/35 (n = 9), L4 = 500/40 (n = 7), and L5 = 500/45 (n = 3). Treatment-related grade 3-4 toxicities: hematologic—neutropenia (86.2%), leukopenia (58.6%), thrombocytopenia (48.3%), anemia (41.4%); nonhematologic—mucosal inflammation (24.1%), febrile neutropenia (24.1%), hand-foot syndrome (13.8%), hypokalaemia (10.3%). Reasons for discontinuation: PD (48.3%), toxicity (27.6%), patient request (13.8%), and investigator request (10.3%). Efficacy: 5 ovarian patients (20.8%) achieved partial response; median time to progression (TTP) was 6.1 months (range, 1.2–12.5). Conclusion: Pemetrexed plus PLD was reasonably tolerated in this heavily–pretreated population. MTD: pemetrexed 500 mg/m² and PLD 40 mg/m² may be carried forward to phase II studies in specific patient populations. TTP in platinum-refractory ovarian patients was greater than expected.     

Phase I trial of weekly cisplatin,irinotecan and paclitaxel in patients with advanced gastrointestinal cancer

Summary   Objectives: To determine the maximum tolerated dose (MTD), toxicities, and suitable dose for weekly 1-h paclitaxel combined with weekly cisplatin and irinotecan to treat advanced gastrointestinal malignancies. Methods: Thirty patients with metastatic or locally advanced (unresectable or recurrent) gastrointestinal solid tumors were enrolled on this single-center, phase I study. Patients were treated with paclitaxel given over 1h at 1 of 4 dose levels (40, 50, 65, or 80 mg/m²). Paclitaxel was followed by fixed doses of cisplatin (30 mg/m²) and irinotecan (50 mg/m²). All treatment was administered sequentially, once a week, in 6-week cycles (4 weeks on, 2 weeks off). Dose-limiting toxicity (DLT) was defined as a 2-week delay in treatment for grade 3 or 4 non-hematologic toxicity, neutropenic fever, a 1-week delay for grade 4 hematologic toxicity, or a 2-week delay for grade 3 hematologic toxicity. Results: Thirty patients were recruited; 28 patients were assessable for safety. Most of the patients (70%) had no prior chemotherapy. The primary first-cycle DLTs were neutropenia, diarrhea, and nausea. Paclitaxel at 65 mg/m² was defined as the MTD. The most common grade 3–4 toxicities observed during all cycles were neutropenia (57%), febrile neutropenia (11%), diarrhea (29%), fatigue (29%), and nausea (18%). No patients had G-CSF (Neupogen, Amgen Inc., Thousand Oaks, CA) support. Responses were observed in gastric, esophageal, and pancreatic cancers. Conclusion: Paclitaxel at 65 mg/m², cisplatin (30 mg/m²), and irinotecan (50 mg/m²) given weekly can be safely administered to patients with solid tumor malignancies. To improve cumulative toxicities, a schedule modification was required (3-week cycle; 2-on, 1-off) Neutropenia was the most common DLT. This combination showed substantial activity, particularly in patients with gastric and esophageal adenocarcinoma, and phase II evaluation could be considered.     

A phase I trial of BMS-247550 (NSC# 710428) and gemcitabine in patients with advanced solid tumors

Summary The purpose of this study is to establish the maximum tolerated dose and define the dose-limiting toxicity of the investigational epothilone BMS-247550 in combination with fixed dose-rate gemcitabine. Patients with advanced, recurrent solid tumors who had received ≤2 prior cytotoxic regimens for recurrent disease were treated with gemcitabine over 90 min on days 1 and 8 plus BMS-247550 over 3 h on day 8, every 21 days in a phase I study. Dose-limiting toxicity definitions were based on severe myelosuppression, or grade 3 or 4 treatment-related non-hematologic toxicity, or dose delay of greater than 2 weeks due to treatment toxicity observed in the first treatment cycle. Dose cohort 1 received gemcitabine 900 mg/m² and BMS-247550 20 mg/m². Grade 4 neutropenia lasting ≥7 days occurred in one of six patients. Two of three patients in cohort 2 (gemcitabine 900 mg/m² plus BMS-247550 30 mg/m²) had dose-limiting toxicities of grade 4 neutropenia. An additional three patients were treated at dose level 1 with no additional dose-limiting toxicities observed. At an intermediate dose level (gemcitabine 750 mg/m² plus BMS-247550 30 mg/m²), two of six patients experienced a dose-limiting toxicity (febrile neutropenia and grade 3 hypophosphatemia in 1, grade 3 hypophosphatemia and grade 3 hyponatremia in (1), and five of six patients experienced dose delays. In the final cohort (gemcitabine 750 mg/m² plus BMS-247550 25 mg/m²), two of two patients experienced a dose-limiting toxicity. Treatment-related toxicites included neutropenia, thrombocytopenia, neutropenic fever, hypophosphotemia, and hyponatremia. Nine of 14 patients evaluable for response had stable disease. The maximum tolerated dose for this schedule is gemcitabine 900 mg/m² over 90 min days 1 and 8 plus BMS-247550 20 mg/m² on day 8. Attempts to increase the dose of BMS-247550 by decreasing the gemcitabine dose did not sufficiently ameliorate myelosuppression. Stable disease was observed in some patients with prior taxane exposure.     

Pharmacokinetic and phase I studies of brequinar (DUP 785; NSC 368390) in combination with cisplatin in patients with advanced malignancies

Brequinar (DUP 785; NSC 368390) is a quinoline carboxylic acid derivative that inhibits pyrimidine synthesis at the level of dihydro-orotate dehydrogenase and revealed synergy with cisplatin in preclinical models. In this study investigating the pharmacokinetic and toxicity of brequinar in combination with cisplatin, patients were initially treated with weekly brequinar, in combination with an every-three-week administration of cisplatin. Due to toxicity, the schedule was modified to a 28-day cycle with brequinar given on days 1, 8, 15, and cisplatin on day 1. A total of 24 patients (16 male, 8 female; median age 57; median performance status 1) received 69 courses of therapy. Six dose levels were explored, with cisplatin/ brequinar doses, respectively, of 50/500, 50/650, 50/860, 60/860, 75/650, and 75/860 mg/m². The serum concentration versus time curves for brequinar were biphasic. A comparison of the pharmacokinetic results after the first and third doses of brequinar indicate that the presence of 50, 60, and 75 mg/m²cisplatin did not change the protein binding and the pharmacokinetics of brequinar in any of the three brequinar-dose groups. Total cisplatin plasma pharmacokinetic followed a triphasic-shape curve and unbound cisplatin decayed at a very rapid rate. Since pharmacokinetic parameters for total cisplatin in this study were similar to those reported in the literature, the presence of brequinar is unlikely to alter the pharmacokinetics of cisplatin. Main dose-limiting toxicities included myelosuppression (including neutropenia and thrombocytopenia) and mucositis. Cisplatin/brequinar doses of 50/500, 50/650, 50/860, 60/860, 75/650, and 75/860 mg/m², were associated with dose limiting toxicity in 0/3, 1/3, 1/3, 1/3, 2/4, 2/5, and 4/6 patients, respectively. This study shows that co-administration of brequinar and cisplatin does not affect the pharmacokinetic properties of either drug and that the MTDs of cisplatin/brequinar combinations are 60/860 mg/m² or 75/650 mg/m². From this study, we conclude that full dose of 75 mg/m² cisplatin (day 1) can be administered with 650 mg/m² brequinar (days 1, 8 and 15) without significant modifications of individual drug pharmacokinetic parameters.     

Pharmacokinetic and phase I studies of brequinar (DUP 785; NSC 368390) in combination with cisplatin in patients with advanced malignancies

Brequinar (DUP 785; NSC 368390) is a quinoline carboxylic acid derivative that inhibits pyrimidine synthesis at the level of dihydro-orotate dehydrogenase and revealed synergy with cisplatin in preclinical models. In this study investigating the pharmacokinetic and toxicity of brequinar in combination with cisplatin, patients were initially treated with weekly brequinar, in combination with an every-three-week administration of cisplatin. Due to toxicity, the schedule was modified to a 28-day cycle with brequinar given on days 1, 8, 15, and cisplatin on day 1. A total of 24 patients (16 male, 8 female; median age 57; median performance status 1) received 69 courses of therapy. Six dose levels were explored, with cisplatin/ brequinar doses, respectively, of 50/500, 50/650, 50/860, 60/860, 75/650, and 75/860 mg/m². The serum concentration versus time curves for brequinar were biphasic. A comparison of the pharmacokinetic results after the first and third doses of brequinar indicate that the presence of 50, 60, and 75 mg/m²cisplatin did not change the protein binding and the pharmacokinetics of brequinar in any of the three brequinar-dose groups. Total cisplatin plasma pharmacokinetic followed a triphasic-shape curve and unbound cisplatin decayed at a very rapid rate. Since pharmacokinetic parameters for total cisplatin in this study were similar to those reported in the literature, the presence of brequinar is unlikely to alter the pharmacokinetics of cisplatin. Main dose-limiting toxicities included myelosuppression (including neutropenia and thrombocytopenia) and mucositis. Cisplatin/brequinar doses of 50/500, 50/650, 50/860, 60/860, 75/650, and 75/860 mg/m², were associated with dose limiting toxicity in 0/3, 1/3, 1/3, 1/3, 2/4, 2/5, and 4/6 patients, respectively. This study shows that co-administration of brequinar and cisplatin does not affect the pharmacokinetic properties of either drug and that the MTDs of cisplatin/brequinar combinations are 60/860 mg/m² or 75/650 mg/m². From this study, we conclude that full dose of 75 mg/m² cisplatin (day 1) can be administered with 650 mg/m² brequinar (days 1, 8 and 15) without significant modifications of individual drug pharmacokinetic parameters.     

A phase I clinical and pharmacokinetic study of tipifarnib in combination with docetaxel in patients with advanced solid malignancies*

ABSTRACT

Purpose: This phase I study assessed the maximum tolerated doses (MTDs), safety, pharmacokinetics, and efficacy of combined tipifarnib and docetaxel treatment in patients with advanced solid malignancies.

Experimental design: The study protocol was sensitive to myelosuppression, as both drugs have been associated with this adverse event. Due to myelosuppression incidence, and in order to determine the MTD of docetaxel, multiple treatment regimens were employed. Tipifarnib was administered orally at 200 or 300?mg, twice daily (BID) for 21 days, 14 days, or 7 days for multiple 21?day cycles; intravenous (IV) docetaxel was administered on day 1 of each cycle at 60, 75, or 85?mg/m².

Results: A total of 36 patients entered into the study. For each drug, MTDs were identified (tipifarnib: 300?mg BID for 14 days with 60?mg/m² docetaxel; tipifarnib: 200?mg BID for 14 days with 75?mg/m² docetaxel). The major dose-limiting toxicity was myelosuppression, particularly febrile neutropenia (44%). Mutual pharmacokinetic interactions (the effect of docetaxel on tipifarnib pharmacokinetics and the effect of tipifarnib on docetaxel pharmacokinetics) were not evident, as maximum plasma concentration (C_max) and the area under the serum concentration–time curve (AUC) values of both tipifarnib and docetaxel were similar (?p ≥ 0.43) whether the two drugs were concomitantly administered or not. Seven of 31 evaluable patients (23%) had an objective response, 11 (35%) had stable disease (six ≥ 24 weeks), and the overall clinical benefit rate (objective response and/or stable disease ≥ 24 weeks) was 42%.

Conclusions: Although the high incidence of febrile neutropenia necessitated a multiple scheduling adaptation of tipifarnib compared to the original protocol, the apparent lack of mutual pharmacokinetic interactions, the ability to coadminister tipifarnib and docetaxel near single-agent MTDs, and suggestive evidence of efficacy make this drug combination attractive for further examination.     

A Phase I Clinical and Pharmacokinetic Study of Fenretinide Combined with Paclitaxel and Cisplatin for Refractory Solid Tumors

Summary Background: Fenretinide is a semi-synthetic retinoid that has pro-apoptotic effects as a single agent and synergistically with chemotherapy in vitro. We performed this study to determine the toxicity of cisplatin, paclitaxel and fenretinide in patients with advanced cancer, the recommended phase II dose of these agents together, and the pharmacokinetics (PK) of fenretinide when administered with chemotherapy. Patients and methods: Fourteen patients (mean age 57.3) were assessable for pharmacokinetics, toxicity and response. Fenretinide was given orally in 2 divided daily doses for 7 days, starting 24 hours prior to cisplatin and paclitaxel. Cisplatin and paclitaxel were given in standard fashion. Cycles were repeated every 3 weeks. Cycle one fenretinide PK was obtained on days 2 and 8. Results: Dose limiting toxicity (Gr 3 diarrhea and Gr 4 neutropenia) was encountered in two patients during cycle one at 80/175/1800 mg/m² of cisplatin/paclitaxel/fenretinide (dose level 2), respectively. Seven patients received 2–8 cycles at the recommended level of 60/135/1800 (dose level 1). Severe cumulative toxicities included fatigue, nausea/vomiting, neuropathy, and dehydration. Two patients had a partial response and 4 patients had stable disease for up to 8 cycles. PK analysis demonstrated a reduction in fenretinide Cmax on day 8 compared to day 2, accompanying a decrease in AUC. Conclusions: Cisplatin/paclitaxel/fenretinide can be administered safely at 60/135/1800 mg/m² respectively on an every three-week schedule. This combination may have activity in a variety of tumors, however, the number of pills required complicates oral dosing of fenretinide, and limits the applicability of this regimen.     

Phase I dose escalation study of pegylated liposomal doxorubicin (Caelyx®) in combination with topotecan in patients with advanced malignancies

Summary Aims of this study were to determine the toxicity profile and the recommended dose of pegylated liposomal doxorubicin (Caelyx) in combination with topotecan in patients with advanced malignancies. Caelyx: 35 (DLI) or 40 (DLII) mg/m²/d1 was followed by 0.5 mg/m²/d topotecan daily for 5 days, every 4 weeks. Twenty-three patients received a total of 82 cycles. At DLII, 2/6 patients experienced dose-limiting toxicity consisting of grade 4 neutropenia lasting for more than 7 days and febrile neutropenia. At DLI, 4/18 and 2/18 patients presented febrile neutropenia and grade 4 sustained neutropenia, respectively. Non-hematological toxicities were mild to moderate. One patient with ovarian cancer presented a complete response. The hematological toxicity was a dose limiting factor that led to the recommended dose of 35 mg/m² Caelyx on day 1 with 0.5 mg/m²/d topotecan on days 1–5. This study results suggest that alternative schedules of this combination are required. Comment: Hervé Ghesquières and Sandrine Faivre contributed equally to this work and shall be regarded as joint first authors.Conflicts of interest: None of the authors declared conflicts of interest.     

Pegylated liposomal doxorubicin hydrochloride (PLD) and paclitaxel in recurrent or metastatic head and neck carcinoma: a phase I/II study conducted by the Hellenic Cooperative Oncology Group (HeCOG)

A phase I pharmacokinetics and dose-finding study and a phase II study of the combination of pegylated liposomal doxorubicin HCl (PLD) and paclitaxel were conducted in patients with recurrent or metastatic head and neck cancer (HNC). Sixty patients with recurrent or metastatic disease were enrolled in the study: 11 patients in the phase I study and 49 patients in the phase II study. In the phase I study, the initial dose level of PLD was 35 mg/m as a 1-h infusion with escalating increments of 5 mg/m until the maximum tolerated dose (MTD) was reached. A fixed dose of paclitaxel (175 mg/m) was administered as a 3-h infusion. The combination was administered every 28 days. Pharmacokinetic studies performed on 10 patients indicated that the sequence of drug administration did not cause clinically significant modifications in the pharmacokinetics of either drug. The MTD for PLD was 45 mg/m (dose level 3) and the dose-limiting toxicity was febrile neutropenia, occurring in three of five patients. The phase II dose of PLD was 40 mg/m (dose level 2) and a total of 214 cycles were delivered. Grade 3 or 4 neutropenia was observed in 26% patients and febrile neutropenia occurred in 16% of patients. Grade 3 palmar-plantar erythrodysesthesia (PPE) was recorded in only one patient. The overall response rate was 28% for patients with non-nasopharyngeal tumors [95% confidence interval (CI) 15-45%] and 28.6% for the study population (95% CI 17-43%). The median survival for the study population was 9.7 months; 1-year survival was 38%. We conclude that the recommended dose for the combination of PLD and paclitaxel is 40 and 175 mg/m every 28 days, without granulocyte colony stimulating factor support. The combination of paclitaxel with PLD demonstrated activity in recurrent or metastatic HNC, a favorable toxicity profile and relative ease of administration.     

Phase I and pharmacokinetic study of docetaxel, irinotecan, and celecoxib in patients with advanced non-small cell lung cancer

Summary Purpose: We studied the toxicities, potential pharmacokinetic interactions, and preliminary antitumor activity of the combination of docetaxel and irinotecan with celecoxib, a selective cyclooxygenase-2 inhibitor. Patients and methods: Eligible patients had advanced non-small lung cancer (NSCLC) with measurable disease, good performance status, and adequate end organ function. Docetaxel and irinotecan were administered intravenously on days 1 and 8, every 21 days, and their doses were escalated on successive patient cohorts at three dose levels: 30/50, 30/60, and 35/60 (doses in mg/m²). Celecoxib was administered at a starting dose of 400 mg orally twice daily without interruption, beginning on day 2 of cycle 1. Pharmacokinetic studies were performed on day 1 of cycle 1 and day 1 of cycle 2. Results: Seventeen patients with advanced NSCLC were enrolled and collectively received 78 cycles of therapy. Diarrhea was the most common toxicity; it was noted in 13 patients (76%). Dose-limiting toxicities occurred at dose level 1 (myocardial infarction in a patient with multiple coronary artery disease risk factors) and dose level 3 (grade 4 neutropenia with fatal urosepsis). Other major toxicities were: grade 3 neutropenia (2 patients); grade 3/4 diarrhea (3/1); grade 3 nausea (2); grade 2 rash (1); and grade 3 pneumonitis (1). The maximum tolerated dose was at dose level 3, i.e., docetaxel 35 mg/m² and irinotecan 60 mg/m² on days 1 and 8, plus celecoxib 400 mg twice daily, repeated every 21 days. Five of 15 evaluable patients achieved an objective response. The pharmacokinetics of docetaxel were not altered by celecoxib. However, we observed an 18% increase in the average elimination clearance of irinotecan coincident with the addition of celecoxib. Conclusions: The addition of celecoxib to docetaxel and irinotecan was generally well tolerated but unpredictable fatal toxicity occurred. Diarrhea was the most common toxicity. Antitumor activity was promising. The alteration of irinotecan pharmacokinetic parameters observed may not be clinically relevant. Supported in part by grant M01 RR-00048 from the National Center for Research Resources, National Institutes of Health, and by Pfizer Global Pharmaceuticals, New York, NY, and by Aventic Pharmaceuticals, a member of the Sanofi-Aventis Group.     

Feasibility of adding everolimus to carboplatin and paclitaxel,with or without bevacizumab,for treatment-naive,advanced non–small cell lung cancer

Introduction One standard of care for advanced non–small cell lung cancer (NSCLC) is paclitaxel plus carboplatin?±?bevacizumab. This two-step phase I study evaluated the feasibility of adding everolimus to paclitaxel plus carboplatin?±?bevacizumab for advanced NSCLC. Methods Adults with advanced NSCLC naive to systemic therapy were enrolled. A Bayesian dose-escalation model was used to identify feasible daily or weekly everolimus doses given with paclitaxel (200 mg/m² q21 days) and carboplatin (AUC 6 mg/mL/min q21 days) (step 1) and paclitaxel (200 mg/m² q21 days), carboplatin (AUC 6 mg/mL/min q21 days), and bevacizumab (15 mg/kg q21 days) (step 2). Primary endpoint was end-of-cycle 1 dose-limiting toxicity (DLT) rate. Secondary endpoints included safety; relative dose intensities of paclitaxel, carboplatin, and bevacizumab; pharmacokinetics; and tumor response. Results Fifty-two patients were enrolled and received everolimus 5 mg/day plus carboplatin and paclitaxel (step 1 daily; n?=?13); everolimus 30 mg/week plus carboplatin and paclitaxel (step 1 weekly; n?=?13); everolimus 5 mg/day plus carboplatin, paclitaxel, and bevacizumab (step 2 daily; n?=?13); or everolimus 30 mg/week plus carboplatin, paclitaxel, and bevacizumab (step 2 weekly; n?=?13). End-of-cycle 1 DLT rate was 16.7 % (step 1 daily), 30.8 % (step 1 weekly), 30.0 % (step 2 daily), and 16.7 % (step 2 weekly). Cycle 1 DLTs were grade 3 neutropenia, anal abscess, diarrhea, and thrombocytopenia and grade 4 myalgia, cellulitis, neutropenia, febrile neutropenia, pulmonary embolism, and thrombocytopenia. The most common adverse events were neutropenia, fatigue, anemia, and thrombocytopenia. One patient (step 2 daily) experienced complete response, 10 patients partial response. Conclusions The feasible everolimus doses given with carboplatin and paclitaxel?±?bevacizumab were 5 mg/day and 30 mg/week. Neither schedule was very well tolerated in this unselected NSCLC population.     

Pharmacodynamics of non-break weekly paclitaxel (Taxol) and pharmacokinetics of Cremophor-EL vehicle: results of a dose-escalation study

We characterized the toxicity and determined the maximum tolerated dose of non-break weekly paclitaxel (Taxol) in chemotherapy-naive cancer patients, and studied pharmacokinetics of the formulation vehicle Cremophor-EL with this schedule. Twenty-three patients with primary refractory solid tumors received weekly paclitaxel at the dose range of 70-200 mg/m2. As dose-limiting toxicity we defined granulocytopenia grade > or =2 causing a treatment delay for more than 2 weeks, or febrile neutropenia or grade >2 organ-specific toxicity. Plasma kinetics of Cremophor-EL were analyzed over the first five courses of treatment. Non-break weekly paclitaxel was feasible at doses up to 110 mg/m2, while granulocytopenia precluded scheduled administration of doses > or =130 mg/m2. Clinically relevant peripheral neurotoxicity tended to occur at around 1500 mg/m2 cumulative dosage at weekly doses > or =110 mg/m2. Detectable Cremophor-EL levels were found in all pre-dose samples, but there was no evidence of accumulation up to the sixth course. Our results, discussed in the light of an overview of published data, suggest that chronic weekly administration of paclitaxel is feasible and with a lack of significant accumulation of Cremophor-EL levels at doses up to 90 mg/m2.