Carboplatin pharmacokinetics in young children with brain tumors

 Purpose: The pharmacokinetic parameters and maximal tolerated systemic exposure were determined for carboplatin in young children given in combination with cyclophosphamide and etoposide. Patients and methods: Carboplatin was administered as part of a multiagent chemotherapy regimen to 21 pediatric patients less than 5 years of age with newly diagnosed, malignant central nervous system tumors. Patients received cyclophosphamide, 1.2 g/m², on day 1 and carboplatin on day 2 followed by etoposide, 100 mg/m², each day. Carboplatin doses were calculated to achieve a targeted area under the serum concentration versus time curve (TAUC) of 5, 6.5 or 8 mg/ml . min based on each patient’s measured glomerular filtration rate (GFR). Carboplatin pharmacokinetic parameters were determined after course 1 and then after every third course of therapy. Results: The median carboplatin clearance and GFR after course 1 were 118 and 98 ml/min per m², respectively. Targeted doses based on measured GFR reliably achieved the TAUC for carboplatin. The median (range) carboplatin clearance for four children less than 1 year of age was 76 (66–84) ml/min per m², significantly lower (P=0.05) than the value of 131 (80–158) ml/min per m² for children from 1 to 4 years of age. The mean carboplatin clearance declined by 23% in 12 patients studied from course 1 to course 4 of therapy. The decrease was greater than 20% (range 20–53%) in 7 of the 12 patients studied. Conclusion: Carboplatin clearance for children aged between 1 and 4 years at diagnosis is approximately 45% higher than previously reported for pediatric patients, but declines after four courses of therapy. For children less than 1 year of age, carboplatin clearance per square meter is approximately 40% lower than patients 1 to 4 years of age. There are corresponding differences in GFR that provide a plausible explanation for the age and therapy-related changes in carboplatin clearance. Toxicity was acceptable for patients treated at a TAUC of 6.5 mg/ml . min for carboplatin given with etoposide and cyclophosphamide. The average carboplatin dose required for this AUC was 767 mg/m². Received: 13 July 1995/Accepted: 18 December 1995     

A phase I study of carboplatin and etoposide administered in conjunction with dipyridamole, prochlorperazine and cyclosporine A

Purpose: In recognition of the variety of available chemotherapeutic modulating agents and their potential to enhance the efficacy of platinum-based therapy, we embarked upon a phase I study to investigate the feasibility of combining fixed doses of carboplatinum (CBDCA) and etoposide (VP-16) with 24-h concurrent infusions of dipyridamole (DP), prochlorperazine (PCZ) and cyclosporine A (CSA) administered in escalating doses. Methods: Patients received intravenous VP-16 (200 mg/m²) and CBDCA (300 mg/m²), each over 30 min, starting at hour 6 of the modulator infusions. Resistance modulators were escalated sequentially to determine their respective maximally tolerated doses (MTDs). The pharmacokinetics (PK) of VP-16, CBDCA, and the three drug resistance (DR) modifiers were studied in eight patients. Results: A total of 59 patients were entered on study. The MTD was established at DP 5 mg/kg per day, PCZ 24 mg/h, and CSA 9.5 mg/kg per day. Dose-limiting toxicities included hypotension and severe sedation, presumably related to PCZ. No objective responses were seen. PK studies were performed when PCZ and DP doses were 24 mg/h and 3.3 mg/kg, and the CSA dose was either 8.5 mg/kg (five patients) or 9.5 mg/kg (three patients). The median clearance of VP-16 was 0.96 l/h per m² (range 0.8–1.5 l/h per m²), which is lower than for VP-16 alone and similar to previously reported effects of CSA on VP-16 elimination. The median measured CBDCA AUC was 3.0 mg/ml · min (range 2.4–4.8 mg/ml · min). CBDCA AUC predicted by the Calvert formula using measured creatinine clearance underestimated the actual AUC in seven of the eight patients, in one case by as much as twofold. The median end of infusion PCZ and total DP plasma concentrations were 1.2 μM (range 0.5–2.2 μM) and 4.4 μM (range 1.3–5.9 μM), respectively, consistent with in vitro resistance modulatory levels. However, free DP was only 0.02 μM (range 0.004–0.04 μM). The median CSA level at 24 h of 1450 μg/l (range 1075–1640 μg/l) is in agreement with concentrations required for partial DR reversal in vitro, although it is much lower than levels achieved in our previous phase I study of CBDCA + CSA alone using similar doses of CSA. The CSA dose on the current trial was escalated beyond the MTD for the previous phase I study, suggesting that there may be an interaction between CSA and one of the other modulators. Conclusion: These results demonstrate that in vitro DR- reversing levels of two of the three agents used in this study can be achieved in vivo, and that this combination of DR modulators has significant effects on the pharmacokinetics of VP-16. Received: 2 September 1999 / Accepted: 25 April 2000     

A phase I/II study of vinorelbine, doxorubicin, and methotrexate with leucovorin rescue as first-line treatment for metastatic breast cancer

Purpose: This study was performed to determine the maximum tolerated dose (MTD) and toxicity of vinorelbine when used in combination with doxorubicin and methotrexate with leucovorin rescue in women with metastatic breast cancer. Methods: Enrolled in the study were 23 women with metastatic breast cancer who had not received prior chemotherapy for metastatic disease. Patients treated at the first dose level received vinorelbine 20 mg/m² on day 1, doxorubicin 40 mg/m² on day 1, methotrexate 100 mg/m² on day 1 and leucovorin 20 mg orally every 6 h for six doses beginning on day 2. Treatment was repeated every 21 days. The vinorelbine dose was escalated by 5 mg/m² for patients treated at subsequent dose levels. The MTD was defined as the dose level at which fewer than one-third of patients enrolled experienced dose-limiting toxicity (DLT). When the MTD of vinorelbine had been determined, the doxorubicin dose was then escalated by 10 mg/m² with the vinorelbine dose held at its MTD. Results: total of 98 courses of treatment (median of 4 per patient, range 2–8) were administered. The MTD of this regimen was found to be vinorelbine 25 mg/m², doxorubicin 40 mg/m², and methotrexate 100 mg/m² with leucovorin rescue. At higher doses of vinorelbine, neutropenia, fatigue, arm pain, malaise, nausea and vomiting were dose-limiting. Higher doses of doxorubicin resulted in universal dose limiting neutropenia, and frequent nonhematologic DLT consisting of arm pain, malaise, stomatitis, nausea and vomiting. Amongst the 20 patients with measurable disease, there were 3 complete responses (15%, 95% confidence interval 3%–38%), 5 partial responses (25%, 95% confidence interval 9%–49%) and an overall response rate of 40% (95% confidence interval 19%–64%). The median survival was estimated to be 25 months from the start of chemotherapy. Conclusions: Vinorelbine at 25 mg/m² can be safely administered with doxorubicin at 40 mg/m² and methotrexate at 100 mg/m² with leucovorin rescue. Response rates observed with this regimen suggest that this combination of chemotherapeutic agents may not be more effective than the combination of vinorelbine and doxorubicin. Received: 27 April 1998 / Accepted: 17 September 1998     

Pharmacokinetic analysis of high-dose toremifene in combination with doxorubicin

Purpose: Toremifene (Fareston) is an orally administered triphenylethylene derivative with chemosensitizing activity in vitro in estrogen receptor-negative multidrug-resistant human breast cancer cells. The purpose of this study was to evaluate the effects of high-dose toremifene (600 mg/day for 5 days) on the plasma pharmacokinetics of doxorubicin in humans. The 600-mg dose had been previously established as the maximum tolerated dose in a phase I study of 35 patients. Methods: Doxorubicin was administered as an intravenous (i.v.) bolus over 15 min at a dose of 60 mg/m² to 11 patients in the absence of toremifene pretreatment to establish baseline doxorubicin pharmacokinetics. Six of these patients received 600 mg/day toremifene for 5 days 4 weeks later, followed by an i.v. bolus dose of doxorubicin (60 mg/m²) on day 5. During toremifene pretreatment, blood specimens (5 ml) were drawn at 0, 2, 4, and 24 h after dosing to assess peak levels. Following doxorubicin administration in each cycle, blood specimens were collected over a 72-h period for determination of the terminal half-life of elimination. Plasma concentrations of doxorubicin and toremifene were assessed by high-performance liquid chromatography (HPLC). Cumulative linear areas under the time-concentration curve (AUC) for doxorubicin were calculated using a noncompartmental model. Results: Prior to toremifene dosing, baseline doxorubicin pharmacokinetic studies showed an average terminal half-life of elimination of 40.04 ± 7.86 h in 4 patients, and an average AUC of 135 600 ± 67 600 μg/ml · h in 11 patients. In 4 of the patients receiving 600 mg/day toremifene for 5 days, the average terminal half-life of elimination was 38.12 ± 7.81 h, and the average AUC was 141 900 ± 62 900 μg/ml · h in 6 patients, i.e. a slight increase of 4.6%. No statistically significant change in the doxorubicin elimination kinetics with or without toremifene therapy was observed. Conclusions: Toremifene does not appear to interfere with the elimination kinetics of doxorubicin. Received: 1 July 1997 / Accepted: 16 December 1997     

GM-CSF,carboplatin, doxorubicin: a phase I study

Dose intensification has the potential to increase the response frequency of chemosensitive tumors to chemotherapy. G-CSF and GM-CSF offer the possibility of dose-intensifying chemotherapy without prohibitive myelosuppression. A phase I study was undertaken to identify the maximum tolerated dose (MTD) of carboplatin that could be administered with a fixed dose of doxorubicin, 60 mg/m², administered every 28 days. Further escalation of the carboplatin dose was then attempted, with the concomitant addition of GM-CSF 10 mg/kg per day on days 1–21. We had 21 patients, 13 with prior therapy, who were eligible. In all, 60 courses of therapy were delivered, all with doxorubicin and with carboplatin doses of 250 mg/m², 325 mg/m² and 400 mg/m². At carboplatin 400 mg/m² and doxorubicin 60 mg/m², thrombocytopenia was dose limiting. The addition of GM-CSF did not allow further escalation. Of the 6 patients treated with carboplatin 400 mg/m², doxorubicin 60 mg/m², and GM-CSF, grade 4 granulocytopenia and thrombocytopenia were seen in 4 and 5 patients, respectively. The severity of thrombocytopenia was related to the calculated carboplatin AUC and also to baseline platelet count and prior therapy. In addition, the interaction of GM-CSF and chemotherapy, especially carboplatin-based, may be more complex than originally anticipated.This investigation was supported in part by the following PHS Cooperative Agreement grant numbers awarded by the National Cancer Institute, DHHS: CA-14028, CA-28862, CA-12213, CA-13612, CA-32102     

Phase I dose escalation study of topotecan combined with alternating schedules of paclitaxel and carboplatin in advanced solid tumors

Background:Combining topotecan with other cytotoxics has been problematic due to marrow suppression. A phase I trial was initiated to identify the optimal sequence and maximum-tolerated dose of topotecan in combination with paclitaxel and carboplatin. Patients and methods:Patients with advanced cancer and performance status ECOG 2. The starting dose was paclitaxel 175 mg/m² day 1, carboplatin AUC 6.0 day 1, and topotecan 0.5 mg/m² daily day 1–5 (early sequence). The next course of paclitaxel and carboplatin administration was delayed to day 5 (late sequence). Treatment was repeated every three weeks. After determining maximum-tolerated dose without cytokines, granulocyte colony-stimulating factor (G-CSF) was added and further dose escalation was pursued. Results:Fifty-one patients were entered; men : women ratio 30 : 21. Dose-limiting toxicity (DLT) for the early sequence was neutropenia at doses paclitaxel mg/m²/carboplatin AUC 5/topotecan mg/m² (PCT) 175/5/0.75 for four to five days. DLT for the late sequence was neutropenia at PCT doses of 175/5/1.0 for four days. G-CSF 5 µg/kg subcutaneously starting day 6 permitted further topotecan dose escalation. After adding G-CSF, late sequence DLT was neutropenia at doses 175/5/1.25 for four days. Forty-six patients were evaluable for response and of those, there were thirteen partial responses. Conclusions:The late sequence resulted in less toxicity and was better tolerated. The early sequence maximum-tolerated dose (MTD) was 175/6/0.5 for five days. The late sequence MTD was PCT 175/5/0.75 for five days. The late sequence MTD with G-CSF was 175/5/1.0 for four days. The recommended phase II PCT dose is the late sequence 175/5/1.0 for four days with G-CSF.     

Phase I study of docetaxel and topotecan in patients with solid tumors

Purpose: Both docetaxel (DOC), a promoter and stabilizer of microtubule assembly, and topotecan (TOPO), a topoisomerase I inhibitor, have shown antitumor activity in a variety of solid tumor malignancies. This phase I trial was conducted to determine the overall and dose-limiting toxicities (DLT), the maximum tolerated dose (MTD) and the pharmacokinetics of the combination of DOC and TOPO in patients with advanced solid tumor malignancies. Methods: DOC was administered first at 60 mg/m² without G-CSF and at 60, 70, and 80 mg/m² with G-CSF by 1-h infusion on day 1 of the odd-numbered cycles (1, 3, 5, etc.) and on day 4 of the even-numbered cycles (2, 4, 6, etc.). TOPO 0.75 mg/m² was administered as a 30-min infusion on days 1, 2, 3 and 4 of each cycle. G-CSF 300 μg was administered subcutaneously (s.c.) on days 5–14. Cycles were repeated every 21 days. All patients were premedicated with dexamethasone 8 mg orally every 12 h for a total of six doses starting on the day before DOC infusion. Results: A total of 22 patients were treated. Six patients were treated in cohort I with DOC and TOPO doses of 60 and 0.75 mg/m², respectively, without G-CSF, and two patients developed DLT (febrile neutropenia). Four patients were treated in cohort II with DOC and TOPO doses of 60 and 0.75 mg/m², respectively, with G-CSF, and no DLT was observed. Four patients were treated in cohort III with DOC and TOPO doses of 80 and 0.75 mg/m², respectively, with G-CSF, and three developed DLT (febrile neutropenia). DOC was then de-escalated to 70 mg/m² and delivered with TOPO 0.75 mg/m² and G-CSF (cohort IV). Eight patients were treated at this dose level, and one DLT (febrile neutropenia) was observed. Two patients developed a severe hypersensitivity reaction shortly after the DOC infusion was started, one in cycle 1 and one in cycle 2. Both patients were removed from the study. Two patients developed severe dyspnea in the presence of progressive pulmonary metastases. Other nonhematological toxicities were mild. One patient with extensively pretreated ovarian carcinoma had a partial response, and eight patients with various solid tumor malignancies had stable disease with a median time to progression of 12 weeks (range 9–18 weeks). Administration of TOPO on days 1–4 and DOC on day 4 resulted in increased neutropenia. Conclusions: DOC 80 mg/m² given first as a 1-h infusion on day 1 with TOPO 0.75 mg/m² given as a 0.5-h infusion on days 1, 2, 3 and 4 with G-CSF was considered the MTD. The recommended phase II dose for DOC given on day 1 is 70 mg/m² with TOPO 0.75 mg/m² given on days 1, 2, 3 and 4 every 21 days with G-CSF 300 μg s.c. on days 5–14. The alternative schedule with DOC given on day 4 and TOPO on days 1–4 is not recommended. Received: 18 February 2000 / Accepted: 19 July 2000     

Phase I/II study of cisplatin, ifosfamide and irinotecan with rhG-CSF support in patients with stage IIIB and IV non-small-cell lung cancer

Purpose: We conducted a phase I/II study in previously untreated patients with stage IIIB or IV non-small-cell lung cancer (NSCLC) to: (1) determine the maximum tolerated dose (MTD) of cisplatin combined with a fixed schedule of ifosfamide and irinotecan with rhG-CSF support; and (2) to determine the overall response rate and median survival of patients entered on this study. Methods: Ifosfamide (1.5 g/m²) and irinotecan (60 mg/m²) were administered at fixed doses on days 1–4 and on days 1, 8 and 15, respectively. Cisplatin was given on day 1 at 60 mg/m² and was increased in 10-mg/m² increments. This regimen was repeated every 4 weeks. rhG-CSF (nartograstim) was administered subcutaneously at a dose of 1 μg/kg on days 5–18 except on the day of irinotecan treatment. Results: Between June 1995 and April 1998, 46 patients were registered onto this phase I/II study. The MTD of cisplatin was defined according to toxicity and the dose during three courses was increased. Since at the 80 mg/m² dose level more than one-third of the patients were treated with dose modification, the dose of 70 mg/m² was recommended for phase II study. The dose-limiting toxicity was leukopenia. The overall response rate was 62.2% (95% CI 48.0–76.4%), the median response duration was 144 days, and the median survival time was 393 days. Conclusion: For phase II study, we recommend doses of cisplatin 70 mg/m² on day 1 combined with ifosfamide and irinotecan with rhG-CSF support. Both the response rate and preliminary survival data in this study suggest a high degree of activity of this combination in previously untreated NSCLC. Received: 29 April 1999 / Accepted: 15 September 1999     

Clinical and pharmacokinetic studies of high-dose levamisole in combination with 5-fluorouracil in patients with advanced cancer

Purpose: To determine the maximum tolerable dose (MTD) and activity of levamisole administered concurrently with 5-fluorouracil (5-FU) in a standard 5-day course. To determine the pharmacokinetics of levamisole during the course of treatment. Patients and methods: Levamisole was administered to 38 patients orally three times a day for 5 days concurrently with a course of 5-FU administered daily by rapid intravenous injection for 5 days. Toxicity was evaluated in 20 patients who received escalating doses of levamisole. The activity of the combination was evaluated in 18 patients who received levamisole at the MTD with 5-FU. The pharmacokinetics of levamisole were characterized in ten patients at the MTD level. Results: Intractable vomiting, confusion and vertigo were the major dose-limiting toxicities. The MTD of oral levamisole was 100 mg/m² administered three times a day concurrently with 450 mg/m² per day intravenous 5-FU for 5 consecutive days. Partial responses lasting 5 and 11 months were observed in 2/18 patients with measurable disease at the MTD. Peak plasma concentrations of 1 μg/ml (range 0.6–1.3 μg/ml) were achieved 90 min (range 60–360 min) after an oral dose of 100 mg/m² levamisole with a 3.5-fold accumulation noted following 4 days of administration. Peak plasma concentrations of p-hydroxylevamisole were about 5% of parent drug. Little parent drug (2–5%) was detected in urine. Conclusions: Levamisole may be administered safely with 5-FU at doses which are up to four to five times greater than those presently given in conventional regimens. The recommended dose of levamisole combined with 5-FU for future research protocols is 75 mg/m² t.i.d for 5 days. Received: 31 December 1996 / Accepted: 11 September 1997     

Dose-finding and pharmacological study of ifosfamide in combination with paclitaxel and carboplatin in resistant small-cell lung cancer

Background:To find the maximum tolerated dose forifosfamide in combination with paclitaxel and carboplatin in small-celllung cancer patients (SCLC), who are resistant to cyclophosphamide,doxorubicin and etoposide (CDE). Patients and methods:Different dose schedules of ifosfamidewere combined with fixed doses of paclitaxel 175 mg/m² andcarboplatin AUC 6 mg/ml · min. Included were 30patients, with a median age of 60 years, and median time off priorcytotoxic treatment of 8 weeks. All patients were previously treatedwith CDE and 11 had received re-induction CDE. Results:Dose limiting toxicity of our schedule waspersistent thrombocytopenia. None of the patients developed neutropenicfever. Non-haematological toxicity was mild, although twotreatment-related deaths occurred. Fifty-four percent of patients had apartial response and median survival time was twenty-five weeks. Conclusions:The maximum tolerated dose of this combinationfor patients with resistant SCLC is ifosfamide 2000 mg/m² incombination with paclitaxel 175 mg/m² and carboplatin AUC 6mg/ml · min administered on the first day of a 21-daycycle.     

Phase 1 and pharmacokinetic study of concurrent carboplatin and irinotecan in subjects aged 1 to 21 years with refractory solid tumors

BACKGROUND:

Preclinical testing suggests the combination of carboplatin and irinotecan has at least additive antitumor activity. The primary objectives of the current study were to determine the maximum tolerated doses (MTDs) and recommended phase 2 doses of carboplatin administered with irinotecan to pediatric patients with refractory solid tumors.

METHODS:

This was a multicenter, open‐label, single‐arm dose escalation study in which subjects with refractory solid tumors received 21‐day treatment cycles of intravenous carboplatin on Day 1 followed by intravenous irinotecan administered daily for 10 days within 2 consecutive weeks. The plasma pharmacokinetics of ultrafiltrable platinum, irinotecan, and 2 irinotecan metabolites were determined during Cycle 1. The interpatient plan for dose escalation at study initiation was to increase irinotecan first followed by increases in carboplatin.

RESULTS:

Twenty‐eight patients with a median age of 8.5 years (range, 1‐21 years) were enrolled with a variety of solid tumors. Two of 6 subjects at the first dose level (carboplatin target area under the curve [AUC], 4.0 mg/mL*min; irinotecan, 18 mg/m²/dose) experienced dose‐limiting gastrointestinal toxicities requiring a dose de‐escalation scheme (carboplatin AUC, 4.0 mg/mL*min; irinotecan, 15 mg/m²/dose). Three of 6 subjects at the second dose level experienced dose‐limiting gastrointestinal complications and bone marrow suppression. A further dose de‐escalation to carboplatin AUC of 4.0 mg/mL*min and irinotecan of 12 mg/m²/dose resulted in dose‐limiting bone marrow suppression in 1 of 13 patients treated at that dose, and therefore was determined to be the MTD. One complete response (in a patient with medulloblastoma) and 3 partial responses (in patients with neuroblastoma, medulloblastoma, and lymphoendothelial carcinoma, respectively) were observed.

CONCLUSIONS:

The recommended phase 2 dose in heavily pretreated pediatric patients is carboplatin (AUC, 4 mg/mL*min on Day 1) and irinotecan (12 mg/m²/ day × 10 days) given every 21 days. Cancer 2009. © 2008 American Cancer Society.     

A phase I evaluation of multitargeted antifolate (MTA, LY231514), administered every 21 days, utilizing the modified continual reassessment method for dose escalation

Purpose: To determine toxicities, maximally tolerated dose (MTD), pharmacokinetic profile, and potential antitumor activity of MTA, a novel antifolate compound which inhibits the enzymes thymidylate synthase (TS), glycinamide ribonucleotide formyltransferase (GARFT), and dihydrofolate reductase (DHFR). Methods: Patients with advanced solid tumors were given MTA intravenously over 10 min every 21 days. Dose escalation was based on the modified continual reassessment method (MCRM), with one patient treated at each minimally toxic dose level. Pharmacokinetic studies were performed in all patients. Results: A total of 37 patients (27 males, 10 females, median age 59 years, median performance status 90%) were treated with 132 courses at nine dose levels, ranging from 50 to 700 mg/m². The MTD of MTA was 600 mg/m², with neutropenia and thrombocytopenia, and cumulative fatigue as the dose-limiting toxicities. Hematologic toxicity correlated with renal function and mild reversible renal dysfunction was observed in multiple patients. Other nonhematologic toxicities observed included mild to moderate fatigue, anorexia, nausea, diarrhea, mucositis, rash, and reversible hepatic transaminase elevations. Three patients expired due to drug-related complications. Pharmacokinetic analysis during the first course of treatment at the 600 mg/m² dose level demonstrated a mean harmonic half-life, maximum plasma concentration (Cpmax), clearance (CL), area under the curve (AUC), and apparent volume of distribution at steady state (Vdss) of 3.08 h, 137 μg/ml, 40.0 ml/min per m², 266 μg · h/ml, and 7.0 l/m², respectively. An average of 78% of the compound was excreted unchanged in the urine. Partial responses were achieved in two patients with advanced pancreatic cancer and in two patients with advanced colorectal cancer. Minor responses were obtained in six patients with advanced colorectal cancer. Conclusions: The MTD and dose for phase II clinical trials of MTA when administered intravenously over 10 min every 21 days was 600 mg/m². MTA is a promising new anticancer agent. Received: 20 October 1998 / Accepted: 30 March 1999     

A pharmacogically guided phase I study of carboplatin in combination with methotrexate and vinblastine in advanced urothelial cancer

 Carboplatin is an alternative for cisplatin in the treatment of urothelial cancers. A pharmacologically guided phase I study of carboplatin in combination with methotrexate (30 mg/m²) and vinblastine (4 mg/m²) was conducted in ten patients by increment of the area under the plasma concentration versus time curve (AUC) for ultrafilterable carboplatin using the Calvert formula. The maximal tolerated AUC was 5 mg ml^-1 min, with neutropenia being the dose-limiting toxicity. There was a significant linear correlation between the percentage of decrease in neutrophil count and the carboplatin AUC. Determination of the glomerular filtration rate by the isotopic method allowed us to adapt the dose of carboplatin given to patients suffering from urothelial cancer, who frequently have impaired renal function. The recommended AUC for phase II study is 4 mg ml^-1 min. Received: 9 May 1994/Accepted: 16 August 1994     

A phase I trial of carboplatin and etoposide for elderly (≥75 year-old) patients with small-cell lung cancer

Purpose: The combination of carboplatin and etoposide is currently considered the most appropriate regimen for treating elderly patients with small-cell lung cancer (SCLC). Previous reports on elderly patients, 70 years or older, found that the recommended dose was close to that of younger patients. Then, we conducted a phase I study of carboplatin and etoposide in elderly patients, 75 years or older, with SCLC. This study aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). Methods: Twenty-six patients fulfilling the eligibility criteria, chemotherapy-naive, performance status (PS) of 0–2, age ≥75, and adequate organ functions were enrolled. Patients’ characteristics were: male/female=21/5; PS 0/1/2=9/11/6; median age (range)=78 (75–82); and limited/extensive stage=16/10. The patients intravenously received carboplatin with a target AUC of 4 or 5 mg min/ml (Chatelut formula) on day 1 and etoposide at 80–120 mg/m² on days 1, 2 and 3. Therapy was repeated four times in every 4 weeks. Results: The MTD of carboplatin/etoposide was AUC=5/80, 4/110, and 4/120. The DLTs were thrombocytopenia, neutropenia, leukopenia, and febrile neutropenia. Overall, grade 4 thrombocytopenia, neutropenia (≥4 days), leukopenia (≥4 days), and febrile neutropenia occurred in 27, 20, 7, and 13% of cases at MTD levels, respectively, and 0% at other levels. Twenty of 26 patients showed objective responses (2CR, 18PR; RR=77%). Conclusion: A dose of carboplatin of AUC=4 and etoposide of 100 mg/m² was recommended in this regimen.The authors indicated no potential conflicts of interest.     

A pilot study of docetaxel-carboplatin versus paclitaxel-carboplatin in Japanese patients with epithelial ovarian cancer

Background It has been reported that a docetaxel-carboplatin combination as first-line chemotherapy for ovarian cancer showed a level of progression-free survival similar to that of paclitaxel-carboplatin while reducing neurotoxicity and improving quality of life. We investigated the recommended doses of docetaxel-carboplatin in Japanese patients with ovarian cancer and conducted a comparative study of docetaxel-carboplatin versus paclitaxel-carboplatin. Methods Thirty-nine patients with ovarian cancer were enrolled in this study and 38 patients were evaluated. We conducted a dose-escalation study using a docetaxel dose of 70 mg/m² and carboplatin AUC 5 and 6. In the comparative study, patients received either docetaxel 70 mg/m² and carboplatin AUC 5 or paclitaxel 175 mg/m² and carboplatin AUC 5. Progression-free survival, survival rate at 2 years, response rate, toxicity, and quality of life were investigated. Results In the dose-finding study, we determined the recommended doses as docetaxel 70 mg/m² and carboplatin AUC 5. In the comparative study, the two arms showed similar progression-free survival. Grade 4 neutropenia occurred more frequently in the docetaxel-carboplatin group (84.6%) than in the paclitaxel-carboplatin group (43.8%), while sensory neurotoxicity was less frequent in the docetaxel-carboplatin group (53.8%) than in the paclitaxel-carboplatin (68.8%) group. There were significant differences in the quality-of-life data in favor of docetaxel-carboplatin. Conclusion We determined the recommended doses of docetaxel-carboplatin for Japanese patients with ovarian cancer to be docetaxel 70 mg/m² and carboplatin AUC 5. In the comparative study, we suggest that the docetaxel-carboplatin combination is effective and well tolerated as first-line chemotherapy for Japanese patients with ovarian cancer.     

Clinical and pharmacokinetic study of TNP-470, an angiogenesis inhibitor, in combination with paclitaxel and carboplatin in patients with solid tumors

Purpose Preclinical studies have demonstrated a synergistic effect with the angiogenesis inhibitor TNP-470 and several cytotoxic agents. A recent clinical trial with the combination of paclitaxel and TNP-470 has shown promising effects. The present study was designed to determine the toxicity and pharmacokinetics of carboplatin in combination with TNP-470 in comparison with the doublet regimen of paclitaxel and carboplatin in patients with solid tumors.Experimental design Enrolled in the study were 17 patients with lung (11), head/neck (3), sarcoma (2) and thymoma (1). The patients received intravenous paclitaxel and carboplatin on day 1 followed by TNP-470 (60 mg/m² i.v. over 1 h administered thrice weekly on Monday, Wednesday, and Friday). Each cycle of therapy consisted of 3 weeks. The initial cohort of three patients received carboplatin at AUC 5 mg/ml×min. No dose-limiting toxic effects occurred, thus the subsequent cohort received carboplatin at AUC 6 mg/ml×min. In addition to toxicity, the pharmacokinetics of carboplatin were evaluated, and tumor response and patient survival rates were assessed.Results The administered regimen of paclitaxel (225 mg/m² i.v. over 3 h) and carboplatin (AUC 6 mg/ml×min i.v. over 1 h) on day 1 followed by TNP-470 (60 mg/m² i.v. over 1 h administered thrice weekly on Monday, Wednesday, and Friday) was defined as both the maximum tolerated and optimal dose. Hematological toxic effects were similar to those expected with the chemotherapy doublet. All neurocognitive impairments were graded as mild to moderate and reversed after discontinuation of TNP-470 administration. No alterations in the pharmacokinetic disposition of carboplatin were noted. Overall, the median survival duration was 297 days. Four patients (24%) had a partial response, and eight (47%) had stable disease.Conclusions The combination of TNP-470, paclitaxel, and carboplatin is a reasonably well tolerated regimen. Further randomized studies of TNP-470 with this doublet regimen are now warranted for non-small-cell lung carcinoma and other solid tumors.     

Phase I multicenter study of combined high-dose ifosfamide and doxorubicin in the treatment of advanced sarcomas

Ifosfamide and doxorubicin are the most active agents in the treatment of sarcomas and are characterized by a marked dose-response relationship. The objective of this study was to determine the maximum tolerated dose (MTD) of both agents in combination under granulocyte-macrophage colony-stimulating factor (GM-CSF) cover.Patients and methods: Thirty-three patients with untreated sarcomas (soft tissue: n = 20; gynecological: n = 11; bone: n = 2) were treated with ifosfamide 12 g/m² by continuous i.v. infusion over five days and doxorubicin with dose escalation from 50 mg/m² i.v. bolus divided on two days, then to 60 mg/m² bolus divided on three days. Ifosfamide was reduced to 10 g/m² and doxorubicin was further escalated up to 90 mg/m². GM-CSF (5 µg/kg/day subcutaneously) was started 24 hours after chemotherapy and continued for 10 days.Results: The MTD was reached with the combination of ifosfamide at 12 g/m² and doxorubicin at 60 mg/m². But with ifosfamide 10 g/m² and doxorubicin 90 mg/m² the MTD was not obtained. While severe leukopenia and granulopenia were observed at all-dose levels, severe anemia was more frequently related to the highest dose of ifosfamide. Severe thrombopenia and mucositis were more commonly observed at the highest dose of doxorubicin. Ifosfamide 10 g/m² and doxorubicin 90 mg/m² induced WHO grade 4 leukopenia in 58%, grade 3–4 thrombopenia in 42%, and anemia in 31% of cycles. Mucositis was minor in 50% of cycles. The overall response rate among 31 evaluable patients was 55% (95 confidence interval (CI): 36%–73%), with four (13%) complete responders and 13 (42%) partial responders. Response rates based on soft-tissue sarcomas or gynecological sarcomas alone were similar. Ten patients could be treated by elective surgery and/or radiotherapy. The total group of patients reached a median survival of two years, with 25% (SE 8%) survivors after three years.Conclusions: The dose level of ifosfamide 10 g/m² and doxorubicin 90 mg/m² with supportive GM-CSF is manageable in a multicenter setting and should be further tested in regular phase II trials, including patients with gynecological and soft-tissue sarcomas. Transient toxicity with myelosuppression should be accepted in order to obtain a high anti-tumor activity of this regimen and a potential improvement in survival.     

Phase I/II study of the combination of carboplatin and paclitaxel as first-line chemotherapy in patients with advanced epithelial ovarian cancer

Purpose: We performed a phase I/II study evaluating the combination ofpaclitaxel and carboplatin as first-line chemotherapy in patients withadvanced ovarian cancer. The aim of this study was to define a feasible andsafe combination regimen that could be recommended for future phase IIIstudies.Design: This study was a parallel two-arm, non-randomized, open trial. Ina first step, carboplatin was administered at a fixed dose of AUC 5 andpaclitaxel was escalated in 25 mg/m² steps starting at 135mg/m². Paclitaxel was given as a three-hour infusion.Carboplatin was administered on day 1 following paclitaxel in one study armand 24 hours after paclitaxel infusion on day 2 in the other study arm.Carboplatin was escalated to AUC 6 and AUC 7.5 after the MTD for paclitaxelhad been defined. Treatment was repeated every three weeks.Patients: Sixty-one patients with untreated histologically confirmedepithelial ovarian cancer were recruited of whom 59 were found eligible andevaluable for toxicity. Thirty-three patients with bidimensionally measurabledisease were evaluable for tumor response.Results: We could not detect any advantage of the two-day schedule comparedwith the more convenient one-day schedule. Dose limiting toxicities wereneutropenia, thrombocytopenia, and neurotoxicity. Except for two patients,toxicity was acceptable and clinically managable. One patient died ofneutropenic sepsis and one further patient developed grade III peripheralneurotoxicity that did not resolve within two months after chemotherapy hadbeen terminated. Overall objective response rate was 70%. The MTD forpaclitaxel was 185 mg/m² and AUC 6 for carboplatin,respectively. Secondary prophylaxis with G-CSF did not allow further doseescalation and therefore is not generally recommended.Conclusions: Paclitaxel 185 mg/m² given as three-hourinfusion followed by carboplatin AUC 6 is a feasible and safe regimen and canbe recommended for phase III trials. Observed response rates justify furtherevaluation of this combination. A randomized phase III trial comparing athree-hour infusion of paclitaxel 185 mg/m² combined witheither carboplatin AUC 6 or cisplatin 75 mg/m² as first-linechemotherapy of advanced ovarian cancer has recently been initiated by ourgroup.     

A phase I study of prolonged ambulatory infusion carboplatin with oral etoposide showing activity in prostate cancer

Purpose: This phase I study aimed to establish the dose for phase II trials of a dose-intense outpatient regimen of ambulatory carboplatin and oral etoposide. Patients and Methods: Cohorts of three patients received escalating doses of carboplatin 15, 20, and 23 mg/m²/day as a 3-week continuous ambulatory infusion with oral etoposide initially at 50 mg/day. Patients entered had prostate, colon, head and neck, breast, unknown primary cancers and mesothelioma. Results: At 23 mg/m² of carboplatin, two patients had WHO grade 3 lethargy and myelosuppression, which were the dose-limiting toxicities. Six patients were entered at the dose recommended for phase II studies, carboplatin 20 mg/m²/day and etoposide 50 mg/day for 21 days repeated every 6 weeks. This was well tolerated except for one patient with multiple bone metastases from prostate cancer experiencing grade 4 myelosuppression and a single patient with grade 3 constipation. Seven patients with hormone-resistant prostate cancer were entered into the study, one at 15 mg/m², four at 20 mg/m² and two at 23 mg/m² of carboplatin, and received a median of four cycles of treatment. The only responses were seen in prostate cancer where there were two partial responses in patients with soft tissue predominant disease. Five patients who could be evaluated with initially elevated PSA exhibited falls of ≥50% after receiving the chemotherapy. All but one patient with prostate cancer experienced significant reduction in pain levels. The median time to progression of the patients with prostate cancer was 4 months. Conclusions: Ambulatory infusion carboplatin and oral etoposide is a tolerable dose- intense outpatient regimen which warrants further testing in phase II trials including hormone-resistant prostate cancer. Received: 13 March 2000 / Accepted: 26 May 2000     

Phase I/II trial of docetaxel and carboplatin in previously untreated patients with advanced non-small-cell lung cancer

Background. This trial was conducted to determine the maximum tolerated dose (MTD) and principal toxicities of combinations of docetaxel and carboplatin administered every 3 weeks to patients with advanced non-small-cell lung cancer (NSCLC) previously untreated with chemotherapy, and to find suitable doses for phase II studies in Japanese subjects. Methods. Japanese patients with advanced NSCLC and performance status 0 to 2 according to the World Health Organization classification, but previously untreated with chemotherapy received docetaxel followed by carboplatin, each infused over a 1-h period. The carboplatin dose was based on the target area under the curve (AUC), using Calvert's formula. Dose levels studied were: docetaxel (mg/m²)/carboplatin AUC (mg/ml·min), 50/4, 60/4, and 60/5, repeated every 3 weeks. Granulocyte-colony stimulating factor (G-CSF) support was first used when dose-limiting toxicities (DLTs) were encountered. Results. Of 14 patients entered, 12 were assessable for toxicity and response. The MTD schedule was: docetaxel, 60 mg/m², with carboplatin, AUC 5 mg/ml·min (DLTs in 3 of 3 patients). The recommended dosage was: docetaxel, 60 mg/m², with carboplatin, AUC 4 mg/ml·min (DLTs in 2 of 6 patients). The main toxic effect was neutropenia, and any nonhematologic toxic effects were mild. No thrombocytopenia occurred. Six of the 12 patients (50%) showed responses; 4 of the 6 at the recommended doses. Conclusion. Docetaxel 60 mg/m², given over a 1-h period, followed by carboplatin, AUC 4 mg/ml·min, given over a 1-h period, is recommended for phase II studies in Japan. This combined chemotherapy has mild toxicity, except for neutropenia, and is useful and easy to administer. We therefore believe that phase II and phase III studies of this therapy would be well justified. Received: October 4, 1999 / Accepted: June 28, 2000