Biweekly docetaxel in recurrent ovarian cancer: a phase I dose finding study

Purpose  To determine the maximum tolerated dose of biweekly docetaxel in patients with recurrent ovarian cancer, aiming at 70 mg/m². Methods  In this phase I trial, 8 patients were treated with biweekly docetaxel 50–65 mg/m². Dose-limiting toxicities were defined as any grade 3–4 non-hematological toxicity, prolonged (≥1 week) grade 4 neutropenia or platelet count <25 × 10⁹/L, any neutropenic sepsis or febrile neutropenia, or any grade 4 thrombocytopenia or grade 3 thrombocytopenia with bleeding. Results  Two groups of 3 patients each were given docetaxel 50 and 60 mg/m², respectively, and 2 patients received 65 mg/m². A total of 43 cycles were given; 26% of these were delayed, while granulocyte colony stimulating factor (G-CSF) support was used in 33%. The main toxicity was neutropenia: at dose levels of 50, 60, and 65 mg/m², grade 3–4 neutropenia occurred in 2/3, 3/3 and 1/2 patients, respectively. One patient experienced febrile neutropenia. A dose reduction was needed in 6 out of 13 cycles at the 65 mg/m² dose level. The study had to be closed prematurely due to the frequent need for G-CSF support, precluding the exploration of the 70 mg/m² dose. Non-hematological toxicities were mild. One patient had a partial response and six patients showed a stable disease. Conclusions  The maximum tolerated dose of biweekly docetaxel could not be determined in this study. It seems that increasing the dose beyond 60 mg/m² without a routine use of G-CSF is difficult.     

A phase I trial of docetaxel and gemcitabine in patients with advanced cancer

Background:Docetaxel and gemcitabine are active in a broad rangeof malignancies. The objective of this phase I trial was to determine themaximally tolerated doses of the combination of docetaxel and gemcitabine. Patients and methods:Patients with advanced cancer, WHOperformance status 0–2, who had received up to one prior chemotherapyregimen were treated with gemcitabine on days 1 and 8 and docetaxel on day 8repeated every 21 days. Prophylactic ciprofloxacin was commenced on day 11 ofeach cycle and continued until the neutrophil count reached 1.0 ×10⁹/l. G-CSF was not administered. Dose levels studied weredocetaxel/gemcitabine: 60/800, 60/1000, 75/1000, 75/1200, 85/1200 and 100/1200mg/m². Results:Thirty-nine patients were entered and all were assessablefor toxicity. The highest administered dose level was 100 mg/m²docetaxel and 1200 mg/m² gemcitabine with dose limiting toxicitiesof febrile neutropenia, grade 4 neutropenia 7 days, grade 4thrombocytopenia, grade 3 stomatitis and/or grade 3 fatigue in three out ofsix patients. Treatment was well tolerated (40 cycles) in the 10 patientstreated at the recommended dose level (85/1200) with only a single episode offebrile neutropenia and grade 3 or 4 non-hematologic toxicity was infrequent.There was no significant pulmonary toxicity. Responses were seen in a rangeof malignancies including non-small-cell lung cancer. Conclusions:The recommended dose level of 85 mg/m²docetaxel and 1200 mg/m² gemcitabine has a favourable toxicityprofile and is suitable for further investigation in phase II trials. Thisnon-platinum containing regimen warrants further investigation as a potentialalternative to platinum containing regimens in non-small-cell lung cancer andother malignancies.     

An EORTC phase I study of epirubicin in combination with fixed doses of cyclophosphamide and infusional 5-fu (CEF-infu) as primary treatment of large operable or locally advanced/inflammatory breast cancer

Purpose. The association of continuous infusion 5-fluorouracil, epirubicin (50mg/m² q 3weeks) and a platinum compound (cisplatin or carboplatin) was found to be very active in patients with either locally advanced/inflammatory (LA/I) [1, 2] or large operable (LO) breast cancer (BC) [3]. The same rate of activity in terms of response rate (RR) and response duration was observed in LA/I BC patients when cisplatin was replaced by cyclophosphamide [4]. The dose of epirubicin was either 50mg/m² [1, 2, 3] or 60mg/m²/cycle [4]. The main objective of this study was to determine the maximum tolerated dose (MTD) of epirubicin when given in combination with fixed doses of cyclophosphamide and infusional 5-fluorouracil (CEF-infu) as neoadjuvant therapy in patients with LO or LA/I BC for a maximum of 6 cycles. Patients and methods. Eligible patients had LO or LA/I BC, a performance status 0–1, adequate organ function and were 65 years old. Cyclophosphamide was administered at the dose of 400mg/m² day 1 & 8, q 4weeks and infusional 5-fluorouracil 200mg/m²/day was given day 1–28, q 4weeks. Epirubicin was escalated from 30 to 45 and to 60mg/m² day 1&8; dose escalation was permitted if 0/3 or 1/6 patients experienced dose limiting toxicity (DLT) during the first 2 cycles of therapy. DLT for epirubicin was defined as febrile neutropenia, grade 4 neutropenia lasting for 7 days, grade 4 thrombocytopenia, or any non-haematological toxicity of CTC grade 3, excluding alopecia and plantar-palmar erythrodysesthesia (this toxicity was attributable to infusional 5-fluorouracil and was not considered a DLT of epirubicin). Results. A total of 21 patients, median age 44 years (range 29–63) have been treated. 107 courses have been delivered, with a median number of 5 cycles per patient (range 4–6). DLTs on cycles 1 and 2 on level 1, 2, 3: grade 3 (G3) mucositis occurred in 1/10 patients treated at the third dose level. An interim analysis showed that G3 PPE occurred in 5/16 pts treated with the 28-day infusional 5-FU schedule at the 3 dose levels. The protocol was subsequently amended to limit the duration of infusional 5-fluorouracil infusion from 4 to 3 weeks. No G3 PPE was detected in 5 patients treated with this new schedule. Conclusions. This study establishes that epirubicin 60mg/m² day 1&8, cyclophosphamide 400mg/m² day 1&8 and infusional 5-fluorouracil 200mg/m²/day day 1-21, q 4 weeks is the recommended dose level. Given the encouraging activity of this regimen (15/21 clinical responses) we have replaced infusional 5-fluorouracil by oral capecitabine in a recently activated study.     

Continuous infusion carboplatin on a 21-day schedule: a phase I and pharmacokinetic study

A phase I study with continuous infusion carboplatin for 21 days every 6 weeks using a venous access port and portable pump was performed over a dose range of 12 to 32 mg/m2/d, with increments of 2 mg/m2/d. Forty-four patients received 107 courses (median, two; range, one to nine). World Health Organization (WHO) grade III/IV leukopenia and thrombocytopenia occurred in one of seven patients at 30 mg/m2/d, and in two of six and four of six patients at 32 mg/m2/d. Cumulative platelet depression was found at dose levels of 28 mg/m2/d or more. Median glomerular filtration rate (GFR) and effective renal plasma flow, monitored by radioisotope clearances at doses greater than or equal to 20 mg/m2/d, decreased 8.2% (P less than .05) and 10.9% (P less than .01) after two courses. There was a relationship (r = .50, P less than .0002) between the percentage of platelet depression and GFR. No other toxicity was observed. Of the 17 patients who were evaluable, one complete response and four partial responses were observed. In addition, six patients had stable disease. Pharmacokinetic analysis of total and ultrafiltrable platinum (UFPt) was performed by atomic absorption spectrophotometry. Steady-state plasma levels for UFPt were reached after 8 hours. These levels could be detected from the 20 mg/m2/d dose. During steady state, carboplatin dose and UFPt plasma levels were not correlated, but steady-state UFPt and GFR (r = -.27, P less than .05) were. Twenty-four percent of total platinum (Pt) was present as UFPt during steady state (x = 160 +/- 10 micrograms/L). Total body clearance of UFPt exceeded GFR 2.2 times. Mean area under the curve (AUC) for UFPt during continuous infusion was 4,921.8 +/- 301.72 mg.min/L. For total Pt, steady-state plasma levels were not reached; total Pt plasma levels increased between day 7 and day 21 (P less than .0001). There was a significant relation between total Pt serum levels day 7, 14, and 21 and the drug dose administered. Immunohistochemical analysis of DNA-bound Pt in leukocytes showed a linear increase from day 7 to day 14 to day 21 (r = .97) between DNA-bound Pt and duration of infusion in individual patients. The maximum-tolerable dose of carboplatin is 30 mg/m2/d for 21 days (total dose 630 mg/m2) and is recommended for phase II studies.     

Carboplatin with weekly docetaxel and ifosfamide in advanced head and neck cancers: a phase I Brown University Oncology Group dose escalation study (HN-93)

Purpose

A phase I study was performed to determine the maximally tolerated dose of carboplatin, ifosfamide, and docetaxel in advanced head and neck cancers.

Methods

Carboplatin (week 1) was administered with weekly docetaxel and ifosfamide for 3 weeks in an every 4-week cycle. Restaging was done after two cycles, while dose level escalation was done in cohorts of three patients.

Results

Fifteen patients (recurrent/metastatic disease, n = 8; bulky locally advanced disease, n = 7) were enrolled. No dose-limiting toxicities were observed. Toxicities included grade 3 neutropenia and anemia (n = 2, each), and grade 2 thrombocytopenia (n = 3). The final level of carboplatin AUC = 6 (week 1) with docetaxel 30 mg/m² per week and ifosfamide 1,000 mg/m² per week was chosen for further evaluation.

Conclusions

This novel regimen of carboplatin with weekly docetaxel and ifosfamide has a favorable toxicity profile and is active in this setting. Phase II study results are awaited.     

Carboplatin and etoposide in advanced lung cancer: — a phase I study

Summary This phase I study was carried out to determine the maximal tolerated dose of carboplatin (Car) together with a fixed dose of etoposide (E) and to recommend the optimal dose for a phase II study. The dose of E was 100 mg/m² given i.v. on days 1–3, and the starting dose of Car was 200 mg/m² given i.v. on day 1. The dose was escalated until WHO grade 4 toxicity developed after two treatment cycles in more than one-third of the patients. A total of 33 patients with advanced lung cancer entered the trial. The maximal tolerated toxicity of the combination was reached at a dose of 500 mg/m² Car. Myelosuppression was moderate, and hematological toxicity of WHO grade 4 was encountered in one of five patients at 475 mg/m² and in two out of five patients at 500 mg/m². The main toxic effects were leucopenia and thrombocytopenia. The frequency of treatment-related infections was low and no deaths were caused by treatment. There was a significant overall correlation between the platelet nadir and creatinine clearance. One complete response and three partial responses were achieved after two treatment cycles. Based on the results of the present study, the dose of carboplatin (combined with 100 mg/m² eposide given on days 1–3) recommended for phase II studies is 450 mg/m².     

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     

A phase I study of ZD0473 combined with paclitaxel for the treatment of solid malignancies

Purpose ZD0473 is a cytotoxic platinum agent, which in preclinical studies has exhibited synergistic activity when combined with paclitaxel. The aim of this open-label phase I study was to determine the maximum tolerated dose (MTD), safety, and antitumour activity of ZD0473 followed by paclitaxel in patients with refractory solid malignancies.Methods Patients received paclitaxel and ZD0473 on day 1 every 3 weeks. Seven dose levels were planned (ZD0473 60–180 mg/m², paclitaxel 135–175 mg/m²), with dose escalation dependent on the incidence of dose-limiting toxicity.Results Included in the study were 23 patients who received 76 treatment cycles at dose levels 1 (60 mg/m² ZD0473, 135 mg/m² paclitaxel) to 6 (150 mg/m² ZD0473, 175 mg/m² paclitaxel). Dose-limiting thrombocytopenia (platelet count <25×10⁹/l) occurred in two of six patients at dose level 6, which defined the MTD. Grade 3/4 haematological toxicities included: anaemia (21.7%), neutropenia (39.1%), thrombocytopenia (34.8%), and leucopenia (34.8%). The most common grade 3/4 non-haematological toxicities included: alopecia (13.0%), pleural effusion (13.0%), somnolence (8.7%), and vomiting (8.7%). Of the 23 patients, 11 (47.8%) had disease stabilization, including 4 with non-small-cell lung cancer (NSCLC) who had a 25% reduction in tumour dimensions.Conclusions ZD0473 combined with paclitaxel has a manageable tolerability profile and shows some evidence of antitumour activity in patients with NSCLC.     

Dose intensity of carboplatin in combination with cyclophosphamide or ifosfamide

In two separate studies of patients with ovarian cancer, subjects were treated on a protocol comprising 400 mg/m² carboplatin in combination with 1 g/m² cyclophosphamide (group A) or 5 g/m² ifosfamide with mesna (group B). The dose intensities achieved in group A were 87.2 mg/m² carboplatin per week and 245.8 mg/m² cyclophosphamide per week (34 patients). In group B, the dose intensities achieved were 124.1 mg/m² carboplatin per week and 2,020 mg/m² ifosfamide per week (25 patients). Two formulae for the prediction of the optimal dose of carboplatin based on renald function and degree of myelosuppression are compared with that based on surface area, and that recently proposed by Calvert is recommended. The importance of dose intensity and the total dose delivered in phase II and III studies is emphasized.Presented at the Satellite Symposium Ifosfamide in Gynecological Tumors of the 5th European Conference on Clinical Oncology and Cancer Nursing, London, Septemberd 3–7, 1989     

A phase I clinical trial of low-dose interferon-α-2A, thalidomide plus gemcitabine and capecitabine for patients with progressive metastatic renal cell carcinoma

Background We have conducted a phase I trial to determine the maximum tolerated dose of gemcitabine in combination with interferon, thalidomide and capecitabine. Methods Patients received oral capecitabine 1,000 mg/m² per day, divided in 2 daily doses, 2 weeks on, 1 week off; subcutaneous interferon-α 1 mIU twice a day without an interruption; daily oral thalidomide 200 mg/day for the first 7 days, then escalated to 400 mg/day without an interruption. Gemcitabine was given by intravenous administration over 30 min on day 1, week 1 and day 8, week 2. Initial dose level of gemcitabine was 400 mg/m². The dose of gemcitabine was the phase I variable. One cycle was 3 weeks. Results and discussion We treated 12 patients, 6 patients were entered at a dose level of 0 (gemcitabine 400 mg/m²) and 6 patients entered at a dose level-1 (gemcitabine 200 mg/m²). Eight of 12 patients completed at least 12 weeks of therapy. Three partial responses and two stable disease were observed. The remaining patients had progressive disease. Non-hematologic toxicity was either grade 1 or 2. Hematologic toxicity at dose level 0 consisted of 3 patients with grade 3/4 neutropenia, and 1 patient with grade 3 thrombocytopenia. At dose level-1 grade 1/2 neutropenia was observed. Conclusions The completion of our phase I experience determined our maximum tolerated dose to be dose level-1. The phase II trial is currently being proposed for patients with rapidly growing clear cell, other histologies that may contain sarcomatoid elements or collecting duct tumor.     

A dose-finding and pharmacokinetic study of nedaplatin in elderly patients with advanced non-small cell lung cancer

Purpose

Nedaplatin is a second-generation platinum showing favorable activity against non-small cell lung cancer (NSCLC). Dose-limiting toxicity (DLT) is thrombocytopenia, predicted by creatinine clearance (Ccr). This study was conducted to determine the recommended dose, and evaluate the toxicities, pharmacokinetics and efficacy for elderly NSCLC patients.

Methods

Patients ≥70 years were stratified into two groups based on renal functions: Group A, Ccr ≥ 60 and Group B, 40 ≤ Ccr < 60. The initial doses were 80 and 60 mg/m² in Groups A and B, respectively. The doses were escalated in 20-mg/m² increments to 100 mg/m² until DLT.

Results

Chemotherapy-naïve 39 elderly patients (Group A/Group B: 22/17) received a total of 83 cycles. Major toxicities were hematological. In Group A, one of the 15 patients at 100 mg/m² experienced DLT (neutropenia) and the recommended dose was determined at 100 mg/m². In Group B, three of the five patients had DLTs (leukopenia, neutropenia, thrombocytopenia and febrile neutropenia) at 100 mg/m², and the recommended dose was determined at 80 mg/m². The percentage decreases of neutrophil were well correlated with total and free-Pt AUCs. Partial responses were observed in 13 (33%) of the 39 patients, and 12 of the 13 patients who responded had a squamous cell carcinoma.

Conclusions

Nedaplatin was administered simply and feasibly by stratifying renal function and exerted favorable antitumor activity for elderly patients with NSCLC, especially on squamous cell carcinoma.     

A phase 1 study of vinblastine in combination with carboplatin for children with low-grade gliomas: a Children's Oncology Group phase 1 consortium study

Both carboplatin and vinblastine have demonstrated single-agent activity in children with low-grade gliomas. A phase 1 trial evaluating 2 different schedules of these 2 agents in combination was performed: (1) Schedule A = carboplatin (140 mg/m²) weekly × 3 + vinblastine (4.5 or 3.5 mg/m²) weekly × 6, every 6 weeks; (2) Schedule B = carboplatin (300, 400, or 500 mg/m²) on day 1 + vinblastine (4.0 mg/m²) weekly × 3, every 4 weeks. Twenty-six patients, median (range) age 4.4 (0.7–14.8) years, were enrolled. Four of 9 patients enrolled on Schedule A had recurrent grade 4 neutropenia, suggesting that this schedule was not feasible. Seventeen patients were enrolled on Schedule B. At the 500 mg/m² carboplatin dose level, 2 of 3 patients developed dose-limiting toxicity (elevated alkaline phosphatase, neutropenia). At the 400 mg/m² carboplatin dose level, none of the 6 patients had dose-limiting toxicity. Ten of 16 patients who received treatment on Schedule B completed the prescribed 12 courses. Of the 21 patients evaluable for response, central review confirmed 1 partial response and 6 minor responses. Eleven patients had stable disease (>3 months) and 3 developed progressive disease. Seven of 9 patients with visual pathway tumors and acute visual changes prior to enrollment had documented improvement. The recommended phase 2 dose and schedule is carboplatin, 400 mg/m²/dose on day 1, and vinblastine, 4 mg/m²/dose, weekly × 3, repeated every 4 weeks. Further study of this regimen in patients with low-grade glioma is warranted.     

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 study of paclitaxel,carboplatin, and bortezomib in the treatment of metastatic malignant melanoma

BACKGROUND:

Chemotherapy has not been reported to have a significant impact on survival for patients with metastatic melanoma. Bortezomib was shown to have additive/synergistic effects with several chemotherapeutic agents, including paclitaxel and platinum. A phase 1 trial of this 3‐drug combination reported that 6 of 28 patients treated with bortezomib followed by paclitaxel and carboplatin achieved a partial response (including 2 of 5 patients with metastatic melanoma).

METHODS:

A 2‐stage phase 2 clinical trial was conducted to assess the antitumor activity of this 3‐agent combination in patients with metastatic melanoma who had received at most 1 prior chemotherapy for metastatic disease. Treatment included bortezomib at a dose of 1.3 mg/m² intravenously on Days 1, 4, and 8; paclitaxel at a dose of 175 mg/m²; and carboplatin at an area under the concentration (AUC) of 6 on Day 2 of a 21‐day cycle. The primary endpoint of this trial was tumor response rate (TRR).

RESULTS:

Seventeen eligible patients were enrolled. A median of 4 cycles were administered (range, 1‐7 cycles). Three patients discontinued treatment due to persistent grade 4 (based on National Cancer Institute Common Terminology Criteria for Adverse Events [version 3.0]) neutropenia with grade 3 leukopenia (2 patients) or grade 4 pulmonary embolism (1 patient). Grade ≥3 toxicities included neutropenia (71%), leukopenia (41%), thrombocytopenia (29%), and arthralgia (12%). Two partial responses were observed (TRR, 11.8%). Four patients had stable disease at >12 weeks. The median progression‐free survival was 3.2 months, and the median overall survival was 7.0 months.

CONCLUSIONS:

Due to insufficient clinical efficacy, this trial did not proceed to second‐stage accrual. The combination of paclitaxel, carboplatin, and bortezomib demonstrated limited clinical benefit and was associated with significant toxicity. Cancer 2010. © 2010 American Cancer Society.     

Cisplatin–epirubicin–paclitaxel weekly administration in advanced breast cancer: A phase I study of the Southern Italy Cooperative Oncology Group

Purpose: Both cisplatin and epirubicin have been shown to enhance the antitumor activity of paclitaxel in vitro. Weekly administration could result in a substantial improvement in the therapeutic index of cisplatin and paclitaxel. This study was aimed at determining the MTDs of epirubicin and paclitaxel given weekly with a fixed dose of cisplatin.Patientsandmethods: Sixty–three breast cancer patients with advanced disease (24 locally advanced and 39 metastatic), who had not received prior chemotherapy (except adjuvant), received weekly cisplatin (CDDP) doses of 30mg/m² together with escalating doses of paclitaxel (PTX) and epirubicin (EPI) for a minimum of six cycles. The dose escalation was stopped if DLT occurred during the first six treatment cycles in >33% of patients of a given cohort.Results: Nine different dose levels were tested, for a total of 506 weekly cycles delivered. G–CSF support on days 3–5 of each week was also given in the last four cohorts (24 patients). An overall 11 patients showed DLT in the first six cycles. EPI and PTX doses up to 40 and 85mg/m²/week, respectively, were safely delivered without G–CSF support. However, the actually delivered mean dose intensity was only 64 in this cohort. Therefore, the dose escalation continued with the addition of filgrastim from day 3 to day 5 each week. Doses of EPI and PTX up to 50 and 120mg/m²/week were administered without observing DLT in the first six cycles in more than one third of the patients enrolled. No toxic deaths were observed. Only two patients had to be hospitalized because of sepsis. Grade 3–4 neutropenia, thrombocytopenia, and anemia occurred in 25, 9, and 16 patients, respectively. Alopecia was almost universal. Other nonhematologic toxicities were generally mild, being of grade 3–4 in only eight patients (fatigue and loss of appetite in two cases, diarrhoea in four cases, peripheral neuropathy and mucositis in one case).abstract     

Randomised phase II study of cisplatin-etoposide versus infusional carboplatin in advanced non-small-cell lung cancer and mesothelioma.

Background:A randomised phase II study was performed to comparestandard combination chemotherapy containing cisplatin and etoposide withinfusional carboplatin. Patients and methods:One hundred twenty patients with locallyadvanced/metastatic non-small-cell lung cancer or mesothelioma were enrolled.All were chemotherapy-naïve and had a Karnofsky performance status of50. Patients were randomised to either four cycles of bolus therapy ofcisplatin 80 mg/m² day 1, etoposide 120 mg/m² day1–3, or continuous infusion of carboplatin 100/mg/m²/week forsix weeks. Results:No patients on infusional therapy incurred grade3–4 toxicity while in the bolus arm, grade 3 and grade 4 leucopeniaoccurred in 17% and 35% of patients, respectively. Grade 4thrombocytopenia occurred in 8% of patients and there were twoinstances of grade 3 renal toxicity. No responses occurred in the pump arm.Eight of forty-six patients with non-small-cell lung cancer responded totreatment (response rate 17.3%) with two complete responses and sixpartial responses. Only one patient with mesothelioma responded to bolustherapy. There was no difference in survival for the subset of NSCLC patients.Survival for mesothelioma patients in the pump arm was superior but this waslikely to be a result of early deaths in the bolus arm. Conclusions:The pump arm was well-tolerated but not active,whilst combination platinum-based therapy demonstrated activity butsignificantly more toxicity than the pump arm. Further studies of infusionalcarboplatin with this schedule are not warranted.     

A phase I trial of oral administration of panobinostat in combination with paclitaxel and carboplatin in patients with solid tumors

Purpose

To determine the maximum tolerated doses and dose-limiting toxicities of oral panobinostat in combination with paclitaxel and carboplatin when administered to patients with advanced solid tumors.

Patients and methods

Patients initially received panobinostat twice weekly. Following amendment #1, patients received panobinostat three times weekly. Paclitaxel and carboplatin were administered intravenously on day 1 of each 21-day treatment cycle. Dose escalation continued until the maximum tolerated dose was determined. A total of 10 patients were treated at the recommended phase II dose to further assess safety.

Results

Twenty-one patients were enrolled across four different dose levels. The dose-limiting toxicity of the combination regimen was myelosuppression (neutropenia and thrombocytopenia), which often warranted panobinostat dose omissions or reductions. Nearly two-thirds of the patients experienced grade 4 neutropenia or grade 3 or 4 thrombocytopenia. Non-hematologic toxicities consisted primarily of diarrhea, fatigue, and vomiting, which were mild to moderate in intensity. No QTc prolongation was reported. Three partial responses were confirmed in patients with carcinoma of unknown primary (two patients) and non-small-cell lung cancer (one patient). Eleven additional patients reported stable disease as their best response to treatment.

Conclusions

The recommended phase II dose is panobinostat 10?mg orally three times weekly in combination with paclitaxel 175?mg/m² and carboplatin AUC 5 administered intravenously on day 1 of every 21-day cycle.     

Phase I study of carboplatin, cisplatin, and cyclophosphamide without and with lenograstim for the treatment of ovarian cancer

Cisplatin and carboplatin are both active in ovarian cancer with different toxicity profiles; thus, dose intensification may be possible by combining them. The aim of the present study was to determine the maximum tolerated dose of carboplatin combined with fixed doses of cisplatin and cyclophosphamide without and with support of lenograstim. Cisplatin (60 mg/m(2)), cyclophosphamide (600 mg/m(2)) and carboplatin (starting dose 200 mg/m(2)) were given on day 1 every 3 weeks for 4 cycles. Escalated dose levels for carboplatin were planned by increments of 50 mg/m(2) per level. Lenograstim (L) (150 mu g/m(2)/day subcutaneously) was given in case of grade 4 leukopenia (levels without support) or from day 5 up to leukocyte >10,000/mm(3) after nadir (levels with support). Four levels were studied (200, 250, 250 + lenograstim, 300 + lenograstim) with 7, 7, 8, and 7 patients enrolled, respectively. Unacceptable toxicity was induced in 1 patient at the level I (grade 4 thrombocytopenia), in 4 patients at the level 2 (2 prolonged grade 2 leukopenia, 1 grade 4 leukopenia with concomitant grade 4 thrombocytopenia and 1 grade 4 thrombocytopenia), in 1 patient at the level 2 + L (grade 4 thrombocytopenia) and in 3 patients at the level 3 + L (3 grade 4 thrombocytopenia). Thus, 200 mg/m(2) and 250 mg/m(2) were defined as carboplatin MTDs without and with lenograstim support, respectively. Median total platinum (cisplatin + 1/4 carboplatin) delivered dose-intensities were 33, 32, 38 and 44 mg/m(2)/week at the four levels, respectively. Hematological toxicity was overall mild. In no case was febrile neutropenia recorded. Grade 4 thrombocytopenia was always transient and never symptomatic. Grade 3 vomiting was the only severe non-hematological toxicity reported in 5 patients. Out of 16 patients with measurable disease, 11 objective responses were obtained (5 complete and 6 partial) for an overall response rate of 69% (95% exact CL 41-89%). Recommended dose of carboplatin is 200 mg/m(2) without and 250 mg/m(2) with support of lenograstim when combined with cisplatin 60 mg/m(2) and cyclophosphamide 600 mg/m(2). Dose limiting toxicity is persistent leukopenia without and grade 4 thrombocytopenia with support of lenograstim.     

Phase I and pharmacokinetic study of weekly oral therapy withvinorelbine in patients with advanced breast cancer (ABC)

Background:A phase I dose-escalation study of a newformulation of oral vinorelbine was conducted to determine the maximumtolerated dose (MTD) of a once weekly regimen and preliminarypharmacokinetic profile in patients with advanced breast cancer (ABC).Twenty-six patients were treated at dose levels ranging from 60 to 100mg/m²/week. Pharmacokinetics was assessed during the firstadministration. Patients and methods:All patients hadhistologically confirmed locally advanced or metastatic breast cancerand had received no more than two prior chemotherapy regimens forABC. Results:The MTD was 100 mg/m²/weekdue to the occurrence of dose-limiting neutropenia, nausea/vomitingand constipation in five of six patients. Toxicities at 80mg/m²/week were manageable, neutropenia being the maintoxicity (grade 3–4 seen in 10 of 13 patients). Nausea, vomitingand diarrhoea were common but rarely severe. Vinorelbine was rapidlyabsorbed with maximum blood concentration (C_max) of 103.8± 41.6 ng·ml^–1 observed 1.2 ± 0.8hours (T_max) after administration of 80 mg/m².Pharmacokinetic exposure increased linearly with dose. Area under theconcentration-time curve (AUC) and concentration measured 24 hours afterdrug intake (C_24h) were significantly correlated withdepletion of neutrophils. Objective tumour responses were reported in 6of the 14 evaluable patients treated at doses 80mg/m²/week. Conclusion:The safety profile oforal vinorelbine appears comparable to that of intravenous dosing. Therecommended phase II dose is 80 mg/m²/week and requiresregular monitoring of neutrophil counts.     

Oral dipyridamole and methotrexate in human solid tumors: a toxicity trial

Summary Dipyridamole (DP) blocks nucleoside salvage by inhibiting uptake at the cell membrane. At the usual oral doses DP has no cytotoxic activity, but when combined with an antimetabolite, it results in synergistic cell kill in vitro. In this study, 45 patients with advanced solid tumors were treated with oral DP and i.v. or i.m. methotrexate (MTX) to define the toxicity of this combination. The DP dose was 75 mg b.i.d. in the first 16 patients, 150 mg b.i.d. in the next 2, and 75 mg q.i.d. in the remaining 27 patients. MTX was given weekly at an initial dose of 10–30 mg/m² and increased weekly by 5–10 mg/m² to the maximum tolerable dose (MTD) or a maximum of 60 mg/m²; thereafter that dose was given every other week. DP levels ranged from 2.76 to 11.46 M, with a mean of 5.67 M in four patients taking 75 mg q.i.d. The combination of oral DP and MTX was generally well tolrated and did not appear to result in any more myelotoxicity or mucositis than that expected for MTX alone. One patient experienced severe headaches related to DP, ten patients experienced grade 3 or 4 neutropenia and/or thrombocytopenia, and four patients had grade 3 mucositis. Although this trial was not designed as a phase II study, one partial remission was observed in a patient with metastatic pleomorphic adenoma of the parotid gland and seven patients showed significant improvement.