Phase II study of nedaplatin and irinotecan for elderly patients with advanced non-small cell lung cancer

We conducted a phase II study of combination chemotherapy with nedaplatin (NP) with irinotecan (CPT) to determine the effects against unresectable non-small cell lung cancer (NSCLC) and to determine the qualitative and quantitative toxicities of this combination chemotherapy in 70 years or older patients. Thirty-eight patients received 100 mg/m2 NP on day 1 and 60 mg/m2 CPT on days 1 and 8 every four weeks. Twenty-five patients achieved PR, nine SD and three PD, and the overall response rate was 65.8%. Nineteen patients (50%) experienced grade 4 neutropenia. Neutropenic fever occurred in 11 patients (29%) and one of them died. Of other grade 3 non-hematologic toxicities, two patients experienced diarrhea; one interstitial pneumonitis; one liver injury; and one rash. The median survival time was 418 days and the one-year survival rate was 55.3%. In conclusion, NP combined with CPT is an active treatment for elderly patients with NSCLC.     

Phase II study with gemcitabine, ifosfamide and cisplatin in advanced non-small cell lung cancer

The aim of the present study was to determine the clinical activity and toxicity of a novel chemotherapy combination regimen of gemcitabine, ifosfamide and cisplatin (GIP), administered every 3 weeks, in patients with inoperable non-small cell lung cancer (NSCLC). From October 1998 to July 1999, 18 previously untreated stages IIIb (4) and IV (14) patients were enrolled into the study. Gemcitabine and ifosfamide (with mesna as uroprotection) was administered on days 1 and 6, at a dose of 1000 and 1500 mg/m², respectively; and cisplatin was given on day 1 at a dose of 60 mg/m², every 3 weeks. All 18 patients were evaluable for response and toxicity profiles. One patient achieved a complete response, and 11 patients achieved a partial response, with an overall response rate of 66.7% (95% CI, 45–89%). The main toxicity was hematological, a NCI grade 3–4 neutropenia in 16 patients (88.9%) during the treatment course. Febrile neutropenia occurred in three patients (16.6%). Grade 3 anemia occurred in eight patients (44.4%) and grade 3–4 thrombocytopenia occurred in 11 patients (61.1%). Non-hematological toxicity was mild and tolerable. No toxic death occurred. The median survival was 12.7 months and 1 year survival was 58.4%. The GIP combination chemotherapy produced a high response rate in advanced NSCLC; however, there was a relatively high percentage of hematological toxicity that still could be tolerated. A randomized trial comparing GIP to a two-drug combination of gemcitabine and cisplatin is planned.     

Phase II study of irinotecan and carboplatin for advanced non-small cell lung cancer

A phase II study was conducted to assess the activity and toxicity of irinotecan (CPT-11) and carboplatin (CBDCA) combination chemotherapy for advanced non-small-cell lung cancer (NSCLC). Eligibility included chemo-naive advanced NSCLC patients with measurable disease and a good performance status. CPT-11 of 50 mg/m(2) was administered as a 90-min intravenous infusion on days 1, 8, and 15. CBDCA dosed to an area under the concentration-time curve of 5 mgmin/ml, using Calvert's formula, was administered by 90-min infusion after the CPT-11 infusion on day 1. Treatment was repeated 28 days interval for at least two cycles. Haematopoietic growth factors were not routinely used. From December 1997 to January 1999, 36 patients were entered into the study. The overall response rate was 25.0% (95% confidence interval: 12.1-42.2%). The median survival time and the 1-year survival rate were 10.2 months and 42.2%, respectively. Major toxicity by Japan Clinical Oncology Group criteria was as follows: grade 3-4 neutropenia 76.5%; grade 3 anemia 26.5%; grade 3/4 thrombocytopenia 47.1%; grade 3 nausea/vomiting 36.1%; grade 3-4 diarrhoea 5.9%; grade 3 alopecia 5.9%; grade 3-4 skin rush 2.9%. Four patients developed febrile neutropenia and only one had serious diarrhea induced by CPT-11. Actual relative delivery dose of CPT-11 to the projected one on days 8 and 15 were 0.86 and 0.43, respectively. It seemed that CPT-11 and CBDCA was more toxic regimen than CPT-11 and CDDP in advanced NSCLC. The relatively disappointing response rate could be related with low dose intensity of CPT-11.     

Phase I study of cisplatin, ifosfamide and irinotecan with rhG-CSF support in advanced non-small cell lung cancer.

A phase I study was conducted in advanced non-small cell lung cancer to determine the maximum tolerated dose (MTD) of irinotecan combined with a fixed schedule of cisplatin and ifosfamide with rhG-CSF support. In addition, efficacy including survival time was evaluated at 2 years after the completion of patient registration. Cisplatin (20 mg/m2) and ifosfamide (1.5 g/m2) were administered at fixed doses on days 1-4, and irinotecan was given on days 1, 8 and 15 starting at 40 mg/m2, which was increased in 10 mg/m2 increments. This regimen was repeated every 4 weeks. rhG-CSF was administered subcutaneously at a dose of 50 microg/m2 on days 5-18 except on the day of irinotecan treatment. Forty-five patients were registered and 35 had received no prior chemotherapy. MTD or irinotecan was defined according to toxicity and the dose during three courses was increased up to 70 mg/m2. The dose 60 mg/m2 was recommended for phase II study. The dose-limiting factor was thrombocytopenia. The overall response rate was 57.8% and the median survival time was 492 days. In chemotherapy-naive patients, the response rate was 65.7% (95% CI; 50-81.4%), median response duration 161 days, median survival time 513 days, 1-year survival rate 62.4%, and 2-year survival rate 27.3%.     

Phase II study of weekly carboplatin and irinotecan as first-line chemotherapy for patients with advanced non-small cell lung cancer

Purpose

Platinum-based doublet chemotherapy has a major role in the treatment of patients with advanced non-small cell lung cancer (NSCLC). The weekly fractionated administration of cisplatin for patients with NSCLC has been shown to be active. Irinotecan and carboplatin are effective against NSCLC and demonstrated synergism with non-cross-resistance in preclinical studies. We conducted a phase II study of weekly combination of carboplatin and irinotecan as first-line chemotherapy for patients with advanced NSCLC.

Methods

From March 2009 to November 2011, 24 patients who were diagnosed with inoperable or metastatic NSCLC were enrolled. Treatment consisted of carboplatin at an AUC 2.5 mg/mL/min over 30-min intravenous infusion and irinotecan 65 mg/m² over 90-min intravenous infusion on day 1 and day 8, respectively. The treatment was repeated every 3 weeks.

Results

One patient (4.2 %) achieved complete response, and seven (29.2 %) showed partial response. Overall response rate was 33.3 %, with median response duration of 4.55 months. Nine patients had stable disease, and disease control rate was 70.8 %. With median follow-up of 12.8 months, median progression-free survival was 4.5 months (95 % CI 1.8–7.2), and median overall survival was 15.5 months (95 % CI 6.9–24.1). Major toxicity was myelosuppression. Grade 3–4 neutropenia and thrombocytopenia occurred in 50 and 20.8 % of patients, respectively. Two patients experienced febrile neutropenia. Non-hematologic toxicities were generally mild. One patient suffered grade 4 diarrhea, and one treatment-related death due to pneumonia was occurred.

Conclusion

The weekly combination of carboplatin and irinotecan showed favorable activity and manageable toxicity profiles in chemo-naïve patients with advanced NSCLC. Our results suggest that this regimen can be a reasonable chemotherapeutic option for patients with advanced NSCLC.     

Phase I study of vinorelbine and irinotecan in previously untreated patients with advanced non-small cell lung cancer

Introduction Vinorelbine alone and irinotecan alone have been shown to have efficacy against non-small cell lung cancer (NSCLC); each drug has different mechanisms of action. A phase I study using a combination of vinorelbine and irinotecan as first-line treatment for advanced NSCLC was done to determine the maximum tolerated dose (MTD) and the dose-limiting toxicity (DLT). Methods Previously untreated patients (≤75 years old) with Stage IIIB or IV NSCLC were enrolled. Based on a 4-week cycle, vinorelbine was given on days 1 and 8, and irinotecan was given on days 1, 8, and 15 intravenously. To prevent an injection site reaction to vinorelbine, the site was treated with topical clobetasol ointment, and the patients were given intravenous dexamethasone prior to vinorelbine treatment. DLT was defined as grade 4 neutropenia lasting ≥4 days or febrile neutropenia, grade 4 thrombocytopenia, ≥grade 3 non-hematological toxicities, or the need to cancel drug administration on both days 8 and 15. Results A total of 23 patients were enrolled. DLT was observed in 1 of 6 patients at level 3 (20 mg/m² vinorelbine, 50 mg/m² irinotecan), in 2 of 3 at level 4 (25 mg/m², 50 mg/m²), and in 2 of 5 at modified level 4 (20, 60 mg/m²). Level 4 and modified level 4 were considered to be the MTD; dose level 3 was therefore recommended. DLTs included liver dysfunction, pneumonitis, colitis, and arrhythmia. Injection site reactions were mild. Hematological and non-hematological toxicities were mild and easily controlled. Conclusion Use of 20 mg/m² vinorelbine on days 1 and 8 followed by 50 mg/m² irinotecan on days 1, 8, and 15 every 4 weeks warrants a phase II study.     

Phase I study of irinotecan and gemcitabine in previously untreated patients with advanced non-small cell lung cancer

BACKGROUND: Irinotecan and gemcitabine are effective against non-small cell lung cancer. We conducted a phase I study of the combined use of irinotecan and gemcitabine in previously untreated patients with advanced non-small cell lung cancer to determine dose-limiting toxicities and maximum tolerated dose. METHODS: Patients were treated with irinotecan followed by gemcitabine on days 1 and 8 every 3 weeks. Gemcitabine dose was fixed at 1000 mg/m2, and irinotecan dose was increased from 60 mg/m2. RESULTS: A total of 16 patients was enrolled. Maximum tolerated dose of irinotecan was determined up to level 3 (irinotecan 100 mg/m2). In Japan, the maximum approved weekly dose of irinotecan is 100 mg/m2, so this was the dose that was used. Only very mild hematological and non-hematological toxicities were noted. CONCLUSION: Use of 100 mg/m2 irinotecan followed by 1000 mg/m2 gemcitabine on days 1 and 8 every 3 weeks warrants a phase II study.     

Phase I and pharmacokinetic study of paclitaxel and irinotecan for patients with advanced non-small cell lung cancer

We conducted a phase I study of paclitaxel and irinotecan (CPT-11) in advanced non-small cell lung cancer (NSCLC). This study aimed to determine the maximum tolerated doses (MTD). The pharmacokinetics of CPT-11 and its major active metabolite, SN-38, were also analysed. Patients received paclitaxel (day 1) followed by CPT-11 (days 1, 8 and 15), in a 4-week cycle, and paclitaxel and CPT-11 were escalated from 120 and 40 mg/m(2), respectively. 28 patients were enrolled, who were evaluated for toxicity. 2 of 6 patients at 210 mg/m(2) paclitaxel and 50 mg/m(2) CPT-11, and 2 of 4 at 180 and 60 mg/m(2) developed dose-limiting toxicity (DLT) (neutropenia, fever, neurotoxicity and diarrhoea). The area under the plasma concentration-time curve (AUC) of CPT-11 on day 1 was significantly higher than that on days 8 or 15 at each dose level (P=0.002). The AUC of SN-38 on day 1 was significantly increased using paclitaxel doses >or=150 mg/m(2). A preceding paclitaxel administration changed the pharmacokinetics of CPT-11 and SN-38. However, the toxicity was tolerable. Paclitaxel 180 mg/m(2) and CPT-11 50 mg/m(2) were the recommended doses for further phase II study of this combination.     

Phase II study of biweekly administration of docetaxel and irinotecan in patients with refractory or relapsed advanced non-small cell lung cancer

We examined the safety and efficacy of the combination of docetaxel and irinotecan administered biweekly in patients with refractory or relapsed advanced non-small cell lung cancer (NSCLC). Patients with previously treated NSCLC of stage III or IV were eligible if they had a performance status of 2 or less, were 75 years or younger, and had adequate organ function. From May 2003 through February 2006, 35 patients (27 men and 8 women; median age 64 years; age range 41–75 years) were enrolled. Patients were treated every 4 weeks with docetaxel (33 mg/m² on days 2 and 16) plus irinotecan (50 mg/m² on days 1 and 15). None of the 35 patients achieved a complete response, but five achieved a partial response, for an overall response rate of 14.3% (95% confidence interval, 4.8–30.3%). The median survival time was 8 months (range 2–29 months). The median time to progression was 3 months (range 1–12 months). Grade 3 to 4 hematologic toxicities included leukopenia in 48.6% of patients, neutropenia in 54.3%, and anemia in 25.7%. No patients had grade 3 to 4 diarrhea or nausea and vomiting. Although one patient had grade 3 drug-induced interstitial pneumonia, all side effects were manageable, and there were no treatment-related deaths. In conclusion, the combination of docetaxel and irinotecan administered biweekly is a safe and effective treatment for refractory or relapsed NSCLC. However, the search for even more active regimens should be continued.     

Phase I and pharmacologic study of irinotecan and amrubicin in advanced non-small cell lung cancer

Purpose We conducted a Phase I trial of irinotecan (CPT-11), a topoisomerase I inhibitor, combined with amrubicin, a topoisomerase II inhibitor. The aim was to determine the maximum tolerated dose (MTD) of amrubicin combined with a fixed dose of CPT-11 as well as the dose-limiting toxicities (DLT) of this combination in patients with advanced non-small cell lung cancer. Patients and methods Eleven patients with stage IIIB or IV disease were treated at 3-week intervals with amrubicin (5-min intravenous injection on days 1–3) plus 60 mg/m² of CPT-11 (90-min intravenous infusion on days 1 and 8). The starting dose of amrubicin was 25 mg/m², and it was escalated in 5 mg/m² increments until the maximum tolerated dose was reached. Results The 30 mg/m² of amrubicin dose was one dose level above the MTD, since three of the five patients experienced DLT during the first cycle of treatment at this dose level. Diarrhea and leukopenia were the DLT, while thrombocytopenia was only a moderate problem. Amrubicin did not affect the pharmacokinetics of CPT-11, SN-38 or SN-38 glucuronide. Except for one patient, the biliary index on day-1 correlated well with the percentage decrease of neutrophils in a sigmoid E _max model. There were five partial responses among 11 patients for an overall response rate of 45%. Conclusion The combination of amrubicin and CPT-11 seems to be active against non-small cell lung cancer with acceptable toxicity. The recommended dose for Phase II studies is 60 mg/m² of CPT-11 (days 1 and 8) and 25 mg/m² of amrubicin (days 1–3) administered every 21 days. This work was presented in part at the 41st Annual Meetings of the American Society of Clinical Oncology, Orlando, FL, USA May 13–17, 2005.     

A Phase II NCCTG study of irinotecan and docetaxel in previously treated patients with non-small cell lung cancer

Purpose: This Phase II study was undertaken to define the efficacy and toxicity of the combination of docetaxel and irinotecan for the second-line treatment of non-small cell lung cancer (NSCLC). Patients and Methods: Forty-six patients with measurable NSCLC who had relapsed after an initial response to chemotherapy or who had failed to respond to initial chemotherapy, received 130 mg/m² of irinotecan IV over 90 minutes and 50 mg/m² docetaxel IV over 60 minutes on Day 1 q3 weeks for 6 cycles. Dexamethasone and diphenhydramine pretreatment were given. Response to treatment was evaluated by response evaluation criteria in solid tumors RECIST criteria, and toxicity was graded according to the National Cancer Institute Common Toxicity Criteria (NCI CTC) version 2.0. Results: The most common severe (NCI CTC Grade 3+) adverse events were neutropenia (67 percent), diarrhea (28 percent), fatigue (20 percent), nausea (17 percent), infection (15 percent), vomiting (13 percent), leucopenia (13 percent), abdominal pain (11 percent), and dyspnea (11 percent). Grade 5 toxic events were seen in 2 patients. One of these 2 cases was a possibly-treatment related event (intestinal fistula). The median number of treatment cycles received was 3. Twelve patients (26 percent) received all 6 cycles of treatment. Five patients (11 percent) had a confirmed response (complete response (CR), partial response (PR), or regression). Median follow-up for the five surviving patients is 26.5 months (range: 25.1-28.4). Forty-two patients have reported progressive disease and 41 patients have died. Median time-to-progression (TTP) and survival are 2.6 months and 7.5 months, respectively. Conclusion: This second-line treatment regimen of irinotecan and docetaxel in NSCLC patients has shown activity, but can not be recommended over single-agent regimens because of significant toxicity.     

Phase I study of daily S-1 combined with weekly irinotecan in patients with advanced non-small cell lung cancer

Background  S-1 is a novel oral fluorouracil prodrug active against non-small cell lung cancer (NSCLC). To determine the feasibility of S-1 combined with weekly irinotecan for patients with advanced NSCLC, we performed a phase I study to determine the maximum tolerated dose (MTD) and the recommended dose (RD) of irinotecan. Methods  Patients with advanced NSCLC received S-1 (80 mg/m²) on days 1–14 and irinotecan (50–80 mg/m²) on days 1, 8, and 15 of each 28-day cycle. Three to six patients were treated with each dose of irinotecan, with the MTD defined as the dose at which dose-limiting toxicity (DLT) appeared in 33% of patients. Results  At doses of 50–70 mg/m², no patients experienced any DLT, whereas, at a dose of 80 mg/m², two of four patients experienced DLTs. Two patients experienced grade 3 toxicities — neutropenia and diarrhea. Conclusion  The MTD of weekly irinotecan was 80 mg/m², making its RD for phase II trials 70 mg/m².     

Phase II study of carboplatin-paclitaxel combination chemotherapy in elderly patients with advanced non-small cell lung cancer

BACKGROUND: More than 30% of cases of non-small cell lung cancer (NSCLC) arise in patients aged > or =70 years. The efficacy and safety of carboplatin-paclitaxel combination chemotherapy in elderly patients with advanced NSCLC were evaluated in a phase II trial. METHODS: Twenty-five patients aged > or =70 years (median, 76; range, 70-83) with chemotherapy-naive advanced NSCLC were enrolled between January 2001 and July 2003. Additional criteria included the presence of measurable lesions, an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate organ function. Patients received carboplatin at an area under the curve of 5 mg/ml/min and paclitaxel at 180 mg/m(2) on the first day of consecutive 3 week periods. RESULTS: The patients included four with stage IIIB, 19 with stage IV and two with recurrent disease. The median number of treatment cycles was three (range, 1-4). One complete response and six partial responses, yielding an objective response rate of 28%, were obtained. The median survival time was 12.3 months and the 1-year survival rate was 52%. Hematological toxicities of grade 3 or 4 included leukopenia (40%), neutropenia (68%) and anemia (4%). Non-hematological toxicities of grade 3 included arthralgia-myalgia (16%) and neuropathy (12%). The objective response rate for patients aged > or =75 years (n = 15) was 26%, and no evidence of excessive toxicity in these patients was apparent compared with those aged <75 years. CONCLUSION: The combination carboplatin-paclitaxel at these doses is a feasible treatment option with a favorable toxicity profile for fit elderly patients with advanced NSCLC.     

Phase II study of vindesine in patients with non-small cell lung cancer

A phase II study of vindesine (VDS) was carried out in 21 patients with non-small cell lung cancer (NSCLC). There were 13 and 8 patients with and without prior chemotherapy, respectively. VDS was administered at a weekly iv dose of 3 mg/m2. Partial response was observed in two of 15 adenocarcinomas and one of 2 adenosquamous cell carcinomas, and the overall response rate was 14.3% (3/21). Myelosuppression, especially leukopenia, was the most common dose-limiting side effect. Neurotoxicity was also a common side effect but the degree was mild. It was concluded that VDS at a dose of 3 mg/m2 every week seems to be active against NSCLC.     

Phase II study of cis-diamminedichloroplatinum in patients with non-small cell lung cancer

A phase II study of cis-diamminedichloroplatinum (CDDP, 80 mg/m2, every 3 weeks) was performed in patients with non-small cell lung cancer (NSCLC). The overall response rate to CDDP was 14% (6/42). In patients without prior chemotherapy, the response rate was 20% (2/10), and in patients with prior chemotherapy, the response rate was 13% (4/31). The major side effect was gastrointestinal toxicity. It was concluded that CDDP at a dose of 80 mg/m2 every 3 weeks is effective against NSCLC.     

Phase II study of carboplatin combined with weekly docetaxel in patients with advanced non-small cell lung cancer

Purpose

This phase II study is performed to evaluate the safety, efficacy and tolerability of carboplatin combined with weekly docetaxel in patients with advanced non-small cell lung cancer (NSCLC).

Patients and methods

All patients were treated with the combination of docetaxel 35 mg/m² by IV infusion over 30–60 min weekly, on days 1, 8, and 15, for 3 weeks followed by 1 week of rest, with intravenous carboplatin (AUC 6) administered immediately afterward on day 1. Cycles were repeated every 28 days.

Results

Forty-seven (95.9%) of the 49 patients were assessable for response, one case of complete response and 17 cases of partial response were confirmed, giving an overall response rate of 36.7% (95% CI 23.2–50.2%). The median time to progression and overall survival (OS) for all patients were 5.2 months (95% CI 4.1–6.3 months) and 10.4 months (95% CI 7.3–13.5 months), respectively. The estimate of OS at 12 months was 37.6% (95% CI 24.0–51.2%). The most severe hematologic adverse event was anemia, which occurred with grade 3/4 intensity in 7 (14.9%) patients. Neutropenia occurred with grade 3 intensity in 4 (8.5%) patients. However, no grade 4 neutropenia was observed. Grade 3 nausea/vomiting, diarrhea, asthenia, nail changes, and skin reaction were observed in 6 (12.8%), 3 (6.4%), 2 (4.3%), 2 (4.3%) and 1 (2.1%) patients. Yet, no grade 4 non-hematologic toxicity was observed.

Conclusions

The combination of carboplatin with weekly docetaxel is a tolerated treatment modality with encouraging activity and survival outcome in previously untreated patients with advanced NSCLC.     

Phase I/II study of weekly irinotecan and concurrent radiation therapy for locally advanced non-small cell lung cancer

A study was undertaken to determine the maximum tolerated dose, the dose-limiting toxicities, and the response rate of irinotecan administered weekly with concurrent thoracic radiation therapy in patients with locally advanced non-small-cell lung cancer. In a phase I/II clinical trial, patients with histologically documented, surgically unresectable stage IIIA or IIIB non-small cell lung cancer (NSCLC) were enrolled. Irinotecan was administered as a 90 min intravenous infusion once weekly for 6 weeks. The starting dose was 30 mg m(-2) and dose escalation was done in 15 mg m(-2) increments. Dose-limiting toxicity was defined as grade 3 nonhaematologic toxicity (excluding nausea, vomiting and alopecia) or grade 4 haematologic toxicity according to the WHO criteria. Radiation was delivered to the primary tumour and regional lymph nodes (40 Gy), followed by a boost to the primary tumour (20 Gy). Twenty-seven patients were entered into this study at three irinotecan dose levels (30, 45 and 60 mg m(-2)). Twenty-six eligible patients were evaluated for toxic effects and clinical outcome. Severe oesophagitis, pneumonitis, and diarrhoea occurred at 45 and 60 mg m(-2). Three of the five patients given 60 mg m(-2) developed grade 3 or 4 oesophagitis and pneumonitis. In addition, one patient died of pneumonitis after completing therapy at 45 mg m(-2) in the phase II study. The objective response rate was 76.9% (95% CI, 53.0-88.9%). Oesophagitis, pneumonitis, and diarrhoea are the dose-limiting toxicities of weekly irinotecan combined with thoracic irradiation. The maximum tolerated dose and the dose for the phase II study were 60 and 45 mg m(-2) wk(-1), respectively. This combined therapy for locally advanced non-small cell lung cancer is promising and shows acceptable toxicity.