Phase I/II study of a combined gemcitabine, etoposide, and cisplatin chemotherapy regimen for metastatic urothelial carcinoma

BACKGROUND: The authors attempted to determine the maximum tolerated dose (MTD) of gemcitabine in combination with etoposide and cisplatin as a chemotherapy regimen and investigated the safety and antitumor activity with the recommended doses of gemcitabine with etoposide and cisplatin for patients with metastatic urothelial carcinoma. METHODS: Patients age 75 years or younger with measurable lesions, creatinine clearance>or=50 mL per minute, and adequate bone marrow and hepatic function were studied. Etoposide and cisplatin were given on Days 1 through 3 at fixed doses of 75 mg/m2 and 25 mg/m2, respectively, and gemcitabine was given on Days 1, 8, and 15. In the Phase I component, gemcitabine was administered at increasing doses from 600 mg/m2. Cycles were repeated every 28 days unless progressive disease was encountered. RESULTS: In Phase I, with the initially fixed doses of etoposide and cisplatin, the MTD of gemcitabine could not be determined because of the occurrence of dose-limiting toxicity at Level 1 in all 3 patients. When the doses of etoposide and cisplatin were modified to 60 mg/m2 and 20 mg/m2, respectively, the MTD of gemcitabine was 1000 mg/m2. Next, 19 additional patients were entered into Phase II with the recommended gemcitabine dose of 800 mg/m2, and 20 patients in all were treated at this dose level. The main toxicity was bone marrow suppression, with Grade 3 or 4 neutropenia and thrombocytopenia recognized in 20 patients (100%) and 14 patients (70%), respectively, although no toxic deaths occurred. In total, all 31 patients at all dose levels had an assessable response, with 6 complete responses and 15 partial responses observed, for an overall response rate of 67.7%. Patients who had visceral metastasis had a significantly worse response rate than patients who had lymph node metastasis alone (50.0% vs. 78.9%; P=.042). The response rate (66.7%) for 21 patients who received prior chemotherapy was not different from that for 10 chemotherapy-naive patients. The median survival for all patients was 13.1 months, and 4 patients survived for >2 years with no evidence of disease. Patients younger than age 65 years had significantly better survival than patients age 65 years or older (P=.026). CONCLUSIONS: Although bone marrow toxicity was considerable, combination chemotherapy with gemcitabine, etoposide, and cisplatin appeared to be very active in patients with urothelial carcinoma and may be especially promising for younger patients, although further study is warranted.     

A parallel dose-escalation study of weekly and twice-weekly bortezomib in combination with gemcitabine and cisplatin in the first-line treatment of patients with advanced solid tumors.

PURPOSE: To establish maximum tolerated dose (MTD) and tolerability of two schedules of bortezomib in combination with cisplatin and gemcitabine as first-line treatment of patients with advanced solid tumors. EXPERIMENTAL DESIGN: Patients were assigned to increasing doses of bortezomib days 1 and 8 (weekly schedule) or days 1, 4, 8, and 11 (twice-weekly schedule), in addition to gemcitabine 1,000 mg/m(2) days 1 and 8 and cisplatin 70 mg/m(2) day 1, every 21 days. Maximum of six cycles. Plasma pharmacokinetics of cisplatin and gemcitabine were determined at MTD. RESULTS: Thirty-four patients were enrolled of whom 27 had non-small cell lung cancer (NSCLC). Diarrhea, neutropenia, and thrombocytopenia were dose-limiting toxicities leading to an MTD of bortezomib 1.0 mg/m(2) in the weekly schedule. Febrile neutropenia and thrombocytopenia with bleeding were dose-limiting toxicities in the twice-weekly schedule, leading to an MTD of bortezomib 1.0 mg/m(2) as well. Most common > or =grade 3 treatment-related toxicities were thrombocytopenia and neutropenia. No grade > or =3 treatment-related sensory neuropathy was reported. Of 34 evaluable patients, 13 achieved partial responses, 17 stable disease, and 4 progressive disease. Response and survival of NSCLC patients treated with twice weekly or weekly bortezomib were similar. However, increased dose intensity of bortezomib led to increased gastrointestinal toxicity as well as myelosuppression. Pharmacokinetic profiles of cisplatin and gemcitabine were not significantly different in patients receiving either schedule. CONCLUSIONS: Weekly bortezomib 1.0 mg/m(2) plus gemcitabine 1,000 mg/m(2) and cisplatin 70 mg/m(2) is the recommended phase 2 schedule, constituting a safe combination, with activity in NSCLC.     

A phase I safety, pharmacological, and biological study of the farnesyl protein transferase inhibitor, lonafarnib (SCH 663366), in combination with cisplatin and gemcitabine in patients with advanced solid tumors

PURPOSE: This phase I study was conducted to evaluate the safety, tolerability, pharmacological properties and biological activity of the combination of the lonafarnib, a farnesylproteintransferase (FTPase) inhibitor, with gemcitabine and cisplatin in patients with advanced solid malignancies. EXPERIMENTAL DESIGN: This was a single institution study to determine the maximal tolerated dose (MTD) of escalating lonafarnib (75-125 mg po BID) with gemcitabine (750-1,000 mg/m(2) on days 1, 8, 15) and fixed cisplatin (75 mg/m(2) day 1) every 28 days. Due to dose-limiting toxicities (DLTs) of neutropenia and thrombocytopenia in initial patients, these patients were considered "heavily pre-treated" and the protocol was amended to limit prior therapy and re-escalate lonafarnib in "less heavily pre-treated patients" on 28-day and 21-day schedules. Cycle 1 and 2 pharmacokinetics (PK), and farnesylation of the HDJ2 chaperone protein and FPTase activity were analyzed. RESULTS: Twenty-two patients received 53 courses of therapy. Nausea, vomiting, and fatigue were frequent in all patients. Severe toxicities were observed in 91% of patients: neutropenia (41%), nausea (36%), thrombocytopenia (32%), anemia (23%) and vomiting (23%). Nine patients withdrew from the study due to toxicity. DLTs of neutropenia, febrile neutropenia, thrombocytopenia, and fatigue limited dose-escalation on the 28-day schedule. The MTD was established as lonafarnib 75 mg BID, gemcitabine 750 mg/m(2) days 1, 8, 15, and cisplatin 75 mg/m(2) in heavily pre-treated patients. The MTD in the less heavily pre-treated patients could not be established on the 28-day schedule as DLTs were observed at the lowest dose level, and dose escalation was not completed on the 21-day schedule due to early study termination by the Sponsor. No PK interactions were observed. FTPase inhibition was not observed at the MTD, however HDJ-2 gel shift was observed in one patient at the 100 mg BID lonafarnib dose. Anti-cancer activity was observed: four patients had stable disease lasting >2 cycles, one subject had a complete response, and another had a partial response, both with metastatic breast cancer. CONCLUSION: Lonafarnib 75 mg BID, gemcitabine 750 mg/m(2) days 1, 8, 15, and cisplatin 75 mg/m(2) day 1 on a 28-day schedule was established as the MTD. Lonafarnib did not demonstrate FTPase inhibition at these doses. Despite the observed efficacy, substantial toxicity and questionable contribution of anti-tumor activity of lonafarnib to gemcitabine and cisplatin limits further exploration of this combination.     

A phase I study of paclitaxel, etoposide, and cisplatin in extensive stage small cell lung cancer.

This Phase I study was designed to determine the maximally tolerated dose (MTD) of paclitaxel with standard doses of cisplatin and etoposide for patients with untreated extensive stage small cell lung cancer (SCLC). Secondary objectives were to determine the toxicities, response rate, response duration, and overall survival in this cohort. Twenty-eight SCLC patients were enrolled into four dose levels. All patients received a fixed dose of cisplatin at 80 mg/m2, i.v., day 1. The first group received etoposide 50 mg/m2, i.v. day 1 and 100 mg/m2 p.o., days 2-3, whereas all subsequent groups received etoposide 80 mg/m2, i.v., day 1 and 160 mg/m2, p.o., days 2-3. The paclitaxel starting dose was 135 mg/m2, i.v., over a 3-h period and was escalated to 175 and 200 mg/m2. Cycles were repeated every 21 days for a maximum of six cycles. Granulocyte-colony stimulating factor was not given prophylactically but was allowed in subsequent cycles according to the American Society of Clinical Oncologists guidelines. All 28 SCLC patients were evaluable for toxicity, and 23 patients were evaluable for response. Myelosuppression was the major toxicity, with grade 4 neutropenia occurring in 23 of 28 patients (82%), but febrile neutropenia was uncommon and developed in 4 patients (14%). Grade 4 thrombocytopenia and anemia were rare, occurring as isolated events in one patient each. Dose-limiting peripheral neuropathy was observed at a paclitaxel dose of 200 mg/m2. Grade 4 nausea/vomiting and diarrhea were also noted at this dose level. Five patients had complete responses (22%), and 14 patients had partial responses (61%). The overall response rate was 83% with a median time to progression of 7.5 months, a median survival of 10 months, and a 1-year survival rate of 39%. This three-drug combination of paclitaxel with cisplatin and etoposide is active with acceptable toxicity. Neurotoxicity was dose limiting at 200 mg/m2 of paclitaxel. Neutropenia was frequent but not associated with significant morbidity. The recommended doses for future clinical trials are 175 mg/m2 paclitaxel, i.v., over a 3-h period on day 1 with 80 mg/m2 cisplatin, i.v., on day 1 and 80 mg/m2 etoposide, i.v., on day 1 and 160 mg/m2 p.o. on days 2 and 3 with growth factor support. The Southwestern Oncology Group has instituted a Phase II study with this dose schedule.     

A phase I study of topotecan/paclitaxel alternating with etoposide/cisplatin and thoracic irradiation in patients with limited small cell lung cancer.

PURPOSE: Topotecan and paclitaxel are promising cytotoxic drugs with novel mechanisms of action relative to other chemotherapies used in the treatment of small cell lung cancer (SCLC). In an effort to integrate paclitaxel and topotecan into the treatment of limited disease (LD) SCLC, we conducted a Phase I study of these agents administered as initial induction therapy. EXPERIMENTAL DESIGN: Escalating doses of topotecan (0.8-1.4 mg/m(2) d1-5) and paclitaxel (110-175 mg/m(2) d1) were administered i.v. every 21 days for two cycles to determine the maximum tolerated dose (MTD) in patients with LD SCLC. This was followed by two cycles of etoposide (120 mg/m(2) d1-3) and cisplatin (60 mg/m(2) d1) with thoracic radiotherapy. The first 5 subjects received 1.8 Gy once daily x 25 fractions, while subsequent subjects received 1.5 Gy twice daily x 30 fractions. Two additional cycles of chemotherapy (topotecan and paclitaxel, followed by etoposide and cisplatin) were given. RESULTS: Common toxicities included grade >/=3 neutropenia in 67% of courses of topotecan and paclitaxel and grade >/=2 esophagitis in 71% of patients. The MTD was based on toxicity during the first two cycles of chemotherapy and defined after accrual of 18 patients to four dose levels. Two of three patients developed grade 3 nonhematological toxicity (pneumonia) at the fourth dose level. Thus, the third dose level (topotecan 1.2 mg/m(2), paclitaxel 160 mg/m(2)) was defined as the MTD recommended for Phase II studies. One subject died suddenly on day 2 of cycle 1 without autopsy confirmation of the etiology. A second subject died during cycle 3 due to thrombocytopenia, gastrointestinal bleeding, and respiratory failure. Response rates after induction of topotecan and paclitaxel: 16 of 18 (88.8%) partial response, 1 of 18 (5.5%) complete response. Response rates after completion of therapy: 10 of 18 (55.5%) partial response, 7 of 18 (38.8%) complete response. CONCLUSIONS: Induction topotecan and paclitaxel before chemoradiotherapy in patients with LD SCLC is feasible and results in expected toxicities. The outcome of a recently closed Cancer and Leukemia Group B Phase II study of similar design (CLB-39808) should help determine whether or not this approach warrants testing in a randomized setting.     

A phase I study of gemcitabine/cisplatin/etoposide in the treatment of small-cell lung cancer

PURPOSE: To define the maximum tolerated dose and toxicity of combined cisplatin, etoposide, and gemcitabine in patients with small-cell lung cancer. METHODS: We undertook a phase I study in patients with either extensive small-cell lung cancer with or without prior chemotherapy, or limited disease who had progressed or recurred despite prior treatment. Patients received cisplatin 75 mg/m2 i.v. day 1, etoposide 50-100 mg/m2 i.v. day 1 followed by oral administration of 50-100 mg/m2 days 2 5, and gemcitabine at either 800 or 1000 mg/m2 i.v. days 1 and 8, on a 3 weekly cycle. RESULTS: We treated 20 patients, 14 at the 800 mg/m2 gemcitabine dose level, and six at the 1000 mg/m2 dose level. The protocol initially used an etoposide dose of 100 mg/m2 etoposide daily (i.v. day 1 and orally days 2-5), but the first two patients died of septic complications. With reduction of the etoposide dose to 50 mg/m2 daily x 5, the regimen was well tolerated. At this etoposide dose, neutropenia, mucositis, and gastrointestinal toxicity occurred in one patient at each of the two gemcitabine dose levels. In addition, one patient receiving gemcitabine at the 1000 mg/m2 level experienced a possible allergic reaction. The overall response rate was 54%. Patients on gemcitabine at the 800 mg/m2 level who had not received prior chemotherapy had the highest response rate, at 75%. CONCLUSION: The recommended phase II doses for this regimen are cisplatin 75 mg/m2 i.v. day 1, etoposide 50 mg/m2 i.v. day 1 and orally days 2-5, and gemcitabine 800 mg/m2 i.v. days 1 and 8. Future trials should further examine the optimal relative doses and schedule of gemcitabine and etoposide.     

Phase I/II study of 3-week cycle cisplatin-gemcitabine in advanced non-small cell lung cancer

BACKGROUND: The combination of cisplatin and gemcitabine is one of the most active chemotherapy regimens against non-small cell lung cancer. However, the optimum schedule for this combination has not been determined. This study was performed to determine the maximum tolerated dose of gemcitabine combined with cisplatin in a 3-week cycle regimen and to observe safety and efficacy for Japanese patients with advanced non-small cell lung cancer. METHODS: 80 mg/m(2) of cisplatin on day 1 and escalated doses of gemcitabine on days 1 and 8 were administered every 3 weeks to patients with previously untreated, advanced non-small cell lung cancer. The initial dose of gemcitabine was 1000 mg/m(2) and was escalated in 250 mg/m(2) increments. RESULTS: Twenty-four patients were enrolled between March and December 2000. In total, 64 courses were given. The main toxicities were neutropenia, thrombocytopenia and hepatotoxicity. The maximum tolerated dose was determined to be 1500 mg/m(2) of gemcitabine combined with 80 mg/m(2 )of cisplatin. Nine of 24 patients (37.5%) achieved a partial response. CONCLUSION: This study demonstrates that the combination of cisplatin and gemcitabine repeated every three weeks is tolerable for Japanese patients with advanced non-small cell lung cancer. We determined 1250 mg/m(2) of gemcitabine combined with 80 mg/m(2 )of cisplatin to be the recommended dose.     

Phase I study of the combination of gemcitabine and nedaplatin for treatment of previously untreated advanced non-small cell lung cancer

This trial was conducted to determine the maximum-tolerated dose (MTD), principal toxicity, and recommend dose for phase II study of the combination of gemcitabine and nedaplatin in patients with advanced non-small cell lung cancer (NSCLC). Patients with previously untreated NSCLC were eligible if they had a performance status of 0-2, were 75 years or younger, and had adequate organ function. The doses of gemcitabine (days 1, 8) and nedaplatin (day 1) studied were 800/60, 800/70, 800/80, 1000/80, and 1000/100 (mg/m(2)), repeated every 3 weeks. Toxicity could be assessed in all 21 patients enrolled, response could be assessed in 20 patients. The patients were 12 men and 9 women with a mean age of 69 years (range, 47-75 years). Four patients had stage IIIB disease and 17 patients had stage IV disease. The most common histologic type was adenocarcinoma. The MTD was not reached even at the highest doses. The most frequent toxic effects were thrombocytopenia and neutropenia: grade 3 or 4 thrombocytopenia was observed in 19% of patients, and grade 3 or 4 neutropenia in 24% of patients. Nonhematologic toxicities were mild. Grade 3 hepatic dysfunction occurred in 3 patients. Relatively few patients required dose modifications. The median dose-intensities were 91.5 and 93.1%, respectively, of the planned doses of gemcitabine and nedaplatin. The overall response rate was 35% (95% confidence interval, 15.4-59.2%). All responses were seen above level 3. The MTD was not reached even at the highest combination doses. We recommend doses of 1000 mg/m(2) of gemcitabine and 100 mg/m(2) of nedaplatin for phase II study. This combination chemotherapy is active and well tolerated and warrants phase II study.     

局限期小细胞肺癌加速超分割放疗同步EP方案化疗的剂量递增I期研究

背景与目的加速超分割放疗（每日两次方案）联合EP方案同步化疗是美国国立综合癌症网络（Na-tional Comprehensive Cancer Network, NCCN）指南推荐的局限期小细胞肺癌的标准治疗方式,但国人对EP方案标准化疗剂量耐受性尚不明确。本研究旨在探讨局限期小细胞肺癌同步放化疗EP方案的最大耐受剂量。方法研究纳入病理证实的局限期小细胞肺癌患者,进行加速超分割放疗同步EP方案（依托泊苷+顺铂）化疗,放疗处方剂量为45 Gy/30 f,1.5 Gy/f,每日两次,同一日两次放疗间隔时间≥6 h,5天/周,共3周完成。化疗方案采用依托泊苷联合顺铂,每21天为1周期,具体依托泊苷100 mg/m2,d1-d3,顺铂采用剂量递增的方式（第1组为70 mg/m2 d1,第2组为75 mg/m2 d1）。主要观察指标为治疗期间的血液学毒性。次要观察指标为非血液学毒性和1年总生存期（overall sur-vival, OS）、无进展生存期（progression free survival, PFS）。根据不良事件常用术语评定标准（Common Terminology Criteria for Adverse Events, NCI-CTCAE）4.0,最大耐受剂量设定为6例患者中不超过1例患者出现剂量限制毒性（4级血液学毒性）的剂量,同时下一剂量组6例患者至少2例出现剂量限制性毒性。结果研究共纳入20例局限期小细胞肺癌患者,平均年龄49.50（30-68）岁。第1组入组6例患者,1例患者出现4度中性粒细胞减少;后第2组入组14例患者,1例患者出现4度中性粒细胞减少。其中,第1组有4例患者出现≥3度血液学毒性,1例患者出现3度以上放射性食管炎;第2组有10例患者出现≥3度血液学毒性,无患者出现3度以上放射性食管炎。中位随访9.0个月（3.2个月-36.2个月）,1年OS、PFS分别为91%、62%。结论局限期小细胞肺癌患者采用加速超分割放疗联合EP方案化疗将顺铂剂量递增至75 mg/m2是安全的,其有效性还需要进一步扩大样本量和随访更长的时间来证实。     

Phase I and pharmacological study of the farnesyltransferase inhibitor tipifarnib (Zarnestra, R115777) in combination with gemcitabine and cisplatin in patients with advanced solid tumours

This phase I trial was designed to determine the safety and maximum tolerated dose (MTD) of tipifarnib in combination with gemcitabine and cisplatin in patients with advanced solid tumours. Furthermore, the pharmacokinetics of each of these agents was evaluated. Patients were treated with tipifarnib b.i.d. on days 1-7 of each 21-day cycle. In addition, gemcitabine was given as a 30-min i.v. infusion on days 1 and 8 and cisplatin as a 3-h i.v. infusion on day 1. An interpatient dose-escalation scheme was used. Pharmacokinetics was determined in plasma and white blood cells. In total, 31 patients were included at five dose levels. Dose-limiting toxicities (DLTs) consisted of thrombocytopenia grade 4, neutropenia grade 4, febrile neutropenia grade 4, electrolyte imbalance grade 3, fatigue grade 3 and decreased hearing grade 2. The MTD was tipifarnib 200 mg b.i.d., gemcitabine 1000 mg m(-2) and cisplatin 75 mg m(-2). Eight patients had a confirmed partial response and 12 patients stable disease. No clinically relevant pharmacokinetic interactions were observed. Tipifarnib can be administered safely at 200 mg b.i.d. in combination with gemcitabine 1000 mg m(-2) and cisplatin 75 mg m(-2). This combination showed evidence of antitumour activity and warrants further evaluation in a phase II setting.     

Dose-intense PEFG (cisplatin, epirubicin, 5-fluorouracil, gemcitabine) in advanced pancreatic adenocarcinoma: a dose-finding study

The aim of this study was to assess the maximum tolerated dose (MTD) of an intensified PEFG regimen administered every 14 days to patients with Stage III or metastatic pancreatic adenocarcinoma. Twenty-nine patients received fixed doses of both epirubicin (30 mg/m2) and 5-fluorouracil (200 mg/m2/day on Days 1-14) and of escalating doses of cisplatin and gemcitabine. The MTD was cisplatin 30 mg/m2 and gemcitabine 800 mg/m2. With respect to classical PEFG, intensified regimen potentially improved the dose-intensity of both cisplatin and epirubicin by 50 percent and of gemcitabine by 33 percent, reduced Grade 3-4 haematological toxicity and the number of outpatient accesses.     

A multicenter, randomized, Phase II study of cisplatin, etoposide, and gemcitabine or cisplatin plus gemcitabine as first-line treatment in patients with poor-prognosis small cell lung carcinoma

BACKGROUND: The objective of this study was to evaluate the activity and toxicity of combined cisplatin, etoposide, and gemcitabine (PEG) and combined cisplatin plus gemcitabine (PG) in previously untreated patients with extensive-stage and poor-prognosis limited-stage small-cell lung carcinoma. METHODS: One hundred forty patients (70 patients in two arms) were randomized to receive either cisplatin 70 mg/m2 on Day 1, etoposide 50 mg/m2 on Days 1-3, and gemcitabine 1000 mg/m2 on Days 1 and 8 or cisplatin 70 mg/m2 on Day 1 plus gemcitabine 1250 mg/m2 on Days 1 and 8. Both regimens were recycled every 21 days. RESULTS: In total, 626 cycles were delivered (303 cycles of PEG and 323 cycles of PG), with a median of 4 cycles per patient in both arms. The objective response rate was 63% (95% confidence interval [95%CI], 49-71%) for PEG and 57% (95%CI, 43-67%) for PG, with the suggestion of a higher complete response rate in the PEG arm (18.6% and 4.3%, respectively). A similar time to disease progression (6 months in the PEG arm and 7 months in the PG arm) and a similar median survival (9.5 months in the PEG arm and 10 months in the PG arm) were observed in both arms. The PEG regimen was associated with more severe hematologic toxicity in terms of neutropenia, febrile neutropenia, and a higher rate of treatment delays and dose reductions, whereas nonhematologic toxicities did not differ between the two arms. CONCLUSIONS: According to the results of this Phase II randomized trial, the PEG regimen produced a higher complete response rate but more toxicity compared with the PG regimen in patients with extensive-stage or poor-prognosis, limited-stage small cell lung carcinoma.     

A phase I and pharmacologic study of belotecan in combination with cisplatin in patients with previously untreated extensive-stage disease small cell lung cancer.

PURPOSE: Belotecan (Camtobell, CKD602) is a novel camptothecin derivative. This study was designed to determine the maximum tolerated dose (MTD), toxicity profile, and dose-limiting toxicity of belotecan in combination with cisplatin in patients with previously untreated extensive-stage disease small cell lung cancer (SCLC). Furthermore, pharmacokinetics and preliminary antitumor activity against SCLC were evaluated. EXPERIMENTAL DESIGN: Belotecan was administered i.v. as intermittent 30-min infusions on days 1 to 4, starting dose of 0.40 mg/m2/d with increment of 0.05 mg/m2/d. Intrapatient dose escalation was not allowed. Cisplatin (60 mg/m2) was given on day 1. The treatments were repeated every 3 weeks. Pharmacokinetics was determined during the first cycle using noncompartmental pharmacokinetic analysis. RESULTS: Seventeen chemotherapy-naive patients with extensive-stage disease SCLC were treated. The MTD of belotecan was 0.50 mg/m2/d with the dose-limiting toxicity of grade 4 neutropenia with fever. A partial response was seen in 13 of 17 patients (76.5%). The most common toxicity was neutropenia but nonhematologic toxicity was very favorable. Pharmacokinetic analysis revealed that, at the dose of 0.50 mg/m2/d, plasma clearance of belotecan was 5.78 +/- 1.32 L/h and terminal half-life was 8.55 +/- 2.12 h. Fraction of excreted amount in urine was 37.36 +/- 5.55%. Pharmacokinetics of belotecan was not altered by administration of cisplatin compared with historical control. CONCLUSIONS: The MTD and recommended dose of belotecan for phase II studies was 0.50 mg/m2/d on days 1 to 4 in combination with 60 mg/m2 cisplatin on day 1 every 3 weeks.     

A dose-escalation and pharmacokinetic study of gemcitabine and oxaliplatin in patients with advanced solid tumors.

BACKGROUND: Gemcitabine and oxaliplatin have broad antineoplastic activity and favorable toxicity. We conducted a phase I study to determine the maximum tolerated doses (MTDs) and dose-limiting toxicities (DLTs) of the combination in patients with advanced solid tumors. PATIENTS AND METHODS: Sixty-eight patients with advanced stage solid tumors were enrolled. Treatment was first-line for 35% of patients, second-line for 27%, and third-line for 38%. Gemcitabine was administered at escalating doses of 1000-2000 mg/m(2) as a 30-min intravenous (i.v.) infusion on days 1 and 8 and oxaliplatin at 60-130 mg/m(2) as a 4-h i.v. infusion on day 8 every 21 days without growth factor support. RESULTS: The MTD was defined at gemcitabine 1800 mg/m(2) on days 1 and 8 and oxaliplatin 130 mg/m(2) on day 8. Twelve dose levels were evaluated and DLTs occurring during the first cycle consisted of grade 4 neutropenia, grade 3 asthenia or mucositis and grade 1-3 neutropenia or thrombocytopenia resulting in treatment delays. A total of 266 cycles were administered with only one episode of febrile neutropenia and no toxic deaths. Seven (3%) and 26 (10%) cycles were complicated by grade 4 and 3 neutropenia, respectively, three (1%) and 13 (5%) by grade 4 and 3 thrombocytopenia, and eight (3%) by grade 3 anemia. The most common non-hematological toxicity was grade 2/3 asthenia observed in 23% of cycles. Responses were observed in patients with a variety of epithelial neoplasms. The pharmacokinetic study revealed no significant interaction between the two drugs. CONCLUSIONS: The combination of gemcitabine and oxaliplatin has excellent tolerability and promising activity in patients with advanced solid tumors. As the MTD exceeds the recommended single-agent dose for gemcitabine, and a dose-response effect has not been established, we recommend using both drugs at full doses, e.g. gemcitabine 1200-1400 mg/m(2) on days 1 and 8 and oxaliplatin 130 mg/m(2) on day 8 for further phase II studies.     

A phase I study of gemcitabine and irinotecan as second line treatment for advanced non-small cell lung cancer

A phase I study was conducted to determine the maximum tolerated dose (MTD) and the dose limiting toxicity (DLT) of gemcitabine and irinotecan combination therapy as second line treatment in patients with advanced non-small cell lung cancer (NSCLC). Twelve patients with measurable NSCLC (age range 46-74 years; 7 males, 5 females; performance status 0 = 4, 1 = 8) who progressed or failed first-line chemotherapy were enrolled. Prior chemotherapy was platinum-based without gemcitabine or irinotecan. Gemcitabine was administered at a fixed dose of 1,000 mg/m2 after irinotecan administration, and irinotecan was administered at doses from 50 to 125 mg/m2 with an increment of 25 mg/m2, both on day 1 and 8. Chemotherapy was repeated every 3 weeks. Grade 3/4 leukopenia occurred in three patients (25%), neutropenia in four (33%), anemia in one (8%), and thrombocytopenia in one (8%). Grade 3 nausea and vomiting was observed in three (25%), grade 2 diarrhea in one (8%), and liver dysfunction in one (8%). Other toxicities were mild. Two of the three patients at level 4 (irinotecan 125 mg/m2) experienced dose limiting toxicity: one patient experienced grade 4 leukopenia and neutropenia, and the other experienced treatment delay of more than 2 weeks. The objective response rate was 16.6% (2/12). The maximum tolerated dose in this combination therapy was gemcitabine 1,000 mg/m2 and irinotecan 125 mg/m2. The dose level of gemcitabine 1,000 mg/m2 and irinotecan 100 mg/m2 on day 1 and 8 of a 3-week cycle is recommended for a phase II study.     

Therapeutic effects and pharmacokinetics of recombinant human granulocyte-macrophage colony-stimulating factor in childhood cancer patients receiving myelosuppressive chemotherapy

Twenty-five children with refractory solid tumors were given recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) in escalated doses of 60 to 1,500 micrograms/m2 as 2-hour intravenous infusions, beginning 24 hours after myelosuppressive treatment with cisplatin and etoposide. Tolerance to rhGM-CSF was exceptional even at dose levels that exceeded the maximum-tolerated dosage (MTD) reported for adults. The agent produced dose-related increases in platelet and neutrophil counts, resulting in significantly shorter durations of severe neutropenia and thrombocytopenia (P less than .01 for each analysis). At the higher dosages (greater than or equal to 750 micrograms/m2), treatment with rhGM-CSF reduced the median number of days of antibiotic therapy for fever and neutropenia by approximately one half. We conclude that rhGM-CSF is well tolerated by leukopenic children in doses as high as 1,500 micrograms/m2. An MTD was not reached in this study. The ability of the growth factor to reduce severe neutropenia and thrombocytopenia suggests it will have an important role in the management of childhood solid tumors.     

Combination phase I study of nedaplatin and gemcitabine for advanced non-small-cell lung cancer

To establish the toxicities and maximum tolerated dose (MTD) of nedaplatin with gemcitabine, and to observe their antitumour activity, we conducted a combination phase I study in advanced non-small-cell lung cancer (NSCLC). Patients received nedaplatin (60-100 mg m(-2) given intravenously over 90 min) on day 1, and gemcitabine (800-1000 mg m(-2) given intravenously over 30 min) on days 1, 8, every 3 weeks. In total, 20 patients with locally advanced or metastatic NSCLC who received no prior chemotherapy or one previous chemotherapy regimen were enrolled. The most frequent toxicities were neutropenia and thrombocytopenia; nonhaematological toxicities were generally mild. Three out of six patients experienced dose-limiting toxicities (neutropenia, thrombocytopenia and delayed anaemia) at dose level 4, 100 mg m(-2) nedaplatin with 1000 mg m(-2) gemcitabine, which was regarded as the MTD. There were three partial responses, for an overall response rate of 16.7%. The median survival time and 1-year survival rate were 9.1 months and 34.1%, respectively. This combination is well tolerated and active for advanced NSCLC. The recommended dose is 80 mg m(-2) nedaplatin with 1000 mg m(-2) gemcitabine. This combination chemotherapy warrants a phase II study and further evaluation in prospective randomised trials with cisplatin- or carboplatin-based combinations as first-line chemotherapy for advanced NSCLC.     

Phase I trial of gemcitabine,administered as a standard and constant dose-rate infusion,in combination with paclitaxel in patients with advanced solid tumors (LOA-2)

The major purposes of this study were to determine the maximally tolerated dose (MTD), dose-limiting toxicity (DLT), toxicity profile, and antitumor activity of gemcitabine and paclitaxel combination therapy when administered to patients with advanced solid tumors, using two infusion schedules of each agent. Paclitaxel was administered on day 1, followed by gemcitabine, and gemcitabine alone was administered on day 8, of each 21-day treatment course. In the initial phase of the trial, paclitaxel was administered during 3 hours and gemcitabine during 30 minutes (schedule A). After the MTD was determined on this schedule, patients were then treated with paclitaxel during 1 hour and gemcitabine at a fixed dose-rate of 10 mg/m(2)/min (schedule B). Forty-six patients were treated with 176 courses at 7 dose levels. The MTD for schedule A was 1,300 mg/m(2) and 200 mg/m(2) and for schedule B was 1,000 mg/m(2) and 200 mg/m(2) for gemcitabine and paclitaxel, respectively. The DLT for schedule A was neutropenia and for schedule B was neutropenia and thrombocytopenia. Nonhematologic toxicity was relatively mild. Gemcitabine and paclitaxel, using both schedules of administration in the current trial, is a promising chemotherapeutic regimen.     

Phase I clinical trial of bortezomib in combination with gemcitabine in patients with advanced solid tumors

BACKGROUND: Bortezomib is the first proteasome inhibitor to show preliminary evidence of activity against solid tumors. Findings from preclinical studies prompted a Phase I trial to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of bortezomib in combination with gemcitabine in patients with recurring/refractory advanced solid tumors. The effect of gemcitabine on proteasome inhibition by bortezomib in whole blood was also investigated. METHODS: Bortezomib was administered as an intravenous bolus injection on Days 1, 4, 8, and 11, with gemcitabine (30-minute infusion) on Days 1 and 8 of a 21-day cycle. Groups of > or =3 patients were evaluated at each dose level. Escalating doses of gemcitabine 500 mg/m(2) to 1000 mg/m(2) with bortezomib 1.0 mg/m(2) to 1.5 mg/m(2) were planned. RESULTS: There were no DLTs in patients receiving bortezomib 1.0 mg/m(2) and gemcitabine 500 mg/m(2) to 1000 mg/m(2) in the first 3 dose levels. Dose-limiting nausea, vomiting, gastrointestinal obstruction, and thrombocytopenia occurred in 4 of 5 evaluable patients in dose level 4 (bortezomib 1.3 mg/m(2), gemcitabine 800 mg/m(2)), establishing bortezomib 1.0 mg/m(2) and gemcitabine 1000 mg/m(2) as the MTD. Most common Grade > or =3 toxicities were neutropenia (6 patients), thrombocytopenia (5 patients), gastrointestinal disorders (6 patients), and general disorders (4 patients) such as fatigue. One patient with nonsmall cell lung carcinoma achieved a partial response and 7 achieved stable disease. Inhibition of 20S proteasome activity by bortezomib was unaffected by gemcitabine coadministration. CONCLUSION: Dosages of bortezomib and gemcitabine suitable for further evaluation of antitumor activity have been established.     

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.