Phase I trial of weekly docetaxel and gemcitabine in patients with refractory malignancies

BACKGROUND: A Phase I study using weekly docetaxel and gemcitabine was conducted to investigate toxicity; to determine the maximum tolerated dose (MTD) of each agent; and, in a preliminary fashion, to determine the antitumor activity of the combination. METHODS: Docetaxel and gemcitabine were administered intravenously on Days 1, 8, and 15 every 28 days. The dose levels of docetaxel and gemcitabine were as follows: Level I, docetaxel 20 mg/m(2)and gemcitabine 400 mg/m(2); Level II, docetaxel 30 mg/m(2)and gemcitabine 400 mg/m(2); Level III, docetaxel 30 mg/m(2)and gemcitabine 600 mg/m(2); Level IV, docetaxel 36 mg/m(2)and gemcitabine 600 mg/m(2); and Level V, docetaxel 36 mg/m(2)and gemcitabine 800 mg/m(2). RESULTS: Thirty-three eligible patients were entered. The diagnoses were as follows: Eleven patients had nonsmall cell lung carcinoma, 3 patients had carcinoma of the bladder, 3 patients had renal carcinoma, 2 patients had adrenal carcinoma, 5 patients had unknown primary tumors, and 9 patients had miscellaneous malignancies. Fifty-nine percent of patients had received prior chemotherapy. The median age was 62 years (range, 27-77 years), and the median Eastern Cooperative Oncology Group performance status was 1 (range, 0-1). Five patients were treated at Dose Levels I and II, 6 patients were treated at Dose Levels III and V, and 11 patients were treated at Dose Level IV. Grade 3-4 toxicities during Cycle I included neutropenia, thrombocytopenia, mucositis, and diarrhea. Dose-limiting toxicity, consisting of neutropenia and thrombocytopenia, occurred in three of six patients at Dose Level V. The combination of docetaxel 36 mg/m(2) and gemcitabine 600 mg/m(2) (Dose Level IV) was determined as the MTD and was the recommended Phase II dose. Two patients had a partial response: one patient with bladder carcinoma (Dose Level II) and one patient with nonsmall cell lung carcinoma (Dose Level III). CONCLUSIONS: Overall, weekly docetaxel and gemcitabine were well tolerated. Further studies using this combination are planned, including a Phase II trial in patients with advanced nonsmall cell lung carcinoma.     

Combination second-line chemotherapy with gemcitabine and docetaxel for recurrent non-small-cell lung cancer after platinum-containing chemotherapy: a phase I/II trial

PURPOSE: In a randomized trial, docetaxel monotherapy yielded longer survival than the best supportive care in patients with non-small-cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy, and combination chemotherapy regimens containing docetaxel have been assessed to enhance the efficacy of second-line chemotherapy. We conducted a phase I/II trial of gemcitabine and docetaxel in patients with recurrent NSCLC after platinum-based chemotherapy and with an ECOG performance status (PS) of 0 or 1. PATIENTS AND METHODS: Docetaxel administration was fixed at a dosage of 60 mg/m(2) on day 8, and gemcitabine was administered on days 1 and 8. The starting dose level of gemcitabine was 800 mg/m(2) (level 0), and the subsequent dose level of gemcitabine was 1000 mg/m(2) (level +1). Treatment was repeated every 3 weeks. RESULTS: In the phase I study, 13 patients were enrolled, and in the phase II study, 29 patients were enrolled. Neutropenic fever and omission of treatment on day 8 due to leukopenia (leukocyte count less than 3000/mm(3)) were dose-limiting toxicities (DLTs). Three of six patients experienced DLTs at level +1, which was the maximum tolerated dose. Gemcitabine 800 mg/m(2) on days 1 and 8 plus docetaxel 60 mg/m(2) on day 8 (level 0) was recommended for the phase II study. An objective response was observed in 8 (28%) of the 29 patients. The median time to disease progression was 4.2 months (95% CI 0.9-7.7 months). The median survival time was 11.1 months (95% CI 9.9-12.4 months), and the 1-year survival rate was 41%. The most common toxicity, though mild, was hematologic, and consisted of grade 4 neutropenia (18%), grade 3 febrile neutropenia (11%), and grade 3 thrombocytopenia (11%). There were no toxic deaths. Grade 3 non-hematologic toxicities included nausea (4%) and rash (4%). CONCLUSIONS: The combination chemotherapy of gemcitabine and docetaxel is active and well tolerated in patients with recurrent NSCLC after platinum-based chemotherapy and with a good PS.     

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.     

Phase I study to evaluate multiple regimens of intravenous 5-fluorouracil administered in combination with weekly gemcitabine in patients with advanced solid tumors: a potential broadly active regimen for advanced solid tumor malignancies.

BACKGROUND: The purpose of this study was to determine the maximum tolerated dose and toxicity profile of gemcitabine given on a weekly schedule with continuous infusion 5-fluorouracil. PATIENTS AND METHODS: Eligible patients with advanced solid tumors received escalating doses of gemcitabine 200 and 300 mg/m(2) weekly as a 30-minute infusion on Days 1, 8, and 15 every 4 weeks (schedule 1) or 450, 600, 800, 1000, 1250, 1500, 1800, and 2200 mg/m(2) on Days 1 and 8 (schedule 2) every 3 weeks, respectively. At the completion of gemcitabine infusion (Day 1), patients received fixed dose continuous infusion of 5-fluorouracil at either 300 mg/m(2) (Days 1-21) or 200 mg/m(2) (Days 1-21; schedule 1) every 4 weeks or 200 mg/m(2) (Days 1-14; schedule 2] every 3 weeks, respectively. Toxicity assessments were performed weekly on study, and efficacy measurements were performed every 6-8 weeks. RESULTS: Seventy patients with advanced solid malignancies received a total of 220 cycles of combination chemotherapy. Eleven (14.3%) patients received no more than 1 treatment cycle of combination therapy. Schedule 1 maximum tolerated dose of gemcitabine was 600 mg/m(2)/week when combined with 5-fluorouracil (5-FU) at 200 mg/m(2)/day (Days 1-21) repeated every 4 weeks. The schedule 2 maximum tolerated dose of gemcitabine was 2200 mg/m(2)/week when combined with 5-FU dosed at 200 mg/m(2)/day (Days 1-14) repeated every 3 weeks. In schedule 1, the limiting factor for gemcitabine delivery was the Day 15 dose that often was omitted because of myelosuppression and/or mucositis. In schedule 1 cycle 1, nonhematologic toxicity was common and included Grade 3-4 toxicities: mucositis (8 patients), fatigue (2 patients), and anorexia (1 patient). One patient had Grade 3-4 neutropenia at dose level 5 (maximum tolerated dose). In schedule 2 cycle 1, hematologic toxicities were more common than nonhematologic toxicity and included Grade 3 anemia (3 patients), Grade 3 neutropenia (4 patients), and Grade 3 thrombocytopenia (2 patients). The nonhematologic toxicities included Grade 3 mucositis (3 patients), Grade 3 fatigue (2 patients), and Grade 3 dehydration (1 patient). Overall, antitumor activity was observed in seven patients. Three of 30 patients with cytokine refractory renal cell carcinoma (RCC; relative risk [RR] 10 %; 95% confidence interval [CI], 0.82-22%) had a partial response. Of the remaining 27 patients with RCC, 4 patients had a minor response, and 10 patients had stable disease lasting a median of 6.4 (range, 4-12) months. The remaining 5 responses occurred in 40 patients (RR, 12.5%; 95% CI, 4.2-26.8%): 2 patients with 5-FU refractory colon carcinoma, 1 patient with hepatoma, 1 patient with paclitaxel-cisplatin-resistant ovarian carcinoma, and 1 patient with cisplatin-resistant head and neck squamous cell carcinoma had a partial response. CONCLUSIONS: For Phase II development, gemcitabine 450-600 mg/m(2) on Days 1, 8, and 15 can be safely combined with 5-FU 200 mg/m(2) given as a continuous infusion (Days 1-21) of a 28-day cycle or gemcitabine 1800 mg/m(2) Days 1 and 8 given with 5-FU 200 mg/m(2) as a continuous infusion (Days 1-14) of a 21-day cycle. The observed antitumor activity in several solid tumors, especially in renal cell carcinoma, warrants broad Phase II evaluation.     

Weekly administration of gemcitabine plus docetaxel in patients with advanced breast cancer: a phase 1 study.

OBJECTIVE: This study was designed to determine the maximum tolerable dose (MTD) of gemcitabine plus docetaxel, both given on a weekly schedule, in patients with pretreated metastatic breast cancer (MBC). METHODS: Heavily pretreated patients with MBC, aged 18-75 years with World Health Organization performance status of 0-2 were enrolled. Three escalating weekly doses of docetaxel (30, 35 and 40 mg/m(2)) followed by a weekly fixed dose of gemcitabine, 800 mg/m(2), were administered on days 1, 8 and 15 of a 28-day cycle. Dose-limiting toxicity (DLT) included grade > 3 hematologic toxicity and grade > 2 stomatitis, asthenia, diarrhea or organ-specific toxicity (except alopecia). Dose escalation was stopped if > or = 3 of 5 patients at any dose level experienced DLT. RESULTS: Eighteen patients (median age 56 years) received a mean of 4.1 (range 1-6) cycles. Asthenia, stomatitis and leukopenia were the main DLTs. One of 5 patients had DLT at dose level 1 and 2 of 5 patients at dose level 2. At dose level 3, 3 of 5 patients had DLTs. Three additional patients treated at dose level 3 confirmed that the MTD had been reached. Therefore, the recommended docetaxel dose in combination with gemcitabine 800 mg/m(2) for phase II studies was established at the next lower dose, 35 mg/m(2). Of 12 evaluable patients, 7 (58%) achieved an objective response. CONCLUSIONS: Gemcitabine 800 mg/m(2) plus docetaxel 35 mg/m(2) on days 1, 8 and 15 of a 28-day cycle is a safe regimen which shows activity in heavily pretreated patients with MBC. Further phase II investigations with this combination are now warranted.     

Phase I and pharmacokinetic study of two sequences of gemcitabine and docetaxel administered weekly to patients with advanced cancer

PURPOSE: To determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and effect of drug sequence on toxicities and pharmacokinetics of the combination of gemcitabine and docetaxel. METHODS: A total of 34 patients with advanced cancers were treated with gemcitabine and docetaxel on days 1 and 8 of each 21-day cycle according to the following dose escalation schedule: level 1, 800 and 30 mg/m2, respectively; level 2, 800 and 40 mg/m2; level 3, 1,000 and 40 mg/m2; and level 4, 1,250 and 40 mg/m2. At each dose level, at least three patients were assigned to one of the two sequences of drug administration: gemcitabine-->docetaxel or docetaxel-->gemcitabine. Once the MTD had been reached, six additional patients, who had received no more than one chemotherapy regimen, were enrolled to dose levels 3 and 4 (gemcitabine-->docetaxel) to determine the MTD in minimally pretreated patients. RESULTS: Neutropenia was the most frequent DLT with an overall incidence of 23.5%. Grade 3/4 neutropenia occurred in 62% of patients (8/13) who had received two or more prior chemotherapy regimens, but not at all (0/15) in patients who had received no more than one prior chemotherapy regimens (P< 0.001). Additional DLTs included grade 4 diarrhea and grade 4 stomatitis in one patient each. The MTD was determined to be gemcitabine 800 mg/m2 and docetaxel 40 mg/m2 in patients who had received two or more prior chemotherapy regimens. However, minimally pretreated patients (no more than one prior chemotherapy regimen) were able to tolerate higher doses with an MTD of gemcitabine 1,250 mg/m2 and docetaxel 40 mg/m2. There were no significant differences in toxicities or pharmacokinetics between the two sequences of administration. Partial and minor responses were observed in 23.5% of patients: non-small-cell lung (two of eight), gastric (two of three), head and neck (one of two), bladder (two of four) and hepatocellular cancer (one of one). CONCLUSIONS: The combination of gemcitabine and docetaxel administered on days 1 and 8 every 21 days was feasible and well tolerated in patients with advanced malignancies. The sequence of administration had no significant effect on the toxicity or pharmacokinetics of either drug. Minimally pretreated patients tolerated higher doses of this combination without significant toxicities. This schedule and combination demonstrated activity in a variety of solid tumors, and merits further evaluation.     

A phase I trial of gemcitabine in combination with patupilone in patients with advanced solid tumors

INTRODUCTION: Chemotherapy regimens including gemcitabine in combination with microtubule inhibitors such as docetaxel and paclitaxel have wide clinical application. Patupilone is a novel tubulin-polymerizing agent with activity against paclitaxel-resistant cell lines. We conducted a phase I trial to assess the maximum tolerated dose, dose limiting toxicity (DLT) and antitumor activity of gemcitabine and patupilone. METHODS: Patients with refractory solid tumors enrolled in cohorts of three. Cohorts received fixed doses of gemcitabine (1,000 or 750 mg/m(2)) along with escalating doses of patupilone (1.5-3 mg/m(2)) on days 1 and 8 of a 21-day cycle. RESULTS: Twenty-seven patients received a total of 99 courses of treatment on study. Hematologic toxicity in the first cohort required a modification of the protocol to decrease the gemcitabine dose. Subsequent patients received gemcitabine 750 mg/m(2) and escalating doses of patupilone from 1.5 to 3 mg/m(2). DLTs were grade 3 asthenia and grade 3 dehydration. There was also one treatment-related death due to neutropenic infection. Other clinically significant toxicities were persistent asthenia and persistent nausea. Four patients, one each with pancreatic cancer, esophageal carcinoma, cholangiocarcinoma and gallbladder carcinoma, experienced a partial response. CONCLUSIONS: The dose-limiting toxicities of gemcitabine and patupilone were asthenia and dehydration. Dose reductions also occurred due to persistent fatigue that was not dose-limiting. However, patients with advanced malignancies were able to tolerate gemcitabine and patupilone at doses that resulted in clinical benefit. The recommended phase II dose for this schedule is gemcitabine 750 mg/m(2) and patupilone 1.5 mg/m(2) on days 1 and 8 of a 21-day cycle.     

Phase I trial of strictly time-scheduled gemcitabine and cisplatin with concurrent radiotherapy in patients with locally advanced pancreatic cancer

PURPOSE: Maximal therapeutic gain in xenograft sarcoma and toxicity for jejunal mucosa is time dependent for concurrent gemcitabine and radiotherapy (RT). We used a time-dependent schedule to determine the maximal-tolerated dose and dose-limiting toxicities (DLTs; Grade 4 hematologic or Grade 3 other toxicity). METHODS AND MATERIALS: Patients with pancreatic cancer (n = 33), periampullary carcinoma (n = 1), or bile duct cancer (n = 2) were treated with 3-day conformal RT with 50.4 Gy (tumor, lymphatics) plus a 5.4-Gy boost. Concurrent cisplatin (20 mg/m(2)/d on Days 1-5 and 29-33) and gemcitabine (initially 600 mg/m(2), weekly on Fridays 68 h before RT) were administered. Because of DLT, the doses were reduced to 500 mg/m(2) weekly and then 500, 400, or 300 mg/m(2) on Days 2, 5, 26, 33. RESULTS: DLT occurred at all dose levels of gemcitabine >300 mg/m(2). Fourteen patients were treated at the recommended Phase II dose of gemcitabine (300 mg/m(2)) without DLT. The response to chemoradiation allowed 10 of 30 initially unresectable patients with primary pancreatic carcinoma to undergo radical surgery, including a complete response in 2 cases. CONCLUSIONS: At the recommended Phase II dose, chemoradiation with gemcitabine and cisplatin can be administered safely in pancreatic carcinoma. However, at higher dose levels, toxicity is severe and frequent. Patients with a chance for conversion to resection could benefit from this schedule.     

A phase I study of weekly gemcitabine and docetaxel in patients with advanced cancer: a Hoosier Oncology Group Study

PURPOSE: To determine the maximum tolerated dose (MTD) of weekly gemcitabine plus docetaxel, a dose escalation trial of both drugs was developed with each administered weekly for 3 weeks out of 4. PATIENTS AND METHODS: Dose levels for gemcitabine (mg/m(2)) and docetaxel (mg/m(2)) were as follows: level 1: 600/25; level 2: 600/35; level 3: 750/35; and level 4: 900/35. Sixteen patients with adequate renal, hepatic, and hematologic function and an Eastern Cooperative Oncology Group performance status of 0-2 were treated. Primary sites included pancreas (12) and others (4). RESULTS: Three patients were treated at each dose level from level 1 through level 4. The dose-limiting toxicity (DLT) was neutropenia, the maximum tolerated dose being 750 mg/m(2) of gemcitabine and 35 mg/m(2) of docetaxel. No grade 4 nonhematologic toxicity was seen. Three patients had grade 4 neutropenia. Of the 12 patients with pancreatic cancer, 1 had a partial remission and 7 had stable disease with a median duration of 8 weeks. CONCLUSIONS: Gemcitabine and docetaxel can be safely administered weekly at a dose of 750 and 35 mg/m(2), respectively. The DLT was neutropenia. Disease stabilization suggests that this may be an active regimen in patients with metastatic pancreatic cancer.     

A Phase I/II study of strontium-89 combined with gemcitabine in the treatment of patients with androgen independent prostate carcinoma and bone metastases

BACKGROUND: The objectives of the current study were to determine the maximum tolerated dose and to evaluate the efficacy of gemcitabine given in combination with strontium-89 to patients with androgen independent prostate carcinoma. METHODS: Patients with androgen-independent prostate carcinoma and painful osteoblastic bone metastases were eligible. On a 12-week course, patients received gemcitabine (600 mg/m(2) or 800 mg/m(2)) on Days 1, 8, 15, 43, 50, and 57. A single dose of strontium-89 (55 microCi/kg) was administered on Day 8. RESULTS: Fifteen patients were registered, and all were assessable for response and toxicity. Four patients were treated at Dose Level 1 (gemcitabine 600 mg/m(2)) without dose-limiting toxicity. Eleven patients received a total of 13 courses at Dose Level 2 (gemcitabine 800 mg/m(2)). Platelet nadirs of 25000-50000 platelets per microL were common at Dose Level 2, and 1 patient had Grade 4 thrombocytopenia that was dose-limiting. Granulocyte nadirs up to < 500 granulocytes per microL occurred in 4 patients at Dose Level 2 and were reversible. There were no responses, as measured by prostate specific antigen concentration, although 6 patients (40%) had stable disease. CONCLUSIONS: The authors concluded that 800 mg/m(2) gemcitabine was the maximum tolerated dose for the combination. The study was terminated on the basis that an overall response rate > than 10% was unlikely. Further study at this dose level and schedule is not warranted. .     

Phase I study of cisplatin and docetaxel plus mitomycin C in patients with metastatic non-small cell lung cancer

BACKGROUND: Docetaxel, cisplatin and mitomycin C are some of the active drugs used in the treatment of patients with metastatic non-small cell lung cancer (NSCLC). The purpose of this study was to determine the maximum tolerated dose (MTD) and recommended dose of the three drugs in combination for such patients. METHODS: Chemotherapy-native patients with metastatic NSCLC were enrolled in this study. The doses of docetaxel and cisplatin were fixed at 60 and 80 mg/m2, respectively. It was planned to increase the dose of mitomycin C from 4 to 6 and 8 mg/m2. All drugs were administered on day 1 and repeated every 3-4 weeks. RESULTS: All six patients received 60 mg/m2 of docetaxel and 80 mg/m2 of cisplatin, three of them with 4 mg/m2 of mitomycin C (level 1) and the other three with 6 mg/m2 of mitomycin C (level 2). Two of the three level 2 patients experienced dose-limiting toxicities (DLTs) in first cycle: febrile neutropenia and grade 3 hyponatremia. Based on these data, the MTD was concluded to be 60 mg/m2 for docetaxel, 80 mg/m2 for cisplatin and 6 mg/m2 for mitomycin C. Evaluation of the data from all of the cycles, however, showed that four of the six patients experienced DLTs. CONCLUSIONS: The addition of mitomycin C to docetaxel and cisplatin resulted in relatively high toxicities. It was impossible to use a high enough dose of mitomycin C to improve the survival of NSCLC patients. We therefore concluded that further evaluation of this combination is unwarranted.     

A Phase II study of gemcitabine and docetaxel in patients with metastatic pancreatic carcinoma

BACKGROUND: Patients with metastatic pancreatic carcinoma have a poor survival. Chemotherapy with gemcitabine is the standard first-line treatment. In a Phase II trial at one academic cancer center, the clinical safety and activity of combining gemcitabine and docetaxel were assessed. METHODS: Patients with previously untreated, advanced pancreatic carcinoma were eligible. Bidimensionally measurable disease or evaluable disease with an elevated tumor marker, good performance status, and adequate organ function were required. Patients received docetaxel 60 mg/m(2) on Day 1 and gemcitabine 600 mg/m(2) on Days 1, 8, and 15 every 28 days. Ciprofloxacin was administered on Days 8-18. Dose attenuations were made as indicated for toxicity. Patients were restaged radiographically after every two cycles. RESULTS: Thirty-four patients were enrolled, and 33 patients were evaluable for response. There were 23 men and 10 women among the evaluable patients. The median age was 63 years, and all patients had an Eastern Cooperative Oncology Group performance status of 0 or 1. Three patients had received prior chemoradiation for postresection adjuvant therapy. One hundred forty-six cycles of chemotherapy were administered, and 5 cycles (3%) in 4 patients (12%) were complicated by febrile neutropenia. Twenty percent and 11% of patients on Day 8 and Day 15 doses of gemcitabine, respectively, were omitted for toxicity. The objective response rate was 18%, and the median survival was 8.9 months (95% confidence interval, 5.2-11.2 months). The 1-year survival rate was 29%. CONCLUSIONS: The combination of gemcitabine and docetaxel in patients with advanced pancreatic carcinoma is well tolerated and is associated with moderate activity despite aggressive dose reduction. Whether combination regimens are more effective than single agents in the treatment of patients with pancreatic carcinoma awaits evaluation in randomized studies.     

A phase II trial of gemcitabine and docetaxel in patients with chemotherapy-naive,advanced nonsmall cell lung carcinoma

BACKGROUND: The goals of the current study were to determine the safety and efficacy of a nonplatinum-containing doublet, gemcitabine and docetaxel, in the treatment of patients with chemotherapy-naive nonsmall cell lung carcinoma (NSCLC). METHODS: Thirty-two patients with advanced, chemotherapy-naive NSCLC were treated with gemcitabine (1000 mg/m(2)) and docetaxel (40 mg/m(2)) administered on Days 1 and 8 every 21 days. All patients were evaluable for toxicity and survival and 27 patients were evaluable for response. RESULTS: This combination was extremely well tolerated with Grade 3 or 4 neutropenia occurring in 6 of 32 patients (19%) (grading was based on the National Cancer Institute Common Toxicity Criteria). There were two episodes of Grade 3 thrombocytopenia and no episodes of Grade 3 or 4 anemia. Grade 3 or 4 nonhematologic toxicities included nausea (occurring in 1 of 32 patients), diarrhea (occurring in 1 of 32 patients), fatigue (occurring in 10 of 32 patients), fluid retention (occurring in 2 of 32 patients), anorexia (occurring in 4 of 32 patients), and transaminitis (occurring in 2 of 32 patients). Six patients experienced Grade 3 pneumonitis that was at least possibly related to the combination of gemcitabine and docetaxel. There was 1 complete response and 7 partial responses for an overall response rate of 30%. The 1-year and median survivals were 35% and 7.9 months, respectively. CONCLUSIONS: In the current study, the regimen of gemcitabine (1000 mg/m(2)) and docetaxel (40 mg/m(2)) administered on Days 1 and 8 every 21 days was well tolerated with manageable hematologic and nonhematologic toxicities. The responses were comparable to those achieved with platinum-based combination chemotherapy and the 2-year survival was an encouraging 19%. These data would support the further study of this nonplatinum doublet in patients with advanced NSCLC.     

Phase I trial of fixed dose rate infusion gemcitabine with gefitinib in patients with pancreatic carcinoma

Purpose: To determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of gemcitabine using a fixed dose rate infusion (FDRI) in combination with gefitinib in patients (pts) with pancreatic adenocarcinoma (PCa). Patients and methods: Patients with advanced PCa were given gemcitabine at the FDRI of 10 mg/m²/min IV on Days 1, 8, and 15 of a 28-day cycle. Dose levels of 1000, 1200, and 1500 mg/m² were evaluated. Oral gefitinib 250 mg was given daily. DLTs were defined as 2 instances of Grade 3 hematologic or 4 nonhematologic or any Grade 4 hematologic toxicity. At least 4 patients were treated at each dose level. Dose escalation occurred in the absence of DLTs. Results: Five women and 8 men were enrolled. Median age was 59 and performance status 1. All had metastatic disease. Four patients received prior adjuvant chemoradiation for PCa, and one chemotherapy for lung cancer. Median cycles were 4 per patient. The MTD was 1,200 mg/m². Toxicity was predominantly hematologic. At 1,500 mg/m², 1 patient had Grade 4 granulocytopenia and 3 patients Grade 3 granulocytopenia. Overall, 8 patients (60 percent) developed Grade 1 or 2 acneiform rashes. One patient had Grade 3 vomiting; no significant diarrhea or liver toxicity was seen. There were no objective responses seen. Median time to progression and overall survival were 4.57 months and 7.13 months, respectively. Conclusion: Combining FDRI gemcitabine with gefitinib is feasible and tolerable. The recommended dose of gemcitabine is 1,200 mg/m² when used with gefitinib 250 mg daily.     

High incidence of pulmonary toxicity of weekly docetaxel and gemcitabine in patients with non-small cell lung cancer: results of a dose-finding study

PURPOSE: To determine the maximum tolerated doses (MTD) and the dose-limiting toxicities (DLTs) of the weekly administration of docetaxel and gemcitabine as first-line treatment in patients with advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Chemotherapy-na?ve patients with histologically or cytologically confirmed unresectable stage III(B) or IV NSCLC were enrolled onto the study. Escalated doses of gemcitabine (starting dose 700 mg/m(2) per week) and docetaxel (starting dose 30 mg/m(2) per week) were given on a weekly basis for three consecutive weeks in cycles of 4 weeks. RESULTS: Twenty-six patients received a total of 94 chemotherapy cycles. At the doses of docetaxel 40 mg/m(2) per week and gemcitabine 1000 mg/m(2) per week, the MTD had not yet been reached. However, the study was prematurely closed because of a high incidence of severe pulmonary adverse events. Six (23%) patients developed fever and pulmonary dysfunction (severe dyspnea, hypoxia in association with diffuse interstitial pneumonitis), which was fatal in two of them. No risk factors were identified contributing to these pulmonary adverse events; four patients had a low absolute number of peripheral blood CD4+ lymphocytes. Grade 3/4 neutropenia occurred in five (19%) patients and grade 3/4 anemia in two (8%). CONCLUSION: The weekly administration of gemcitabine and docetaxel in patients with advanced NSCLC is associated with a high incidence of severe pulmonary toxicity, which does not seem to be dose-related. The regimen cannot be used outside a clinical protocol.     

Phase I study of weekly gemcitabine as a radiation sensitizer for unresectable pancreatic cancer

PURPOSE: To determine the maximal tolerated dose and dose-limiting toxicities (DLTs) of weekly gemcitabine with concurrent radiotherapy (RT) in patients with unresectable adenocarcinoma of the pancreas. METHODS AND MATERIALS: Patients who had locally advanced or recurrent unresectable pancreatic cancer were eligible. Gemcitabine was administered as a 30-min infusion once weekly for a total of five cycles during the course of RT. The starting dose of gemcitabine was 350 mg/m(2)/wk. Doses were escalated by increments of 25% in successive cohorts of 3-6 patients. RT was delivered at 180 cGy/d to a total dose of 5400-5580 cGy to the gross tumor volume. RESULTS: Nineteen patients were entered in this study through three dose levels (350-550 mg/m(2)/wk). The maximal tolerated dose was determined to be 440 mg/m(2)/wk. The DLTs were neutropenia, thrombocytopenia, and failure to receive all five cycles of gemcitabine. Other non-DLTs included 16 Grade III toxicities, which consisted of thrombosis, infection, nausea, vomiting, hypotension, constipation, diarrhea, and fatigue. One patient at each gemcitabine dose level experienced Grade IV vomiting, and the patient at the 550 mg/m(2) dose developed Grade IV anorexia. CONCLUSION: The maximal tolerated dose of gemcitabine when administered as a 30-min infusion once weekly during RT for unresectable pancreatic cancer was found to be 440 mg/m(2)/wk. The DLTs were neutropenia, thrombocytopenia, and failure to receive all five cycles of chemotherapy. Concurrent gemcitabine and RT is reasonably well tolerated and deserves additional evaluation against the current standard of care.     

Low-dose radiotherapy as a chemopotentiator of gemcitabine in tumors of the pancreas or small bowel: a phase I study exploring a new treatment paradigm

PURPOSE: To determine the maximum tolerated dose of upper abdominal low-dose fractionated radiotherapy (<1.0 Gy per fraction) given in combination with, and as a chemopotentiator for, gemcitabine. METHODS AND MATERIALS: Gemcitabine was given at 1,250 mg/m(2) at 10 mg/m(2)/min on Days 1 and 8 of a 3-week cycle. Low-dose fractionated radiotherapy was tested at two dose levels: 60 cGy per fraction and 70 cGy per fraction. Radiotherapy was given b.i.d. on Days 1, 2, 8, and 9. Four cycles were planned. RESULTS: Twenty-seven patients have been put on study. Ten patients have been entered in Phase I: 6 with metastatic/recurrent pancreatic carcinoma and 4 with unresectable pancreatic/small bowel carcinoma. Two of four patients at Dose Level 2 experienced dose-limiting toxicity. The overall radiographic response was 30%, and median survival was 11 months (range, 4-37 months). CONCLUSION: Low-dose fractionated radiotherapy to the upper abdomen is well tolerated at 60 cGy per fraction when combined with gemcitabine. Phase II evaluation is ongoing.     

Phase I study of pegylated liposomal doxorubicin and gemcitabine in patients with advanced malignancies

BACKGROUND: Pegylated liposomal doxorubicin (PEG-LD) and gemcitabine have single-agent activity in breast and ovarian carcinoma patients. We conducted a Phase I trial to evaluate the maximum tolerated dose (MTD) and toxicities of this combination in patients with advanced malignancies. METHODS: Twenty-six patients with refractory or recurrent malignancies were enrolled in this dose escalation trial. Dose escalation proceeded from a starting level of PEG-LD 20 mg/m(2) and gemcitabine 1000 mg/m(2) administered on Days 1 and 15 of a 28-day cycle. RESULTS: The MTD was PEG-LD 20 mg/m(2) and gemcitabine 2000 mg/m(2) administered on Days 1 and 15 of a 28-day cycle. Dose-limiting toxicity, a Grade 3 rash, was observed in one patient during Cycle 1 and Grade 3 stomatitis and a rash were observed in a second patient during Cycle 2 after administration of PEG-LD 25 mg/m(2) and gemcitabine 2000 mg/m(2). Other side effects included palmar-plantar erythrodysesthesia, nausea, and fatigue. One complete and two partial responses were observed. CONCLUSIONS: The recommended Phase II dose is PEG-LD 20 mg/m(2) with gemcitabine 2000 mg/m(2) on Days 1 and 15 of a 28-day cycle. A trial with this combination is currently ongoing at this institution comprising patients with refractory ovarian carcinoma.     

Phase I dose and sequencing study of pegylated liposomal doxorubicin and docetaxel in patients with advanced malignancies

BACKGROUND: Pegylated liposomal doxorubicin (PEG-LD) and docetaxel have single-agent activity in several malignancies. The authors conducted a Phase I trial to evaluate the maximum tolerated dose (MTD), toxicities, and effect of dose sequencing of this combination in patients with advanced malignancies. METHODS: Twenty-two patients were enrolled in this two-arm, accelerated, dose escalation trial. Both drugs were administered on Days 1 and 15 of a 28 day cycle. In Arm A, dose escalation proceeded from a sequence and starting dose of 15 mg/m(2) PEG-LD and 30 mg/m(2) docetaxel. In Arm B, dose escalation proceeded from a sequence and starting dose of 30 mg/m(2) docetaxel and 15 mg/m(2)PEG-LD. In both arms, the dose of each drug was increased alternately by 5 mg/m(2) at each dose level. RESULTS: The MTD for Arm A was 20 mg/m(2) PEG-LD and 40 mg/m(2) docetaxel, both of which were administered on Days 1 and 15 of a 28-day cycle. The MTD for Arm B was 35 mg/m(2) docetaxel and 20 mg/m(2) PEG-LD, both of which were administered on Days 1 and 15 of a 28-day cycle. Dose-limiting toxicities were Grade 3 (according to the National Cancer Institute Common Toxicity Criteria) skin toxicity and thrombocytopenia. One partial response was observed and stable disease was documented for three patients. CONCLUSIONS: The recommended sequence and dose is 20 mg/m(2) PEG-LD followed by 40 mg/m(2) docetaxel on Days 1 and 15 of a 28-day cycle in Phase II trials for patients with breast and ovarian carcinoma to establish the efficacy of this well tolerated regimen.     

A phase I study of combination chemotherapy with gemcitabine and oral S-1 for advanced pancreatic cancer

OBJECTIVE: The aim of this study was to determine the maximum-tolerated dose and dose-limiting toxicity (DLT) of combination therapy with gemcitabine and S-1 in patients with advanced pancreatic cancer. METHODS: Chemotherapy-naive patients with histologically or cytologically proven unresectable or metastatic pancreatic cancer were enrolled. The patients received gemcitabine intravenously over 30 min on days 1 and 8 and S-1 orally twice daily from days 1 to 14. Cycles were repeated every 21 days until disease progression. Patients were scheduled to receive gemcitabine (mg/m(2)/week) and S-1 (mg/m(2)/day) at four dose levels: 800/60 (level 1), 1,000/60 (level 2), 1,000/70 (level 3) and 1,000/80 (level 4). RESULTS: Eighteen patients were enrolled in this study. The maximum-tolerated dose was not reached even at the highest dose level (level 4) because only 2 of the 6 patients at this level experienced DLT. The DLTs were neutropenia and rash. Six (33%) of the 18 patients achieved a partial response and median overall survival time was 7.6 months. CONCLUSIONS: Combination chemotherapy with gemcitabine and S-1 was well tolerated and showed good antitumor activity in the treatment of pancreatic cancer. We recommend a gemcitabine dose of 1,000 mg/m(2)/week and an S-1 dose of 80 mg/m(2)/day in further studies with this schedule.