A phase I study of radiation therapy and twice-weekly gemcitabine and cisplatin in patients with locally advanced pancreatic cancer

PURPOSE: In vitro studies suggest that low-dose gemcitabine sensitizes cells to radiation therapy and that this effect persists for 48 h after drug exposure. Cisplatin is a radiation sensitizer and is also synergistic with gemcitabine in some in vitro tumor systems. Gemcitabine's radiosensitizing properties can theoretically be exploited by twice-weekly administration. This study assessed toxicity in patients with pancreatic cancer treated with radiation therapy, gemcitabine, and cisplatin. METHODS AND MATERIALS: Patients with locally advanced pancreatic or gastric cancer were eligible. Gemcitabine and cisplatin were given twice weekly for 3 weeks during radiation therapy (50.4 Gy in 28 fractions). The starting dose of gemcitabine was 5 mg/m(2) i.v. The starting dose for cisplatin was 5 mg/m(2). Chemotherapy doses escalated every 3 to 6 patients according to a standard Phase I study design. RESULTS: Twenty-four evaluable patients, all with pancreatic cancer, were treated on this protocol. Grade 3 neutropenia occurred in 2 patients, Grade 3 thrombocytopenia occurred in 2, and Grade 4 lymphopenia occurred in 1. There was no clear relationship between chemotherapy dose and hematologic toxicity. The most common Grade 3-4 nonhematologic toxic responses were vomiting (7 patients) and nausea (7 patients). Dose-limiting toxicity consisting of Grade 4 nausea and vomiting occurred in 2 of 3 patients at dose Level 6 (gemcitabine 45 mg/m(2) i.v. and cisplatin 10 mg/m(2) i.v.). Six patients were treated at dose Level 5 (gemcitabine 30 mg/m(2) i.v. and cisplatin 10 mg/m(2) i.v.) without dose-limiting toxicity. CONCLUSION: Gemcitabine 30 mg/m(2) i.v. twice weekly and cisplatin 10 mg/m(2) i.v. twice weekly may be given concurrently with radiation therapy (50.4 Gy in 28 fractions) with acceptable toxicity.     

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.     

A phase I trial of weekly gemcitabine and concurrent radiotherapy in patients with locally advanced pancreatic cancer

This study investigated the maximum-tolerated dose of gemcitabine based on the frequency of dose-limiting toxicities of weekly gemcitabine treatment with concurrent radiotherapy in patients with locally advanced pancreatic cancer. Fifteen patients with locally advanced pancreatic cancer that was histologically confirmed as adenocarcinoma were enrolled in this phase I trial of weekly gemcitabine (150-350 mg x m(-2)) with concurrent radiotherapy (50.4 Gy in 28 fractions). Gemcitabine was administered weekly as an intravenous 30-min infusion before radiotherapy for 6 weeks. Three of six patients at the dose of 350 mg x m(-2) of gemicitabine demonstrated dose-limiting toxicities involving neutropenia/ leukocytopenia and elevated transaminase, while nine patients at doses of 150 mg x m(-2) and 250 mg x m(-2) did not demonstrate any sign of dose-limiting toxicity. Of all 15 enrolled patients, six patients (40.0%) showed a partial response. More than 50% reduction of serum carbohydrate antigen 19-9 level was observed in 13 (92.9%) of 14 patients who had pretreatment carbohydrate antigen 19-9 levels of 100 U x ml(-1) or greater. The maximum-tolerated dose of weekly gemcitabine with concurrent radiotherapy was 250 mg x m(-2), and this regimen may have substantial antitumour activity for patients with locally advanced pancreatic cancer. A phase II trial of weekly gemcitabine at the dose of 250 mg x m(-2) with concurrent radiation in patients with locally advanced pancreatic cancer is now underway.     

Eastern Cooperative Oncology Group Phase I trial of protracted venous infusion fluorouracil plus weekly gemcitabine with concurrent radiation therapy in patients with locally advanced pancreas cancer: a regimen with unexpected early toxicity.

PURPOSE: We performed a phase I trial of protracted venous infusion (PVI) fluorouracil (5-FU) plus weekly gemcitabine with concurrent radiation therapy in patients with locally advanced pancreas cancer to determine the maximum-tolerated dose of gemcitabine that could be safely administered. We also sought to identify the toxicities associated with this treatment protocol. PATIENTS AND METHODS: Seven patients with locally advanced pancreas cancer were treated with planned doses of radiation (59.4 Gy) and PVI of 5-FU (200 mg/m(2)/d) with gemcitabine doses of 50 to 100 mg/m(2)/wk. RESULTS: Two of three patients at the 100-mg/m(2)/wk dose level experienced dose-limiting toxicity (DLT), as did three of four at the 50-mg/m(2)/wk dose level. One patient experienced a mucocutaneous reaction described as a Stevens-Johnson syndrome that was attributed to chemotherapy. Three patients developed gastric or duodenal ulcers with severe bleeding requiring transfusion. One patient developed severe thrombocytopenia lasting longer than 4 weeks. Three of the five episodes of DLT developed at radiation doses < or = 36 Gy. CONCLUSION: Based on this experience, we cannot recommend further investigation of regimens incorporating gemcitabine into regimens of radiation with PVI 5-FU. The mechanism of this synergistic toxicity remains to be determined.     

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 trial of the dual farnesyltransferase and geranylgeranyltransferase inhibitor L-778,123 and radiotherapy for locally advanced pancreatic cancer.

PURPOSE: Preclinical and clinical studies have demonstrated that inhibition of prenylation can radiosensitize cell lines with activation of Ras and produce clinical response in patients with cancer. The aim of this study was to determine the maximally tolerated dose of the dual farnesyltransferase and geranylgeranyltransferase I inhibitor L-778,123 in combination with radiotherapy for patients with locally advanced pancreatic cancer. EXPERIMENTAL DESIGN: L-778,123 was given by continuous intravenous infusion with concomitant radiotherapy to 59.4 Gy in standard fractions. Two L-778,123 dose levels were tested: 280 mg/m2/day over weeks 1, 2, 4, and 5 for dose level 1; and 560 mg/m2/day over weeks 1, 2, 4, 5, and 7 for dose level 2. RESULTS: There were no dose-limiting toxicities observed in the eight patients treated on dose level 1. Two of the four patients on dose level 2 experienced dose-limiting toxicities consisting of grade 3 diarrhea in one case and grade 3 gastrointestinal hemorrhage associated with grade 3 thrombocytopenia and neutropenia in the other case. Other common toxicities were mild neutropenia, dehydration, hyperglycemia, and nausea/vomiting. One patient on dose level 1 showed a partial response of 6 months in duration. Both reversible inhibition of HDJ2 farnesylation and radiosensitization of a study patient-derived cell line were demonstrated in the presence of L-778,123. K-RAS mutations were found in three of the four patients evaluated. CONCLUSIONS: The combination of L-778,123 and radiotherapy at dose level 1 showed acceptable toxicity in patients with locally advanced pancreatic cancer. Radiosensitization of a patient-derived pancreatic cancer cell line was observed.     

Gemcitabine,paclitaxel, and radiation for locally advanced pancreatic cancer: a Phase I trial

PURPOSE: To determine the maximum tolerated dose (MTD) and dose-limiting toxicities of gemcitabine, paclitaxel, and concurrent radiation for pancreatic cancer. METHODS AND MATERIALS: Twenty patients with locally unresectable pancreatic cancer were studied. The initial dose level was gemcitabine 75 mg/m(2) and paclitaxel 40 mg/m(2) weekly for 6 weeks. Concurrent radiation to 50.4 Gy was delivered in 1.8 Gy fractions. The radiation fields included the primary tumor, plus the regional peripancreatic, celiac, and porta hepatis lymph nodes. RESULTS: Dose-limiting toxicities of diarrhea, dehydration, nausea, and anorexia occurred in 3 of 3 patients at the second dose level of gemcitabine, 150 mg/m(2)/week. An intermediate dose level of gemcitabine, 110 mg/m(2)/week, was added, but gastrointestinal toxicity and pulmonary pneumonitis were encountered. The MTD therefore was gemcitabine 75 mg/m(2)/week with paclitaxel 40 mg/m(2)/week and concurrent radiation. Two of 11 patients treated at the MTD had Grade 3/4 toxicity. Four of 10 assessable patients treated at the MTD responded (40%), including one pathologic complete response. CONCLUSION: The maximum tolerated dosage of gemcitabine is 75 mg/m(2)/week with paclitaxel 40 mg/m(2)/week and conventional 50.4 Gy radiation fields. A Phase II Radiation Therapy Oncology Group study is under way.     

A phase I study of combined UFT plus leucovorin and radiotherapy for pancreatic cancer

PURPOSE: This Phase I study combines tegafur and uracil (UFT) with leucovorin and conventional radiation for the treatment of pancreatic cancer. The design seeks to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of this regimen as well as to define a future Phase II dose level. METHODS: Patients with locally advanced and unresectable pancreatic cancer were treated with 45 Gy of radiation therapy. The initial UFT dose was 150 mg/m(2)/day given with leucovorin 90 mg/day, both divided into 3 daily doses for 35 days concurrent with radiation. UFT doses were escalated at increments of 50 mg/m(2)/day. Dose-limiting toxicity (DLT) was defined as Grade 3 or greater nausea, vomiting or diarrhea despite medical intervention; or Grade 3 or greater neutropenia/thrombocytopenia; or Grade 3 or greater hepatic toxicity; or inability of the patient to take 75% or more of the planned UFT/leucovorin; or radiotherapy interruption of greater than 1 week. The MTD for UFT/leucovorin was exceeded by one dose level when a certain dose caused DLT in 2 or more patients of 6. RESULTS: Five evaluable patients had Stage I resectable disease but had pathologic adenopathy. Seven had Stage II unresectable disease. Compliance with therapy was excellent. At a daily dose of 300 mg/m(2) of UFT, we noticed minimal diarrhea and hematologic toxicity with mild-moderate nausea, anorexia, and fatigue. Three patients had Grade 4 toxicity: 1 had neutropenia on Day 38, 1 had diarrhea on Day 55, and 1 had vomiting on Day 15. CONCLUSION: Oral UFT/leucovorin and radiation therapy offers patients a viable treatment option for pancreatic cancer. The major known toxicity of diarrhea was tolerable. The MTD was not reached in this study. Our current plan is to expand this into a Phase I/II trial beginning at a UFT dose of 300 mg/m(2) and correlate this with clinical pharmacologic parameters. The potential benefit of long bioavailability and oral delivery of UFT compares favorably with continuous infusion regimens without the added morbidity of a catheter and pump.     

Phase I study of twice-weekly gemcitabine and concomitant external-beam radiotherapy in patients with adenocarcinoma of the pancreas

To determine the maximum tolerated dose and dose-limiting toxicity associated with twice-weekly gemcitabine and concomitant external-beam radiotherapy in patients with adenocarcinoma of the pancreas.

Twenty-one patients with biopsy-proven adenocarcinoma of the pancreas were treated with external-beam radiotherapy to a dose of 50.4 Gy in 28 fractions, concurrent with gemcitabine, infused over 30 min before irradiation on a Monday and Thursday schedule. The dose of gemcitabine was escalated in 5 cohorts of 3–6 patients each. Initial gemcitabine dose was 10 mg/m², with dose escalation until dose-limiting toxicity was observed.

The maximum tolerated dose of gemcitabine was 50 mg/m², when given in a twice-weekly schedule with radiation. Dose-limiting toxicity was seen in 2 patients at 60 mg/m², and consisted of severe upper gastrointestinal bleeding approximately 1 month after completion of treatment. Six patients had radiographic evidence of response to treatment, and 5 of these underwent complete surgical resection. Three patients who underwent complete resection had been deemed to have unresectable tumors before enrollment on trial. Four patients are alive, including 2 without evidence of disease more than 1 year after resection.

The combination of external-beam radiation and twice-weekly gemcitabine at a dose of 50 mg/m² is well tolerated and shows promising activity for the treatment of pancreatic cancer. Our data suggest a higher maximum tolerated dose and different dose-limiting toxicity than previously reported. Further investigation of this regimen is warranted.     

Gemcitabine and oxaliplatin for patients with advanced or metastatic pancreatic cancer: a North Central Cancer Treatment Group (NCCTG) phase I study.

BACKGROUND: The study was performed to determine the maximum tolerated dose (MTD) of gemcitabine and oxaliplatin in patients with advanced or metastatic pancreatic adenocarcinoma (ACA). PATIENTS AND METHODS: Pancreatic ACA patients, with previously untreated advanced or metastatic disease, were enrolled in a dose escalation study of gemcitabine and oxaliplatin. Oxaliplatin was given intravenously on day 1 and gemcitabine intravenously on days 1 and 8 of a 3-week cycle. Doses of both drugs were increased with sequential cohorts of patients until dose-limiting toxicity (DLT) was observed. RESULTS: A total of 18 patients were enrolled to three dose levels. DLT of neutropenia and a severe infection was noted at a dose of gemcitabine 1250 mg/m2 and oxaliplatin 130 mg/m2. Hematological toxicity and nausea and vomiting were the most common grade 3/4 toxicities. The MTD, gemcitabine 1000 mg/m2 and oxaliplatin 100 mg/m2, was well tolerated. Three confirmed responses were seen. CONCLUSIONS: The MTD of gemcitabine and oxaliplatin in patients with pancreatic ACA was determined. A phase II study of this combination is ongoing and will be reported separately at a later date.     

Radiation therapy and concurrent fixed dose amifostine with escalating doses of twice-weekly gemcitabine in advanced pancreatic cancer.

PURPOSE: To determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of twice-weekly gemcitabine (TW-G) when administered in conjunction with fixed dose amifostine (A) during external radiotherapy (RT) in patients with advanced pancreatic cancer. METHODS AND MATERIALS: Ten patients with previously untreated, locally advanced, or asymptomatic-metastatic pancreatic adenocarcinoma were enrolled in this study. RT was delivered by using the standard four-field technique (1.8 Gy daily fractions, 45 Gy followed by a boost of 5.4 Gy, in 5-1/2 weeks). The starting dose of TW-G was 60 mg/m(2) (i.v., 30-min infusion), which is equal to the upper limit of previously reported MTD of TW-G when given without A during RT. A was given just before the TW-G, at a fixed dose of 340 mg/m(2) (i.v., rapid infusion). TW-G doses were escalated by 30-mg/m(2) increments in successive cohorts of 3 to 6 additional patients until DLT was observed. Toxicities were graded using the Radiation Therapy Oncology Group and National Cancer Institute Common Toxicity Criteria, version 2.0. RESULTS: In general, therapy was well tolerated in patients treated at the first two dose levels of 60 mg/m(2) and 90 mg/m(2). The DLT of TW-G given in conjunction with A during RT were neutropenia, thrombocytopenia, and nausea/vomiting at the dose level of 120 mg/m(2). Of the 10 patients eligible for a median follow-up of 10 months, 5 remain alive; 1 complete responder, 3 partial responders, and 1 with stable disease. CONCLUSION: A dose of TW-G at a level of 90 mg/m(2) produced tolerable toxicity and it may possess significant activity when delivered in conjunction with 340 mg/m(2) dose of A during RT of the upper abdomen. Due to the higher MTD of TW-G seen in our study, we consider that the A supplementation may optimize the therapeutic index of TW-G-based chemoradiotherapy protocols in patients with pancreatic carcinoma.     

Phase I and pharmacokinetic study of irofulven, a novel mushroom-derived cytotoxin, administered for five consecutive days every four weeks in patients with advanced solid malignancies.

PURPOSE: To evaluate the toxicity and pharmacologic behavior of the novel mushroom-derived cytotoxin irofulven administered as a 5-minute intravenous (IV) infusion daily for 5 days every 4 weeks to patients with advanced solid malignancies. PATIENTS AND METHODS: In this phase I trial, 46 patients were treated with irofulven doses ranging from 1.0 to 17.69 mg/m(2) as a 5-minute IV infusion (two patients received a 1-hour infusion) daily for 5 days every 4 weeks. The modified continual reassessment method was used for dose escalation. Pharmacokinetic studies were performed on days 1 and 5 to characterize the plasma disposition of irofulven. RESULTS: Forty-six patients were treated with 92 courses of irofulven. The dose-limiting toxicities on this schedule were myelosuppression and renal dysfunction. At the 14.15-mg/m(2) dose level, renal dysfunction resembling renal tubular acidosis occurred in four of 10 patients and was ameliorated by prophylactic IV hydration. The 17.69-mg/m(2) dose level was not tolerated because of grade 4 neutropenia and renal toxicity, whereas the 14.15-mg/m(2) dose level was not tolerable with repetitive dosing because of persistent thrombocytopenia. Other common toxicities included mild to moderate nausea, vomiting, facial erythema, and fatigue. One partial response occurred in a patient with advanced, refractory metastatic pancreatic cancer lasting 7 months. Pharmacokinetic studies of irofulven revealed dose-proportional increases in both maximum plasma concentrations and area under the concentration-time curve, while the agent exhibited a rapid elimination half-life of 2 to 10 minutes. CONCLUSION: Given the results of this study, the recommended dose of irofulven is 10.64 mg/m(2) as a 5-minute IV infusion daily for 5 days every 4 weeks. The preliminary antitumor activity documented in a patient with advanced pancreatic cancer and the striking preclinical antitumor effects of irofulven observed on intermittent dosing schedules support further disease-directed evaluations of this agent on the schedule evaluated in this study.     

A phase I study of erlotinib in combination with gemcitabine and radiation in locally advanced, non-operable pancreatic adenocarcinoma.

PURPOSE: To determine the maximum tolerated dose (MTD) of erlotinib when administered concurrently with twice weekly gemcitabine and radiation therapy (RT) for locally advanced pancreatic cancer, assess the safety and toxicity profile of this combination and secondarily evaluate response, time to tumor progression and overall survival. METHODS: Patients with untreated locally advanced pancreas cancer were treated with daily erlotinib in combination with gemcitabine 40 mg/m(2)/30 min twice weekly and RT delivered at 180 cGy/day in 28 fractions over 5.5 weeks for a total of 5040 cGy. Erlotinib was dose escalated in successive cohorts (100 mg, 125 mg). When the MTD was determined, the cohort was expanded to better define toxicity and preliminarily efficacy. All patients were surgically staged. After chemoradiation, patients received maintenance weekly gemcitabine 1000 mg/m(2) on days 1 and 8 of a 21 day cycle and daily erlotinib for four cycles. RESULTS: Three patients were treated at dose level 1 (erlotinib 100 mg) without limiting toxicity. Two of six patients at dose level 2 (erlotinib 125 mg) had dose-limiting toxicities, neutropenia and thrombocytopenia, causing dose delay and elevated liver enzymes. The MTD for erlotinib in combination with twice weekly gemcitabine-based chemoradiation was 100 mg/day. Eleven additional patients were treated at dose level 1. All twenty patients were assessable for toxicity. Seventeen patients were assessable for response. The partial response rate was 35% and 53% had stable disease. The median survival for all patients was 18.7 months. CONCLUSION: In combination with fixed dose gemcitabine at 40 mg/m(2) twice weekly and radiation at 180 cGy/day, the MTD of erlotinib was found to be 100 mg/day. This is a relatively well tolerated, biologically active combination in a poor prognostic cancer.     

Phase I-II study of gemcitabine and fluorouracil as a continuous infusion in patients with pancreatic cancer.

PURPOSE: To determine the maximum-tolerated dose (MTD), dose-limiting toxicities, and efficacy of gemcitabine combined with fluorouracil (5-FU) in patients with pancreatic cancer. PATIENTS AND METHODS: Patients with measurable, locally advanced, nonresectable or metastatic pancreatic cancer were candidates for the study. 5-FU was given via protracted venous infusion (PVI) at a fixed dosage of 200 mg/m2/d, and gemcitabine was administered weekly for 3 consecutive weeks every 4 weeks. The initial dose of gemcitabine was 700 mg/m2 and was escalated in increments of 100 mg/m2/wk until the appearance of severe toxicity. Measurements of efficacy included the following: response rate; clinical benefit response, which is a composite measurement of pain, performance status, and weight loss; time to disease progression; and survival. RESULTS: Twenty-six patients received a total of 109 courses. Dose-limiting toxicity, which consisted of grade 4 neutropenia with fever (one patient) and grade 4 thrombocytopenia (one patient), was observed in two of three patients treated with 1,100 mg/m2/wk of gemcitabine. On the basis of these results, the MTD of gemcitabine with 5-FU via PVI on this schedule was 1,000 mg/m2. Sixteen patients developed grade 3-4 neutropenia, and three patients developed grade 3-4 thrombocytopenia. Grade 3-4 nonhematologic toxicity consisted of diarrhea (two patients) and cutaneous toxicity, asthenia, edema, mucositis, and nausea and vomiting (one patient each). The delivered dose-intensity of gemcitabine was similar at the 1,000 mg/m2 dose level (599 mg/m2/wk) as at the 900 mg/m2 (601 mg/m2/wk) dose level. For this reason, the recommended dose of gemcitabine for phase II evaluation on this schedule was 900 mg/m2. Five patients had objective responses (one complete response and four partial responses; response rate, 19.2%; 95% confidence interval [CI], 6.5 to 39.3), and 10 patients had improvement of disease-related symptoms (45%; 95% CI, 24 to 67). After a median follow-up of 17.7 months (range, 7.8 to 24.8 months), the median progression-free survival and overall survival times were 7.4 months (95% CI, 3.3 to 11.4) and 10.3 months (95% CI, 8.1 to 12.5), respectively. CONCLUSION: The MTD of gemcitabine when combined with 5-FU via PVI on this schedule was 1,000 mg/m2/ wk; however, on the basis of administered dose-intensity, the recommended dose for additional investigation is 900 mg/m2. This combination chemotherapy regimen was well tolerated and showed promising antitumor activity in the treatment of pancreatic cancer.     

Dose escalation study of irinotecan combined with carboplatin for advanced non-small-cell lung cancer

From December 1994 to July 1997, we conducted a dose escalation study of irinotecan combined with carboplatin in 17 patients with advanced non-small-cell lung cancer (NSCLC) to determine the maximum tolerated dose and the dose-limiting toxicities. Irinotecan was administered intravenously over 90 min on days 1, 8 and 15, with carboplatin given at an area under the concentration-time curve dose of 5 mg/ml x min (calculated using Calvert's formula) on day 1. The starting dose of irinotecan was 30 mg/m2 and dose escalation was done in 10-mg/m2 increments. Treatment was repeated at 28-day intervals for at least two cycles. The dose-limiting toxicities were neutropenia and thrombocytopenia, since three out of five patients given 60 mg/m2 of irinotecan developed grade 4 neutropenia and thrombocytopenia. The overall response rate was 35.3%. The median survival time and the 1-year survival rate were 10.5 months and 35.3%, respectively. The maximum tolerated dose of irinotecan with this regimen was 60 mg/m2, while 50 mg/m2 can be recommended for future use. Further studies of this combination in advanced NSCLC are warranted.     

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.     

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.     

Combined radiochemotherapy of locally advanced unresectable pancreatic adenocarcinoma with mitomycin C plus 24-hour continuous infusional gemcitabine

BACKGROUND: In locally advanced pancreatic cancer, the combination of chemotherapy with radiotherapy is gaining increasing importance; although, in view of the reported long-term results of several contemporary trials, further improvements are certainly warranted. The aim of the present study was to evaluate the effectiveness and safety of a combined-treatment modality consisting of systemic chemotherapy with 24-h continuous infusional gemcitabine and mitomycin C, plus external beam radiotherapy in patients with localized unresectable adenocarcinoma of the pancreas. METHODS AND MATERIALS: Systemic chemotherapy consisted of mitomycin C 8 mg/m2 given as i.v. bolus injection on day 1 and gemcitabine administered as a 24-h continous infusion once weekly for 3 of 4 weeks. The starting dose of gemcitabine was 100 mg/m2 and dose levels were escalated in consecutive cohorts of 3-6 patients to 130 and 160 mg/m2, utilizing an escalating-dose Phase I trial design. Radiation therapy using megavolt irradiation (total dose, 45 Gy, 1.8 Gy/day) of 6 MV photons or greater with a 3- or 4-field technique was delivered concurrently for 5-6 weeks. RESULTS: Between January 1997 and August 1998, a total of 15 patients were enrolled in this trial, all of whom were assessable for toxicity, response, and survival. The dose-limiting toxicities at the 160 mg/m2 gemcitabine level were myelosuppression, specifically neutropenia +/- thrombocytopenia, and gastrointestinal symptoms, including stomatitis, vomiting, and diarrhea. Only 1 partial response was observed (7%), and disease was stabilized in 10 additional patients (67%). The median time to progression was 5.5 months (range, 2-12 months). Whereas all patients developed distant metastases, locoregional failure occurred in only 3. The median survival time was 8.3 months (range, 2.5 to 22.0+ months), and the 1-year survival rate was 13.3%. CONCLUSION: The MTD of gemcitabine when given as prolonged infusion in combination with mitomycin C and radiation therapy was 130 mg/m2/week. Therapeutic results suggest that combined chemoradiation with this regimen is feasible and effective for local control of pancreatic cancer, but essentially ineffective in counteracting metastatic tumor growth.     

Phase I-II trial of twice-weekly gemcitabine and concomitant irradiation in patients undergoing pancreaticoduodenectomy with extended lymphadenectomy for locally advanced pancreatic cancer

PURPOSE: Define the maximum tolerated dose (MTD), tolerability, and efficacy of gemcitabine given concomitantly with radiotherapy in patients with locally advanced pancreatic cancer. METHODS AND MATERIALS: Patients were required to have locally advanced T1-T3 resectable pancreatic cancer. Gemcitabine, given twice weekly before irradiation as a 30-min infusion, was tested at 3 dose levels: 20, 50, and 100 mg/m(2). The radiation dose was 50.4 Gy (ICRU) in 28 fractions. The targeted irradiation volume included the tumor, edema, and a 1-cm margin. RESULTS: Twenty-eight of 34 patients was eligible for analysis of the treatment. The median age was 67 years (range 38-82). Six patients had T1, 9 had T2, and 19 had T3 diseases (AJCC). Dose-limiting toxicities were Grade 4, fatigue and nausea; Grade 3, thrombocytopenia, diarrhea, and infection. The MTD established was at the 50-mg/m(2) gemcitabine dose. A total of 21 of 28 patients underwent surgery: 18 had pancreaticoduodenectomy, 2 had total pancreatectomy, and 1 for palliative surgery. At the time of analysis, 13 of 28 (46%) were disease-free. The estimated median survival was 25 months and overall survival rate at 2 years (Kaplan-Meier) was 55%. CONCLUSION: Gemcitabine 50 mg/m(2) given twice weekly with concomitant irradiation induces acceptable and manageable toxicity and might prolong survival.     

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.