Phase I study with dose escalation of gemcitabine and cisplatin in combination with ifosfamide (GIP) in patients with non-small-cell lung carcinoma

Gemcitabine (G) and cisplatin (P) are active reference agents in patients with non-small-cell lung cancer (NSCLC). Ifosfamide (I) has also been approved for NSCLC treatment. This phase I trial aimed to determine the dose-limiting toxicity (DLT), maximum tolerated dose [maximum tolerated dosage (MTD)], and recommended dose (RD) of a GIP combination in patients with advanced/metastatic NSCLC. In this study, one cycle of chemotherapy combined the following: ifosfamide: 3 g/m2 fixed dose (24-hour intravenous infusion) combined with mesna, day 1; gemcitabine: starting dose 1,000 mg/m2/d, escalating by 250 mg/m2 increments, days 1 and 15; cisplatin: starting dose 80 mg/m2, subsequently 100 mg/m2, day 15; in cohorts of at least 3 patients. Cycles were repeated every 28 days and no hematopoietic growth factors were administered. DLT was evaluated after the first chemotherapy cycle. Thirty-three patients (30 men, 3 women) with stage III (14 patients)/IV (19 patients) NSCLC were treated at eight dose levels, receiving 109 cycles of chemotherapy. Neutropenia was the only DLT reported. Although the MTD was not reached at the highest tested dose level, the RD chosen corresponds to the full doses of the GP3000 doublet standard (G: 3,000 mg/m2; P: 100 mg/m2 per cycle) every 28 days. Nonhematologic toxicities were mainly grade I-II. Relative dose intensities of G, I, and P at the RD were 96%, 98%, and 96%, respectively. Sixteen of 33 patients with measurable/evaluable disease had an objective response including two complete responses. In conclusion, GIP chemotherapy is safe and appears to be active in patients with NSCLC. The RD is gemcitabine: 1,500 mg/m2 days 1 and 15; ifosfamide: 3 g/m2 day 1; cisplatin: 100 mg/m2 day 15. A confirmatory phase II study is currently under way, before a phase III trial of GIP versus GP.     

Phase I evaluation of sequential doxorubicin gemcitabine then ifosfamide paclitaxel cisplatin for patients with unresectable or metastatic transitional-cell carcinoma of the urothelial tract.

PURPOSE: This phase I trial sought to evaluate the toxicity of and determine the maximum-tolerated dose (MTD) for the two-drug regimen doxorubicin and gemcitabine (AG) followed by the three-drug regimen of ifosfamide, paclitaxel, and cisplatin (ITP) in patients with unresectable or metastatic transitional-cell carcinoma. PATIENTS AND METHODS: Patients received AG every other week for six cycles followed by ITP every 3 weeks for four cycles. Five AG dose levels were investigated, up to doxorubicin 50 mg/m(2) and gemcitabine 2, 000 mg/m(2), to determine the MTD of the regimen. The dose and schedule of ITP were constant: ifosfamide 1,500 mg/m(2) (days 1 to 3); paclitaxel 200 mg/m(2) (day 1); and cisplatin 70 mg/m(2) (day 1). Granulocyte colony-stimulating factor was given between all cycles of therapy. RESULTS: Fifteen patients enrolled onto this phase I trial. AG was well tolerated at all dose levels, with no grade 3 or 4 myelosuppression. Toxicity experienced with ITP included grade 3 and 4 granulocytopenia in four patients and grade 3 nausea/vomiting in three patients. No grade 3 and 4 neurotoxicity was observed. Eight of 14 assessable patients experienced a major response to AG, including five of six patients treated at the two highest AG dose levels. After completion of AG-ITP, nine of 14 assessable patients had a major response (three complete responses and six partial responses). CONCLUSION: AG is a well-tolerated and active regimen. Sequential chemotherapy with AG-ITP is also well tolerated, and phase II investigation at the highest dose level is ongoing.     

Phase I and pharmacokinetic study of PKC412, an inhibitor of protein kinase C.

PURPOSE: N-Benzoyl staurosporine (PKC412) is a protein kinase C inhibitor with antitumor activity in laboratory models. We determined the toxicity of oral PKC412 administered daily for repeat cycles of 28 days. PATIENTS AND METHODS: Thirty-two patients with advanced solid cancers were treated at seven dose levels (12.5 to 300 mg daily) for a total of 68 cycles. RESULTS: The most frequent treatment-related toxicities were nausea, vomiting, fatigue, and diarrhea. At the two top dose levels (225 and 300 mg/d), 15 of 16 patients experienced nausea/vomiting (common toxicity criteria [CTC], version 1), grade 2 in nine of 16 and grade 3 in three of 16 patients; and six of 16 patients developed CTC grade 2 diarrhea. After 1 month of treatment, there were significant reductions in circulating lymphocyte (P <.02) and monocyte (P <.01) counts in patients receiving doses > or = 100 mg/d. Nevertheless, only two patients developed myelosuppression (both grade 2). Of two patients with progressive cholangiocarcinoma, one attained stable disease lasting 4.5 months and one a partial response lasting 4 months. There was a linear relationship between PKC412 dose and area under the curve (0-24 hours) and maximum plasma concentration with marked interpatient variability. The estimated median elimination half-life was 1.6 days (range, 0.9 to 4.0 days), and a metabolite with a median half-life of 36 days was detected. Steady-state PKC412 plasma levels at the top three dose cohorts (150 to 300 mg) were five to 10 times the cellular 50% inhibitory concentration for PKC412 of 0.2 to 0.7 micromol/L. CONCLUSION: PKC412 can be safely administered by chronic oral therapy, and 150 mg/d is suitable for phase II studies. The pharmacokinetics and lack of conventional toxicity indicate that pharmacodynamic measures may be additionally needed to optimize the drug dose and schedule.     

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.     

Phase II study of a closely spaced ifosfamide--cisplatin schedule with the addition of G-CSF in advanced non-small-cell lung cancer and malignant melanoma

BACKGROUND:: Ifosfamide and cisplatin are frequently combined cytotoxic agents.Both have a dose-response relationship. In view of this it appearsattractive to study regimens with a higher dose intensity thanusual. One way to increase the dose intensity is to shortenintervals between chemotherapy cycles. As bone marrow toxicityis dose limiting in ifosfamide-cisplatin combinations we starteda phase II study with both drugs administered every 2 weeksin combination with G-CSF. PATIENTS AND METHODS:: Patients with advanced non-small-cell lung cancer or malignantmelanoma were eligible for the study. The treatment consistedof ifosfamide 2 gram/m²/day days 1–3 combined with mesna,and cisplatin 33 mg/m²/day days 1–3, administered in hypertonicsaline (3% NaCl). G-CSF was started on day 4 at a dose of 5µg/kg/day and was continued until day 12. The cycles wereto be repeated every 2 weeks for a maximum of 6 cycles. RESULTS:: Thirty-two patients were entered in the study; 30 patients wereevaluable for response and toxicity. Neutropenia (grade 4 in16 patients) and thrombocytopenia (grade 4 in 15 patients) werethe most common toxicities. Thrombocytopenia incidence and -durationincreased per cycle and was the main cause of treatment delaysespecially after the third cycle. Only 4 patients were ableto complete the planned treatment without any delay or dosereduction and reached the intended dose intensity of 3 gram/m²/weekof ifosfamide and 50 mg/m²/week of cisplatin. Non haematologictoxicities were generally mild. Out of 22 evaluable patientswith non-small cell lung cancer 6 responded (27%; 95% CI: 10%–48%)while only one out of 8 patients with melanoma responded. Themedian response duration was 26 weeks (range 16–36 weeks). CONCLUSION:: The planned high-dose intensity of ifosfamide and cisplatincould be reached only for the first 2–3 cycles. Haematologictoxicity, especially cumulative thrombocytopenia, necessitatedtreatment delays jeopardizing the dose intensity. The responserate in non-small-cell lung cancer and melanoma was not superiorto what can be expected from more conventional regimens. cisplatin, G-CSF, ifosfamide, phase II study     

Combination therapy with gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, gemcitabine and cisplatin in patients with advanced solid tumors.

BACKGROUND: The aim of this study was to investigate the tolerability, pharmacokinetic interaction and antitumor activity of gefitinib ("Iressa", ZD1839), an orally active, selective epidermal growth factor receptor tyrosine kinase inhibitor, combined with gemcitabine and cisplatin in chemotherapy-na?ve patients with advanced solid tumors. PATIENTS AND METHODS: This was an open-label feasibility trial evaluating two doses of gefitinib (250 and 500 mg/day) in combination with gemcitabine and cisplatin. Gefitinib was administered daily from day 2 onwards. Gemcitabine 1250 mg/m(2) was given on days 1 and 8 and cisplatin 80 mg/m(2) on day 1 for up to six 3-week cycles. Patients could then continue to receive gefitinib monotherapy. RESULTS: Eighteen patients were entered, nine at each gefitinib dose level. Two patients developed dose-limiting toxicity: one grade 3 convulsion (250 mg/day dose group) and one grade 3 rash (500 mg/day dose group). The most frequently occurring adverse events in the combination phase were vomiting (17 patients), asthenia (16), nausea (14), diarrhea (14) and skin rash (13). The most common grade 3/4 adverse events were vomiting (seven patients), asthenia (six), thrombocytopenia (six), diarrhea (five) and anorexia (five). Pharmacokinetic analyses showed no apparent pharmacokinetic interaction between gefitinib and cisplatin or gemcitabine, with the exception of a possible small increase in the geometric mean exposure to gemcitabine seen on day 8 of therapy when given alone with the higher dose of gefitinib. Of 17 evaluable patients, nine had confirmed partial responses, seven had stable disease and one had progressive disease. CONCLUSIONS: Combination therapy of gefitinib with cisplatin and gemcitabine had a manageable and predictable safety profile, no major effect on exposure to any of the three drugs and antitumor activity.     

Phase I study of gemcitabine hydrochloride (LY 188011) combination therapy with cisplatin in the patients with non-small cell lung cancer]

The combination Phase I study of gemcitabine hydrochloride with cisplatin was conducted in the patients with non-small cell lung cancer (NSCLC) at 5 investigation sites. Gemcitabine was administrated on day 1, 8 and 15 and cisplatin on day 1 of each 28-day cycle. The dosage of cisplatin was fixed to 80 mg/m2 and the dosage of Gemcitabine was gradually escalated in 3 dosing level from 600, 800 to 1,000 mg/m2. The maximum tolerated dose (MTD) and the recommended dose was determined with Continual Reassessment Method. For each dose level, 6 cases, 3 cases and 6 cases were registered respectively and all 15 cases were evaluable. In the dose level 3 with 1,000 mg/m2 of gemcitabine and 80 mg/m2 of cisplatin, grade 4 neutropenia was observed as DLT in 3 out of 6 cases, thus dose level 3 was considered as MTD and the recommended dose. Major adverse events were leukopenia, neutropenia, nausea/vomiting and anorexia. The incidence of such adverse events seemed to be dose-dependent and especially the grade of neutropenia seemed to be more serious as the dose increased. Also, the grade of liver function tests abnormal seemed to be more serious as the dose increased but the incidence as well as the grade did not have tendency of dose-dependent in another events including renal function tests abnormal. On the other hand, as to the efficacy PR was observed in 4 out of 15 cases. Based upon the results, it is necessary to discuss further the efficacy in the recommended dose in the combination therapy of gemcitabine and cisplatin.     

Phase II study of combination chemotherapy with gemcitabine and irinotecan in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens

OBJECTIVE: The aim of this study was to evaluate the efficacy and toxicity of gemcitabine combined with irinotecan in patients with previously treated non-small-cell lung cancer (NSCLC). METHODS: Patients who failed to respond to platinum-containing first-line chemotherapy were enrolled and treated with gemcitabine 1000 mg/m(2) and irinotecan 150 mg/m(2) on days 1 and 15. Cycles were repeated every 4 weeks. RESULTS: Twenty-seven of 30 registered patients were evaluated. There were previous combination treatments of platinum and taxane regimens in 21 out of 27 patients, with 17 patients treated with carboplatin and paclitaxel and 4 patients treated with cisplatin or carboplatin and docetaxel. A total of 87 cycles was administered and the median number of cycles administered per patient was 3.5 cycles. Objective responses were observed in 5 out of 27 patients (18.5%). No severe hematologic and non-hematologic toxicities were observed (grade 3 leukopenia in 3 patients; grade 3 anemia in 3 patients; grade 3 thrombocytopenia in 2 patients; grade 3 diarrhea in 1 patient). The median survival time was 7.7 months and 1-year survival rate was 34.8%. CONCLUSION: Bi-weekly gemcitabine and irinotecan was well tolerated and had an acceptable response rate and a reasonable median survival time for patients with NSCLC who had previously been treated with platinum-based chemotherapy.     

Phase I/II trial of gemcitabine plus cisplatin and etoposide in patients with small-cell lung cancer

OBJECTIVE: The objectives of this phase I/II study were to define the maximum tolerated dose (MTD), safety, and activity of cisplatin, etoposide, and gemcitabine (PEG) in the treatment of previously untreated patients with small-cell lung cancer (SCLC). PATIENTS AND METHODS: Chemonaive patients received fixed doses of gemcitabine (1000 mg/m(2) on days 1 and 8) and cisplatin (70 mg/m(2) on day 2) and escalating doses of etoposide (starting dose of 50 mg/m(2) on days 3, 4, and 5) every 3 weeks. No prophylactic granulocyte colony-stimulating factors were used. RESULTS: From September 1998 to April 2000, 56 patients with limited- or extensive-stage SCLC were enrolled and received a total of 235 cycles. Two different etoposide doses were tested in eight patients. At the second level (75 mg/m(2)), two out of two patients experienced dose-limiting toxicities (neutropenia and thrombocytopenia) and no further dose-escalation was attempted, thus an etoposide dose of 50 mg/m(2) was defined as the MTD. In the subsequent phase II evaluation, 48 additional patients were enrolled, for a total of 54 patients treated at the MTD. Grade 3/4 neutropenia and thrombocytopenia occurred in 66.7 and 53.7% of patients, respectively. Non-hematologic toxicity was mild, with grade 3 diarrhea and fatigue as the main side effects. Two patients died of neutropenic sepsis (one at 75 mg/m(2) and the other at 50 mg/m(2) etoposide). Ten complete and 29 partial responses were reported, for an overall response rate of 72.2% (95% confidence interval, 56.6-85.0%). The median duration of response and median survival were 8.0 and 10 months, respectively, with a 1-year survival probability of 37.5%. CONCLUSIONS: The combination of PEG is feasible and well tolerated as front-line chemotherapy in SCLC. A randomized comparison of this triplet is underway.     

A dose-escalation study of irinotecan (CPT-11) in combination with gemcitabine in patients with advanced non-small cell lung cancer previously treated with a cisplatin-based front line chemotherapy

PURPOSE: CPT-11 and gemcitabine are both active agents against non-small cell lung cancer (NSCLC). We conducted a phase I study to determine the maximum-tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of their combination in patients with previously treated advanced NSCLC. PATIENTS AND METHODS: Twenty-seven patients with histologically confirmed NSCLC, who had failed cisplatin-based front-line chemotherapy, were enrolled. The patients' median age was 56 years, 24 were male and 22 had a performance status (WHO) 0-1. Gemcitabine was administered on days 1 and 8, as a 30-minute i.v. infusion, at escalated doses ranging from 900 to 1200 mg/m2. CPT-11 was given over a 60-minute i.v. infusion on day 8 at escalated doses ranging from 200 to 350 mg/m2, following gemcitabine administration. The treatment was repeated every three weeks. RESULTS: The MTD was exceeded at dose-level 7 with CPT-11 350 mg/m2 and gemcitabine 1200 mg/m2, where all three enrolled patients presented DLTs (one patient grade 4 thrombocytopenia, one grade 3 diarrhea and one grade 3 asthenia). The recommended doses for future phase II studies are CPT-11 300 mg/m2 on day 8 and gemcitabine 1200 mg/m2 on days 1 and 8. A total of 107 treatment cycles were administered. Grade 3/4 neutropenia was observed in 13 (13%) cycles, febrile neutropenia in 3 (3%) and grade 3/4 thrombocytopenia in 2 (2%). Grade 2/3 diarrhea was seen in 6 (6%) cycles, grade 2/3 nausea and vomiting in 13 (13%) and grade 2/3 asthenia in 8 (8%). Other toxicities were mild. Among 23 patients evaluable for response, PR was achieved in one (4.5%), SD in 12 (52.5%) and PD in 10 (43%). CONCLUSION: The results of this phase I study clearly demonstrate that gemcitabine and CPT-11 can be efficiently combined in a low-toxicity regimen with doses equal or near monotherapy levels. Further studies are needed to evaluate the efficacy of this combination in both chemotherapy-naive and pre-treated patients with advanced NSCLC.     

Phase I/II trial of gemcitabine plus cyclophosphamide in patients with metastatic breast carcinoma previously treated with taxanes

The purpose of this study was to determine the maximum tolerated dose (MTD) of infusional gemcitabine given in conjunction with intravenous (i.v.) cyclophosphamide, and to determine whether the regimen produced a response rate of at least 40% in patients with metastatic breast cancer who have been previously treated with taxanes. Patients received cyclophosphamide (600 mg/m2) i.v. followed immediately by gemcitabine (100, 150, or 200 mg/m2) given as a 24-hour infusion (every 3 weeks) using an accelerated dose-escalation schema. Dose-limiting toxicity was defined as a neutrophil nadir < 500/microL, platelet nadir < 50,000/microL, or > or = grade 2 nonhematologic toxicity (> or = grade 3 toxicity during the standard dose-escalation portion of the study). Twelve patients received a total of 32 cycles of therapy. The MTD of gemcitabine was 150 mg/m2. Dose-limiting toxicities at 200 mg/m2 included neutropenia and mucositis. One patient with lymphangitic lung metastases had a partial response (8%; 95% confidence intervals: 0%, 23%). This patient developed grade 4 transaminase and total bilirubin elevation that occurred after the sixth cycle of therapy. The study was terminated due to an insufficient number of responses. The MTD of gemcitabine given as a 24-hour infusion is 150 mg/m2 when used in conjunction with cyclophosphamide (600 mg/m2) every 3 weeks. This regimen is not likely to produce more than a 40% response rate in patients with metastatic breast cancer previously treated with taxanes.     

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.     

Phase I study of combination chemotherapy with gemcitabine and irinotecan for non-small cell lung cancer

A phase I study combining a fixed dose of gemcitabine with differing doses of CPT-11 every two weeks for previously treated non-small cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: A total of 21 patients with previously treated non-small cell lung cancer were treated every two weeks with CPT-11 followed by gemcitabine. The gemcitabine dose was fixed at 1000 mg/m2. The starting dose of CPT-11 (50 mg/m2) was then escalated different patients in 25 mg/m2 increments until 150 mg/m2 (level 5), the recommended dose as a single agent in Japan. RESULTS: Dose-limiting toxicity was only observed at level 5, in three of nine patients receiving the highest dose of CPT-11. One patient had grade 3 diarrhea, and two could not continue chemotherapy with grade 1 diarrhea or grade 1 neutropenia on day 15. Hematologic toxicity with this combination regimen, however, was generally mild. No grade 4 neutropenia, and only one case of grade 3 leukopenia was noted at level 5. Compliance with the combination regimen was good and there was no cumulative toxicity with the subsequent courses. Twenty-five courses of therapy were given at level 5 and the percentage of actual delivered doses/planned doses was 82%. CONCLUSIONS: The combination chemotherapy has only very mild toxicity and dose which can be recommended with this regimen are 1000 mg/m2 for gemcitabine and 150 mg/m2 for CPT-11 every two weeks.     

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 clinical study of infusional 5-fluorouracil with oxaliplatin and gemcitabine (FOG regimen) in patients with solid tumors.

BACKGROUND: The aim of this study was to determine the maximum tolerated dose, recommended phase II dose (RPTD) and toxicities of the FOG regimen (infusional 5-fluorouracil, oxaliplatin, gemcitabine). PATIENTS AND METHODS: Patients with advanced solid tumors were treated in an accelerated titration scheme. 5-Fluorouracil was administered intravenously at 200 mg/m(2)/day for 14 days and repeated every 21 days (one cycle). Gemcitabine was administered on days 1 and 8 over 30 min at 450-650 mg/m(2). Oxaliplatin was administered on day 1 over 2 h at 85-130 mg/m(2). For cycles 1, 3 and beyond, gemcitabine followed oxaliplatin; for cycle 2, gemcitabine preceded oxaliplatin. RESULTS: Forty-five and 39 patients were assessable for toxicity and response, respectively. Cycle 1 dose-limiting toxicities (DLT) included neutropenia, thrombocytopenia and diarrhea. No DLT was observed in cycle 1 at the first four dose levels (DL). At DL-5, two of four (50%) patients experienced DLT in cycle 1. Expanding DL-4, nine of 26 (35%) patients experienced DLT in cycle 1. Because recurrent grade 3 toxicities were observed in three of six (50%) patients at DL-3, DL-2 was considered the RPTD. At the RPTD, three patients had a partial response (response rate 23%). CONCLUSIONS: The RPTD for the 5-fluorouracil-oxaliplatin-gemcitabine combination is 200/100/450 mg/m(2). This novel regimen has demonstrated activity in advanced solid tumors and merits further investigation.     

A phase I-II study of weekly cisplatin and gemcitabine with concurrent radiotherapy in locally advanced cervical carcinoma.

BACKGROUND: The purpose of this study was to determine the maximum-tolerated dose (MTD) and the antitumor activity of gemcitabine when administered in combination with concurrent cisplatin and radiotherapy in locally advanced cervical carcinoma (LACC). PATIENTS AND METHODS: Patients with histologically confirmed LACC (International Federation of Gynecology and Obstetrics IIB-IVA), previously untreated, were eligible for entry in the study to receive radiotherapy and concomitant weekly chemotherapy with cisplatin 40 mg/m(2) and gemcitabine at increasing doses levels until the MTD was found. RESULTS: Thirty-six patients were included. Sixteen patients were entered at four dose levels. The MTD was 150 mg/m(2) and the recommended dose of gemcitabine for phase II was 125 mg/m(2). Twenty additional patients were entered at this level. Toxicity at the recommended dose was acceptable with grade 3/4 toxicity in <20% of patients. Thirty-five of thirty-six patients (97.3%) achieved an objective response, 32 (88.8%) a complete response (CR) three a (8.3%) partial response and one (2.7%) stable disease. At a median follow-up of 26 months, 28 of 36 patients (77.7%) are in sustained complete remission and seven of 36 (19.4%) have relapsed. The 3-year disease-free and overall survival rates are 67% and 72%, respectively. CONCLUSION: The association of cisplatin and gemcitabine with concurrent radiotherapy is active and well-tolerated in untreated LACC.     

A phase II trial of vinorelbine and cisplatin in previously untreated inoperable non--small-cell lung cancer

Weekly vinorelbine injection with cisplatin had been used in treatment of non-small-cell lung cancer. We performed a phase II trial to evaluate the efficacy and toxicity of a new schedule of vinorelbine and cisplatin in patients with previously untreated, inoperable (stage IIIB or stage IV) non-small-cell lung cancer. From April 1996 to May 1997, 52 patients were enrolled for study, and 50 patients were eligible and evaluable for both response and toxicity assessment. Therapy consisted of vinorelbine, 30 mg/m2, intravenously on days 1 and 5 of a 21-day cycle, and cisplatin 100 mg/m2 (reduced to 80 mg/m2 after the first seven patients) given on day 1. A total of 211 treatment courses were administered; the median number of cycles administered per patient was 4.5 (range: 1-6), the median dose intensity for vinorelbine was 16.9 mg/m2/week (84.4%), whereas that of cisplatin was 22.8 mg/m2/week (84.7%). Twenty-five patients responded to therapy for an overall response rate of 50%; one patient attained a complete response (2%). The main toxicities were vomiting, myelosuppression, and diarrhea, which included World Health Organization grade 3 or 4 nausea/vomiting (58% patients), anemia (41% patients), neutropenia (12% patients), and diarrhea (14%). The median duration of responses was 9 months. The median time to disease progression was 6.8 months (range 0.4-18.1 months). Median survival was 13 months, and 54% of patients were alive at 1 year. We conclude that this new schedule of vinorelbine and cisplatin achieves a high response with acceptable toxicity profile in patients with advanced non-small-cell lung cancer.     

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 dose-escalation study of irinotecan (CPT-11) in combination with cisplatin in patients with advanced non-small cell lung cancer previously treated with a docetaxel-based front line chemotherapy

Purpose: A phase I study was conducted to determine the maximum-tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of a CPT-11 plus cisplatin combination as salvage treatment in patients with advanced non-small cell lung cancer (NSCLC). Patients and methods: Twenty-two patients with histologically confirmed NSCLC, who had failed taxotere-based front-line chemotherapy, were enrolled. The patients’ median age was 61 years, 19 (86%) were male, and 17 (77%) had a performance status (World Health Organization (WHO)) 0–1. CPT-11 was administered as a 60-min i.v. infusion at a fixed dose of 100 mg/m² on day 1 and at escalating doses on day 8, starting from 100 mg/m² with increments of 10 mg/m² ; cisplatin was administered at a fixed dose of 80 mg/m² on day 8, 2 h after CPT-11 administration. Treatment was repeated every 3 weeks. Results: At the dose of CPT-11 120 mg/m² , three out of four enrolled patients presented DLTs (grade 4 neutropenia, febrile neutropenia and delayed diarrhea); the addition of G-CSF at this level did not permit further dose-escalation. Grade 3/4 neutropenia was observed in 12 (18%) cycles, febrile neutropenia in four (6%), and grade 3/4 thrombocytopenia in four (6%). Grade 3/4 diarrhea was seen in six (29%) patients, and grade 2/3 nausea and vomiting in 12 (57%). Neurotoxicity grade 2 was observed in six (29%) patients and grade 3 in one (5%). Other toxicities were mild. The MTD was CPT-11 100 mg/m² on day 1 and 110 mg/m² on day 8 in combination with CDDP 80 mg/m² on day 8. Among 12 patients evaluable for response, partial response was achieved in two (16.7%) patients and stable disease in five (41.7%). Conclusion: The combination of CPT-11 and cisplatin has substantial but manageable toxicity and marginal activity as salvage treatment of patients with NSCLC who have failed taxotere-based front-line chemotherapy; further investigation is warranted to define its precise role in the second-line setting.     

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

The role of non-platinum combination chemotherapy in the treatment of advanced non-small-cell lung cancer (NSCLC) has not yet been clarified. In this phase I study, the dose-limiting toxicity (DLT), the maximum tolerable dose (MTD) and the antitumor activity of a two-drug combination of docetaxel (DCT) and irinotecan (CPT) in patients with advanced NSCLC were evaluated. Previously untreated patients with NSCLC in stage IIIB with malignant pleural effusion or stage IV were eligible. Both drugs were administered by 1-h intravenous infusion on day 1, and repeated every 3 weeks. DCT was given before CPT administration. Five escalating dose levels of DCT/CPT (40/135, 50/135, 50/150, 60/150, and 60/165 mg/m2) were studied. Eighteen patients received 44 courses. The DLT was considered to be neutropenia, because grade 4 neutropenia lasting for 3 days or more was observed in three patients, which was accompanied with three episodes of febrile neutropenia. As a non-hematological toxicity, grade 3 diarrhea occurred in three patients. Since all the three patients treated at the fifth dose level (DCT at 60 mg/m2 and CPT at 165 mg/m2) experienced DLT (grade 4 neutropenia in two patients and grade 3 hepatic toxicity in one), this dose level was determined to be the MTD. The objective response rate was 33.3%, and the median survival time was 13.6 months. To confirm the effectiveness of this combination for advanced NSCLC which was suggested in the present study, a phase II study with the recommended doses (150 mg/m2 for CPT and 50-60 mg/m2 for DCT) is warranted.