Phase II evaluation of mitoxantrone plus cis-platinum in patients with advanced breast cancer

Summary The Southwest Oncology Group studied the response rate and toxicity of mitoxantrone (7.5 or 10 mg/m² to 12.0 mg/m²) and cis-platinum (100 mg/m²) in 30 patients with advanced breast cancer as second-line therapy. There were 2 partial responses in 29 eligible patients. Toxicity was considerable, with 27 patients having grade 3 or 4 toxicity. Grade 3–4 toxicity included vomiting, thrombocytopenia, granulocytopenia, leukopenia and anemia. The combination of mitoxantrone plus cis-platinum has minimal activity as second-line therapy in metastatic breast cancer.     

A phase I trial of BMS-247550 (NSC# 710428) and gemcitabine in patients with advanced solid tumors

Summary The purpose of this study is to establish the maximum tolerated dose and define the dose-limiting toxicity of the investigational epothilone BMS-247550 in combination with fixed dose-rate gemcitabine. Patients with advanced, recurrent solid tumors who had received ≤2 prior cytotoxic regimens for recurrent disease were treated with gemcitabine over 90 min on days 1 and 8 plus BMS-247550 over 3 h on day 8, every 21 days in a phase I study. Dose-limiting toxicity definitions were based on severe myelosuppression, or grade 3 or 4 treatment-related non-hematologic toxicity, or dose delay of greater than 2 weeks due to treatment toxicity observed in the first treatment cycle. Dose cohort 1 received gemcitabine 900 mg/m² and BMS-247550 20 mg/m². Grade 4 neutropenia lasting ≥7 days occurred in one of six patients. Two of three patients in cohort 2 (gemcitabine 900 mg/m² plus BMS-247550 30 mg/m²) had dose-limiting toxicities of grade 4 neutropenia. An additional three patients were treated at dose level 1 with no additional dose-limiting toxicities observed. At an intermediate dose level (gemcitabine 750 mg/m² plus BMS-247550 30 mg/m²), two of six patients experienced a dose-limiting toxicity (febrile neutropenia and grade 3 hypophosphatemia in 1, grade 3 hypophosphatemia and grade 3 hyponatremia in (1), and five of six patients experienced dose delays. In the final cohort (gemcitabine 750 mg/m² plus BMS-247550 25 mg/m²), two of two patients experienced a dose-limiting toxicity. Treatment-related toxicites included neutropenia, thrombocytopenia, neutropenic fever, hypophosphotemia, and hyponatremia. Nine of 14 patients evaluable for response had stable disease. The maximum tolerated dose for this schedule is gemcitabine 900 mg/m² over 90 min days 1 and 8 plus BMS-247550 20 mg/m² on day 8. Attempts to increase the dose of BMS-247550 by decreasing the gemcitabine dose did not sufficiently ameliorate myelosuppression. Stable disease was observed in some patients with prior taxane exposure.     

A phase I study of gemcitabine, 5-fluorouracil and leucovorin in patients with advanced, recurrent, and/or metastatic solid tumors

Introduction: This was a dose escalation phase I trial designed to establish the MTD (maximum tolerated dose) and toxicity profile of the combination of gemcitabine, leucovorin and 5-fluorouracil (5-FU).Methods: Standard eligibility criteria were required for patients with advanced malignancy to enrol. Gemcitabine was escalated from an initial dose of 800 mg/m². Gemcitabine was administered prior to leucovorin (25 mg/m²) followed by bolus 5-FU (600 mg/m²) every week for 3 weeks followed by 1 week of rest.Results: Of 21 patients enrolled, 20 were eligible for MTD determination. Patients received a median of three 4-week cycles of chemotherapy (range: 1 to 8 cycles). Toxicity was predominantly hematologic or gastroenterologic. Four dose levels were studied. At a gemcitabine dose of 1,500 mg/m² systemic symptoms of fatigue accompanied hematologic toxicity and patients refused further therapy. At 1,250 mg/m², full dose intensity was not delivered during the first cycle in 7 of 8 patients treated. Therefore, 1,000 mg/m² was established as the recommended phase II dose for gemcitabine in this study. Antitumor activity was seen at all dose levels.Conclusions: The combination of gemcitabine, leucovorin and 5-FU was tolerable at full doses of all 3 drugs with an expected toxicity profile. Recommended phase II dose for gemcitabine was 1,000 mg/m². Initial evidence of clinical activity was seen in a variety of tumor types.     

Phase I study of 17-allylamino-17 demethoxygeldanamycin,gemcitabine and/or cisplatin in patients with refractory solid tumors

Purpose: To determine the maximum tolerated dose (MTD) and characterize the dose-limiting toxicities (DLT) of 17-AAG, gemcitabine and/or cisplatin. Levels of the proteins Hsp90, Hsp70 and ILK were measured in peripheral blood mononuclear cell (PMBC) lysates to assess the effects of 17-AAG. Experimental design: Phase I dose-escalating trial using a “3 + 3” design performed in patients with advanced solid tumors. Once the MTD of gemcitabine + 17-AAG + cisplatin was determined, dose escalation of 17-AAG with constant doses of gemcitabine and cisplatin was attempted. After significant hematologic toxicity occurred, the protocol was amended to evaluate three cohorts: gemcitabine and 17-AAG; 17-AAG and cisplatin; and gemcitabine, 17-AAG and cisplatin with modified dosing. Results: The 39 patients enrolled were evaluable for toxicity and response. The MTD for cohort A was 154 mg/m² of 17-AAG, 750 mg/m² of gemcitabine, and 40 mg/m² of cisplatin. In cohort A, DLTs were observed at the higher dose level and included neutropenia, hyperbilirubinemia, dehydration, GGT elevation, hyponatremia, nausea, vomiting, and thrombocytopenia. The MTD for cohort C was 154 mg/m² of 17-AAG and 750 mg/m² of gemcitabine, with one DLT observed (alkaline phosphatase elevation) observed. In cohort C, DLTs of thrombocytopenia, fever and dyspnea were seen at the higher dose level. The remaining cohorts were closed to accrual due to toxicity. Six patients experienced partial responses. Mean Hsp90 levels were decreased and levels of Hsp70 were increased compared to baseline. Conclusions: 17-AAG in combination with gemcitabine and cisplatin demonstrated antitumor activity, but significant hematologic toxicities were encountered. 17-AAG combined with gemcitabine is tolerable and has demonstrated evidence of activity at the MTD. The recommended phase II dose is defined as 154 mg/m² of 17-AAG and 750 mg/m² of gemcitabine, and is currently being investigated in phase II studies in ovarian and pancreatic cancers. There is no recommended phase II dose for the cisplatin-containing combinations.     

Prolonged infusion of gemcitabine in advanced solid tumors: A phase-I-study

Summary Background: Gemcitabine is a pro-drug that has to be phosphorylated to gemcitabine-triphosphate in order to exhibit its antineoplastic activity. This reaction involves the enzyme deoxycytidine kinase which is saturated at plasma concentrations following standard 30-min infusions. Pharmacological studies indicate that prolonged administration of gemcitabine might result in higher intracellular concentrations of active metabolites. This phase I trial was therefore initiated to determine the optimal dose of gemcitabine administered over 4h in patients with advanced solid tumors. Patients and Methods: Patients were treated with gemcitabine as 4h-infusion on day 1, 8 and 15 in 4 week intervals. The starting dose was 350 mg/m². Doses were escalated in 50 mg/m² increments.Results: Twenty-one patients were treated at doses ranging from 350 to 450 mg/m². The maximum tolerated dose was 400 mg/m² with neutropenia, thrombocytopenia, stomatitis and elevation of liver enzymes being dose limiting toxicities (DLTs). Hematologic and nonhematological toxicities were generally mild to moderate. Most common side effects were myelosuppression, nausea, elevation of liver enzymes and asthenia. Objective responses were noted in patients with hepatocellular carcinoma and cholangio-carcinoma.Conclusion: In this phase I study of gemcitabine as 4h-infusion, DLTs were neutropenia, thrombocytopenia, stomatitis and elevation of liver enzymes. The recommended dose for phase II studies is 400 mg/m².     

Docetaxel–ifosfamide combination in patients with <Emphasis Type="Italic">HER2</Emphasis>-non-overexpressing advanced breast cancer failing prior anthracyclines

Summary The feasibility of the docetaxel–ifosfamide combination, as well as the definition of maximum tolerated doses (MTD) in a previous phase I study, led us to continue evaluating the regimen in an extended phase II study in patients with HER2-non-overexpressing, anthracycline pre-treated advanced breast cancer. Patients with histologically confirmed metastatic breast cancer failing prior anthracycline-based chemotherapy were treated with docetaxel 100 mg/m² over 1 h on day 1 followed by ifosfamide 5 g/m² divided over days 1 and 2 (2.5 g/m²/day over 1 h), and recycled every 21 days with prophylactic granulocyte-colony stimulating factor (G-CSF) administration from day 3—until a neutrophil count >10,000/μl. Between March 1999 and June 2002, 71 patients with a median age of 55 years (range, 28–72) and performance status (World Health Organization; WHO) of 1 (range, 0–2) were treated; all were assessable for toxicity and 70 patients for response. Clinical response rates (RRs), on an intention-to-treat basis were: 41/71 [58%; 95% CI, 46.5–69.5%]; 7 complete remissions (CRs), 34 partial remissions (PRs), 15 stable disease (SD) and 15 progressive disease (PD). The median response duration was 7.5 months (2–28 months), median time-to-progression (TTP) 6 months (0.1–30 months), and median overall survival (OS) 12 months (0.1–36 months). Grade 3/4 toxicities included; neutropenia in 63% of patients—with 52% developing grade 4 neutropenia (≥7 days) and in 11% of these febrile neutropenia (FN), while no grade 3/4 thrombocytopenia was observed. Other toxicities included; peripheral neuropathy grade 2 only in 7%, grade 1/2 reversible central nervous system (CNS) toxicity in 11%, no renal toxicity, grade 2 myalgias in 7%, grade 3 diarrhea in 4%, skin/nail toxicity in 11%, and grade 1/2 fluid retention in 28% of patients. The present report has demonstrated encouraging activity of the docetaxel–ifosfamide combination in anthracycline-pretreated, HER2-negative advanced breast cancer. Therefore, future randomized phase III studies versus single-agent docetaxel or currently established combinations of the latter with other agents in this setting with established clinical activity, such as capecitabine or gemcitabine, will be warranted.     

Phase I trial of mitoxantrone and granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with advanced solid malignancies

SummaryPurpose To determine the maximally tolerated dose (MTD) and pharmacokinetics of high-dose mitoxantrone and document the toxicities and side effects of mitoxantrone when administered with GM-CSF.Patients and methods Twenty-three patients with advanced solid tumors were entered into a phase I and pharmacokinetic study. Mitoxantrone was administered at doses of 12, 21, 28, 32, 37, and 48 mg/m² on day 1; GM-CSF (5 g/kg once or twice daily) was administered on days 2 to 14. Therapy was repeated every 3 weeks. Dose escalation continued in sets of three patients until the dose limiting toxicity (DLT) was observed. The DLT was based on hematologic, non-hematologic, and cardiac toxicity, and delay of therapy by more than 1 week due to toxicity. Plasma samples were assayed for mitoxantrone concentrations using high performance liquid chromatography (HPLC).Results Twelve patients required either mitoxantrone dose reductions or delays. DLT of neutropenia was observed at a mitoxantrone dose of 48 mg/m²/day. Therefore, we conclude the MTD was 37 mg/m²/day. Myelosuppression appeared to be cumulative. Two patients were withdrawn from the study due to a drop in left ventricular ejection fraction (LVEF). Two of 23 patients experienced a partial response. The mean area under the curve (AUC) and peak mitoxantrone levels increased linearly with dose; triexponential elimination of mitoxantrone was observed. No statistically significant correlation was observed between either peak mitoxantrone level or AUC and duration of absolute neutrophil count (ANC) < 500/mm³.Conclusion The use of GM-CSF allows administration of mitoxantrone at a dose greater than three times that given in standard therapy; treatment is well tolerated. Further studies are needed to determine whether mitoxantrone has cumulative cardiac or hematologic toxicity.     

Mitoxantrone as first-line chemotherapy in advanced breast cancer: results of a collaborative European study

Summary Mitoxantrone (Novantrone^®; dihydroxyanthracenedione) is a substituted anthraquinone with a spectrum of activity similar to doxorubicin in experimental tumors.One hundred and seventy three patients with advanced breast cancer and no prior cytotoxic therapy for advanced disease entered a phase II study of mitoxantrone, 14 mg/m² i.v. repeated every 3 weeks. At the time of this analysis 116 patients were evaluable. Eight patients achieved a complete response and 27 a partial response, the overall response rate being 30% (95% confidence limits: 22–39%). The median time until response was recorded was 15 weeks. The median duration of response was 74+ weeks and the median time to progression or death for all 116 patients was 22+ weeks.Mitoxantrone was well tolerated with myelosuppression as the dose-limiting toxicity. The most frequent non-haematological toxicities were nausea and vomiting (65%) but they were rarely severe. Total alopecia occurred in only 6% of the patients. Four patients developed clinically significant evidence of cardiotoxicity after cumulative mitoxantrone doses of 174–256 mg/m².Thus, mitoxantrone offers comparable efficacy and less acute toxicity than the most active single agents currently available in the treatment of advanced breast cancer.     

A phase I trial of vinorelbine in combination with mitoxantrone in patients with refractory solid tumors

Vinorelbine (Navelbine®) is a unique semi-synthetic vinca-alkaloid with a favorable safety profile that has demonstrated significant antitumor activity in patients with non-small cell lung cancer, advanced breast cancer, advanced ovarian cancer and Hodgkin's disease. The most common dose-limiting toxicity is neutropenia, while other reported toxicities are minimal. Mitoxantrone (Novantrone®) is an anthracene derivative that has demonstrated antitumor activity in patients with breast cancer, ovarian cancer, acute leukemia, and lymphoma. Mitoxantrone also has a very favorable toxicity profile with significantly less nausea and vomiting, alopecia, and stomatitis as compared with anthracyclines. The dose-limiting toxicity for mitoxantrone is leukopenia. The study was designed to determine the safety and maximally tolerated dose of IV vinorelbine used in combination with a fixed dose of mitoxantrone for the treatment of patients with refractory solid tumors. Vinorelbine was administered on days 1 and 8 of the treatment regimen as a short IV infusion. The starting dose was 15 mg/m². Mitoxantrone was administered as a 20-min infusion on day 1 only at a fixed dose of 10 mg/m². Seventeen patients with solid malignancies were entered in the study. For personal reasons, one patient decided to discontinue the treatment after day 1 of cycle 1. Therefore, 16 patients were evaluable for toxicity. The main toxicity was myelosuppression which was dose-limiting and resulted in dose reductions and delays. The use of G-CSF had a minimal overall impact on this regimen. Stable disease was observed in three cases. In patients previously treated with chemotherapy, the maximally tolerated dose was defined as vinorelbine 20 mg/m² on days 1 and 8 and mitoxantrone 10 mg/m² on day 1 without growth factor support. These doses can be recommended for phase II study of the regimen as salvage treatment.     

A phase I trial of vinorelbine in combination with mitoxantrone in patients with refractory solid tumors

Vinorelbine (Navelbine®) is a unique semi-synthetic vinca-alkaloid with a favorable safety profile that has demonstrated significant antitumor activity in patients with non-small cell lung cancer, advanced breast cancer, advanced ovarian cancer and Hodgkin's disease. The most common dose-limiting toxicity is neutropenia, while other reported toxicities are minimal. Mitoxantrone (Novantrone®) is an anthracene derivative that has demonstrated antitumor activity in patients with breast cancer, ovarian cancer, acute leukemia, and lymphoma. Mitoxantrone also has a very favorable toxicity profile with significantly less nausea and vomiting, alopecia, and stomatitis as compared with anthracyclines. The dose-limiting toxicity for mitoxantrone is leukopenia. The study was designed to determine the safety and maximally tolerated dose of IV vinorelbine used in combination with a fixed dose of mitoxantrone for the treatment of patients with refractory solid tumors. Vinorelbine was administered on days 1 and 8 of the treatment regimen as a short IV infusion. The starting dose was 15 mg/m². Mitoxantrone was administered as a 20-min infusion on day 1 only at a fixed dose of 10 mg/m². Seventeen patients with solid malignancies were entered in the study. For personal reasons, one patient decided to discontinue the treatment after day 1 of cycle 1. Therefore, 16 patients were evaluable for toxicity. The main toxicity was myelosuppression which was dose-limiting and resulted in dose reductions and delays. The use of G-CSF had a minimal overall impact on this regimen. Stable disease was observed in three cases. In patients previously treated with chemotherapy, the maximally tolerated dose was defined as vinorelbine 20 mg/m² on days 1 and 8 and mitoxantrone 10 mg/m² on day 1 without growth factor support. These doses can be recommended for phase II study of the regimen as salvage treatment.     

Phase II trial of ixabepilone,an epothilone B analog,given daily for three days every three weeks,in metastatic breast cancer

Summary Twelve patients with metastatic breast cancer previously exposed to taxanes were treated on a Phase II trial with ixabepilone. Eligible patients had histologically confirmed metastatic breast cancer with measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST), and adequate hematopoietic, renal, and hepatic function. Ixabepilone 8 mg/m²/day was given intravenously daily for 3 days for the first 3-week cycle and increased to 10 mg/m²/day for subsequent cycles if patients did not have hematologic or other toxicity after the first cycle. Patients continued treatment until progressive disease or unacceptable toxicity. Three, 29, and 33 of 65 cycles administered were at the 7 mg/m², 8 mg/m² and 10 mg/m² dose levels respectively. Grade 4 leukopenia (n=1), grade 3 neutropenia (n=2), grade 2 neuropathy (n=3), and grade 2 transaminase elevation (n=2) were the most notable toxicities. Ten patients had stable disease for at least 6 weeks. No complete or partial responses were observed in 12 evaluable patients treated with ixabepilone daily for 3 days. Although ixabepilone was well-tolerated, the dose of 8–10 mg/m² daily for 3 days is not an effective therapy in metastatic breast cancer previously exposed to taxanes.This work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health.     

Phase I/II study of gemcitabine plus vinorelbine in non-small cell lung cancer

Background: Because gemcitabine andvinorelbine have demonstrated single-agentactivity in non-small cell lung cancer(NSCLC), we conducted this phase I/II studyto determine the maximum tolerated dose(MTD) and activity of these drugs combined. Patients and methods: Patients withinoperable or advanced NSCLC and no priorchemotherapy were treated with gemcitabineplus vinorelbine on days 1 and 8 every 21days. The initial doses of gemcitabine1,000 mg/m² and vinorelbine25 mg/m² were escalated by250 mg/m² and 5 mg/m²,respectively, in separate patient cohortsuntil the MTD was established. Results: In phase I, 32 patientsreceived a total of 115 cycles. Dose-limiting toxicities were neutropeniaand hepatotoxicity, occurring at the doselevel of 1,500 mg/m² and30 mg/m². Thus, the MTD used forphase II was 1,250 mg/m² and30 mg/m². Of 41 patients in phase II,16 (39%) achieved objective responses(95% confidence interval [CI] 24% to54%), with a median time to progression of4.2 months. Overall survival was 9 months(95% CI 5.7 to 12.7 months) and the 1-yearsurvival rate was 31%. World HealthOrganization (WHO) grade 3neutropenia and reversible thrombocytosisoccurred in 15% and 65% of patients,respectively. Non-hematologic toxicity wasmild at all dose levels. Grades 3 and 4hepatotoxicity were reported in one patienteach. Conclusion: The combination of1,250 mg/m² gemcitabine and30 mg/m² vinorelbine on days 1 and 8every 21 days is well tolerated and activein patients with NSCLC. These resultsshould be confirmed in comparativestudies.     

Cisplatin plus gemcitabine on days 1 and 4 every 21 days for solid tumors: Result of a dose-intensity study

Summary Background: Three and 4-week cisplatin-gemcitabine schedules have shown similar dose-intensity (DI) and activity in non-small-cell lung cancer (NSCLC). The 3-week schedule is generally preferred because it enables better treatment compliance. To improve DI and compliance further, we delivered gemcitabine plus cisplatin over 4 days every 21 days. Methods: Patients with any stage NSCLC or epithelial neoplasms and an ECOG PS ≤2 were given gemcitabine 1000 mg/m² on days 1 and 4 plus cisplatin 70 mg/m² on day 2 of a 21-day cycle. Minimax design was used and a received DI for gemcitabine of ≥580 mg/m²/wk was considered successful. Results: Thirty-nine patients (34 NSCLC, 5 epithelial neoplasias) were enrolled. SWOG grade 3–4 neutropenia and thrombocytopenia were observed in 17.9% and 12.8% of patients, respectively. Nonhematological toxicity was minimal. Twenty-eight (18%) of 158 cycles required dose modifications and/or delays. Twenty-five patients received a gemcitabine dose intensity of ≥580 mg/m²/wk. The received DIs were 601.8 mg/m²/wk for gemcitabine and 21.0 for cisplatin, with a relative DIs of 90.3% and 90.1%, respectively. The response rate of 27 evaluable patients with NSCLC was 44% (95% confidence interval [CI], 25.3 to 62.7%). Conclusions: The shorter schedule of gemcitabine on days 1 and 4 plus cisplatin on day 2 produces an effective DI and a toxicity profile comparable to that of weekly regimens.     

Phase I study of eniluracil,oral 5-fluororacil and gemcitabine in patients with advanced malignancy

Purpose: The objectives of this trial wereto assess the maximal tolerated dose andtoxicity of the combination of oraleniluracil and 5-fluorouracil andintravenous gemcitabine. Patients and methods: Patients withhistologically confirmed, incurablemalignancy (solid tumor or lymphoma)refractory to standard therapy or for whichno standard therapy exists were enrolled. The treatment plan consisted of weeklygemcitabine for three weeks with twicedaily dosing of 5-FU and eniluracil for 21days beginning on day one of gemcitabine. Cycles repeated on an every four weekschedule. The initial cohort receivedgemcitabine 800 mg/m², oral 5-FU 0.6 mg/m²and eniluracil 6.0 mg/m². Results: Twenty-six patients were enrolled. Eight patients received less than 2 cyclesof therapy. Hematologic andgastrointestinal toxicity predominated,with 48% of courses resulted in grade oneor two neutropenia. Hematologic toxicitywas dose limiting. One treatment relateddeath occurred. Conclusions: The combination of eniluracil,5-fluorouracil and gemcitabine offers anoral alternative for 5-FU administration.The recommended phase II dose isgemcitabine 1000 mg/m², 5FU 1.2 mg/m² andeniluracil 12 mg/m².     

Phase I/II trial of dipyridamole, 5-fluorouracil,leukovorin, and mitoxantrone in metastatic breast cancer

Summary Based upon the hypothesis that dipyridamole would potentiate the cytotoxicity of mitoxantrone and the combination of 5-fluorouracil (5-FU) and leukovorin, we performed a phase I/II trial of the combination of dipyridamole, 5-FU, leukovorin, and mitoxantrone in patients with metastatic breast cancer. The dose of dipyridamole was fixed at 175 mg/m² by mouth every 6 h (700 mg/m²/day), based upon a previous phase I trial of oral dipyridamole with 5-FU and leukovorin. Dipyridamole therapy began 24 h prior to the first dose of chemotherapy and continued until 24 h after the last dose of chemotherapy for each course of treatment. At the initial dose level, leukovorin 200 mg/m² was given intravenously immediately prior to 5-FU 375 mg/ m² intravenously on days 1–5. Mitoxantrone 6 mg/m² was given as a single dose on day 3. Unacceptable toxicity was observed at this dose level, leading to successive dose decrements rather than dose increments. The maximum tolerated dose was leukovorin 200 mg/m² days 1–2, 5-FU 375 mg/m² days 1–2, mitoxantrone 6 mg/m² on day 2, and dipyridamole 175 mg/m² every 6 h on days 0–3. Two responses were produced in 15 patients. This regimen is not recommended for further investigation in the treatment of breast cancer.     

A phase I study of topotecan and gemcitabine in advanced solid tumors

Purpose Gemcitabine and topotecan are commonly used anti-tumor agents with a wide spectrum of activity in vitro and in vivo. A phase I trial of a combination of these two agents was initiated based on the premise that both gemcitabine and topotecan cause DNA damage and interfere with DNA repair by different mechanisms. Synergism has been demonstrated in vitro when gemcitabine and other topoisomerase I inhibitors have been combined. Patients and Methods Seventeen patients with advanced solid tumors signed consent and were treated on this study with at least one cycle. Treatment consisted of gemcitabine at doses of 400 to 625 mg/m² days 1 and 5 in combination with topotecan at doses of 0.8 to 1 mg/m² given on days 2 through 5 every 21 days. Results The dose limiting toxicities of granulocytopenia and thrombocytopenia were reached at the highest dose level of gemcitabine 625 mg/m² and topotecan 1 mg/m². A diffuse skin rash was also seen in four treated patients and responded well to treatment with steroids. One partial response and seven stable disease were seen as best response in 16 evaluable patients. Conclusion The combination of gemcitabine and topotecan was found to be tolerable with interesting preliminary activity. The recommended phase II dose for this combination is gemcitabine at 500 mg/m² on days 1 and 5 with topotecan at 0.8 mg/m² on days 2 to 5.     

A phase II study of mitoxantrone in advanced squamous cell cancer of the head and neck

Summary Twenty patients with advanced squamous cell carcinomas (SCC) of the head and neck were entered into a phase II study of mitoxantrone at a dosage of either 12 mg/m² or 14 mg/m² given at 3 weekly intervals. None of the patients had received prior chemotherapy. One patient had a partial remission. Two patients died from unrelated causes. One patient withdrew from the trial prior to receiving any chemotherapy. Sixteen patients either failed to respond or progressed during the course of the treatment. Side effects included nausea and vomiting in 6 patients and neutropenia in 6 patients. This study failed to detect a significant response of squamous cell carcinomas of the head and neck to mitoxantrone therapy at the described doses.     

Phase I study of a 3-drug regimen of gemcitabine/cisplatin/pemetrexed in patients with metastatic transitional cell carcinoma of the urothelium

Summary Objectives: Gemcitabine (G) plus cisplatin (C) is standard care for metastatic transitional cell carcinoma (TCC) of the urothelium. Pemetrexed (P), alone or in combination with G, is active in metastatic TCC. However, the safety and efficacy of P combined with GC therapy is unknown. This phase I trial was designed to determine the maximum tolerated dose (MTD) of GC followed by P + G in patients with metastatic TCC. Methods: Cohorts of 3 to 6 patients received escalating doses 28-day cycles (maximum 6 cycles): G 800–1,000 mg/m² on days 1 and 15; P 400–500 mg/m² on day 15; and C 50–70 mg/m² on day 1. All patients received folic acid, vitamin B₁₂, and full supportive care. The 3+3 standard phase I escalation rule was used to determine MTD. Results: Fifteen patients registered: 13/15 white males; median age 70 years (range, 53–82); 11/15 had KPS ≥ 90. At dose level 0, 2/4 patients experienced unrelated DLTs, and 1 patient was replaced (completed <1 cycle). Dose escalation proceeded to dose level 1. At level 1, 4/6 patients experienced DLTs; dosing decreased to level 0 and 4/5 patients experienced DLTs. The MTD was not determined. The 2 patients that completed 6 cycles both had partial responses. Grades 3–4 hematologic toxicities included neutropenia (60%), leukopenia (20%), and febrile neutropenia (13%). Conclusion: Adding P to the standard GC regimen as first-line therapy for metastatic TCC produced no benefit. The MTD exceeded therapeutic gemcitabine and cisplatin doses for urothelial cancer and thus the study was aborted.     

Primary systemic therapy with intermittent weekly paclitaxel plus gemcitabine in patients with stage II and III breast cancer: a phase II trial

The purpose of this study was to evaluate pathologic complete response (pCR) rates and adverse events with primary systemic therapy (PST) of intermittent weekly paclitaxel and gemcitabine in patients with stage II and III breast cancer. Node-positive patients with stage II and III breast cancer received paclitaxel 80 mg/m² followed by gemcitabine 1,200 mg/m² on day 1 and day 8, every 3 weeks for four cycles. Postoperatively, four cycles of doxorubicin 60 mg/m² and cyclophosphamide 600 mg/m² every 3 weeks were given. Of 44 enrolled patients, 73% had stage III breast cancer with 68% hormone-receptor positive and 41% HER2 positive tumors. Eight patients achieved pCR in primary tumors (18%), 11 in axillary nodes (25%), and five in both tumor and axillary nodes (11%). Breast conservation was possible in 28 patients (64%). Grade III/IV toxicities were neutropenia (57%), leukopenia (14%), febrile neutropenia (2%), and headache (2%). In conclusion, PST with intermittent weekly paclitaxel and gemcitabine in patients with stage II/III breast cancer is both well tolerated and effective, showing 18% pCR rate in the breast.     

Phase I/II study of amrubicin,a novel 9-aminoanthracycline,in patients with advanced non-small-cell lung cancer

Purpose: Amrubicin is a novel, totally synthetic 9-aminoanthracycline. The present phase I/II study was performed to define its maximum-tolerated dose (MTD), efficacy and toxicity in the treatment of previously untreated patients with advanced non-small-cell lung cancer (NSCLC). Patients and Methods: Chemonaive patients were required to have cytologically or histologically proven measurable NSCLC, an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2, and adequate organ functions. Amrubicin was administered by daily intravenous injection for 3 consecutive days every 3 weeks. Results: In a phase I study, four patients were enrolled at dose level 1 (40 mg/m²/day) and four at dose level 2 (45 mg/m²/day). No dose limiting toxicity (DLT), which was defined as toxicity consisting of grade 4 neutropenia and leukopenia lasting four days or more, and grade 3 or 4 toxicity other than neutropenia, leukopenia, anorexia, nausea/vomiting, and alopecia, was observed at these dose levels. Subsequently, at dose level 3 (50 mg/m²/day), 3 of 5 patients experienced DLTs (leukopenia, neutropenia, thrombocytopenia, or gastrointestinal complications). The MTD and recommended dose (RD) were determined to be 50 mg/m²/day and 45 mg/m²/day, respectively. Three partial responses (PRs) were achieved in 13 patients (response rate, 23.1%) in a phase I study. In a phase II study, 15 patients were assessable for efficacy and toxicity at the RD, and four PRs were obtained (response rate, 26.7%). The major toxicities were leukopenia and neutropenia, while non-hematologic toxicities were mild. The overall response rate in the combined patient population of the phase I/II study was 25.0% (7 PRs in 28 patients), with a 95% confidence interval of 10.7% to 44.9%. Conclusion: Amrubicin exerted promising antitumor activity on NSCLC with acceptable toxicity.