Phase II study of vindesine in patients with advanced breast cancer

Vindesine, a new vinca alkaloid, was administered to 20 patients with advanced refractory breast cancer in a phase II trial. The drug was given at a dose of 3 mg/m2 by iv bolus each week for 6 consecutive weeks, and responding patients were maintained on a dose of 4 mg/m2 every 2 weeks. Nineteen patients were evaluable for disease response; partial remissions were obtained in five patients, for a response rate of 26%. Leukopenia was the major dose-limiting toxic reaction, but most patients were able to tolerate this schedule without difficulty. Neurotoxicity was mild and did not require dose reduction.     

Phase II trial of retinol in patients with advanced cancer

We have completed a phase II trial of oral retinol (200,000 units/m2) in 65 patients with advanced cancer. All patients were followed at 4-week intervals for tumor response and clinical or chemical evidence of toxicity. Seventeen patients had non-small cell lung cancer, 15 had melanoma, 12 had adenocarcinoma of the colon, and 17 had miscellaneous tumors. There were one partial response, five mixed responses, two patients with stable disease, and 47 patients with progressive disease. Thirty-seven of 60 patients reported no side effects; 13 developed mild cutaneous symptoms; and 12 developed reversible central nervous system symptomatology. Oral retinol appears to have limited activity in patients with advanced cancer.     

Phase II study of tamoxifen and high-dose retinyl acetate in patients with advanced breast cancer

Summary Retinoids have shown a tumor growth inhibition and a synergistic activity with hormonal manipulations in human breast cancer cell lines and rat mammary carcinoma. To investigate the potential usefulness of this synergistic activity in human breast cancer, 33 postmenopausal patients with advanced disease were treated with the combination of tamoxifen (10 mg p.o. three times a day) and retinyl acetate (300 000 IU p.o. daily). Out of 31 evaluable patients, 3 achieved complete response, 9 partial response (overall response rate: 38.5%, 95% confidence interval=21%–56%) and 16 (52%) showed no change. The median duration of response was 11.5 months (range: 3–19+months), while the 2-year overall survival rate for the entire group of patients was 63%. Toxicity was generally mild, hot flushes, nausea (and/or vomiting), headache and cutaneous itching being the most frequent side-effects. Only 1 patient discontinued treatment for severe toxicity. These preliminary results suggest that the combination of tamoxifen and high-dose retinyl acetate is a safe and effective regimen for breast cancer patients. However, the study design does not allow us to establish whether the very low rate of early disease progression we observed might be related to a possible synergistic effect between retinoids and antiestrogens or rather to the quite indolent disease of the patients who have been selected for entry into this trial.     

Phase I study of N-methylformamide in patients with advanced cancer

N-Methylformamide (N-MF) belongs to a class of polar-planar compounds which induce cellular differentiation. Preclinical antitumor activity was demonstrated against human mammary, colon, and lung tumor xenografts and L1210 and P388 murine leukemias. This phase I study used a single bolus infusion of N-MF given weekly X 3 doses every 6 weeks. Thirty-five patients were treated with N-MF at doses which ranged from 125 to 3125 mg/m2/week. The dose-limiting toxic effects included nausea and vomiting, anorexia, malaise, and liver function abnormalities. No myelosuppression was seen. The recommended dose for phase II trials of N-MF with this schedule is to initiate therapy at 2000 mg/m2 weekly X 3 and escalate to 2500 mg/m2 if the initial dose was well tolerated.     

Phase II study of elliptinium in advanced breast cancer

A group of 74 patients with advanced breast cancer received elliptinium as second- or third-line treatment (100 mg/m2/week). The objective response rate was 19% (30% in soft tissue metastases), lasting from 3 to 12 months. This drug appears to have no marrow toxicity. Mild to moderate nausea and mouth dryness were the most frequently encountered side effects. Hemolysis occurred in five patients who had an IgM antibody and represents the dose-limiting toxicity. Cumulative renal toxicity (World Health Organization, grade 2) was observed in one of ten patients who had received greater than 2000 mg of elliptinium.     

Phase II study of high dose epirubicin in combination with cyclophosphamide in patients with advanced breast cancer

Abstract Background: Combination chemotherapy for metastatic breast cancer will palliate symptoms in the majority of patients but only a small percentage will have prolonged survival. Higher doses of doxorubicin lead to increased response rates in breast cancer and early studies have shown that epirubicin could be tolerated in higher doses with less relative toxicity than doxorubicin. Aims: This study was initiated to assess the dose of epirubicin that could be tolerated by escalating its dose while maintaining a fixed dose of cyclophosphamide. Simultaneously tumour response rate, spectrum of toxicities, duration of response and overall survival in patients with metastatic breast cancer were assessed. Methods: Patients with metastatic breast cancer commenced chemotherapy with a starting dose of epirubicin of 120 milligram per metre squared (mg/m²) and cyclophosphamide 600 mg/m². The dose of epirubicin was to be escalated or reduced depending on toxicity. Results: Forty female patients were entered into this study and three patients withdrew because of toxicity. Overall tumour response rate was 75% with 27.5% of patients obtaining a complete response. Median time to progressive disease was 35 weeks and median overall survival was 48 weeks, with median survival for complete responders being 103 weeks. Thirty-one (77%) patients completed five or more courses of treatment. Haematological toxicity was the main side effect and 70% of patients required a dose reduction. No patients were eligible for a dose escalation. One patient died as a consequence of neutropenic sepsis. Four (10%) patients had treatment ceased because of decrease in left ventricular ejection fraction and one patient died as a consequence of heart failure. Four patients remain alive. Conclusions: High dose epirubicin combined with cyclophosphamide is an effective treatment regimen for metastatic breast cancer obtaining higher overall response rates with increased percentage complete responses compared to conventional dose chemotherapy. Although toxicity was increased, high dose chemotherapy was well tolerated and mortality associated with treatment was not increased. No dose escalations of epirubicin were possible and a dose of 90mg/m² of epirubicin would be the maximum dose when used in combination with cyclophosphamide. Further trials are required to determine the influence of this high dose therapy on survival duration and whether comparable benefits can be achieved with shorter durations of therapy. (Aust NZ J Med 1995; 25: 474–478.)     

Phase II trial of 4'-deoxydoxorubicin in patients with advanced breast cancer

4'Deoxydoxorubicin (25 mg/m2 iv every 3 weeks) was evaluated in 20 patients with advanced breast cancer. The patients had good performance status and had not been heavily pretreated. Although all patients experienced leukopenia, no major therapeutic responses were observed. Nonhematologic toxicity was mild. Further evaluation of 4'-deoxydoxorubicin at this dose and schedule is not warranted in patients with advanced breast cancer.     

Phase II evaluation of bleomycin in patients with advanced epithelial ovarian cancer

Twenty-four patients received bleomycin twice weekly im. Treatment was given for 3 weeks initially, and if there was no evidence of disease progression treatment was given for another 3 weeks. Four patients had partial responses of 2, 4, 4, and 5 months' duration. Three patients had stable disease which did not progress for at least 4 months. There were ten patients with ascites; three of these showed a significant reduction in the amount of ascites present during treatment. There was a partial reduction of tumor in one of these patients. Toxicity was minimal with this regimen, and bleomycin deserves further study in the treatment of ovarian cancer.     

Phase II study of anguidine in advanced breast cancer.

A phase II evaluation of anguidine was carried out in 30 patients with advanced refractory breast cancer. A dose of 5.0 mg/m2 daily for 5 days was explored. The main toxic effects were nausea and vomiting, fever and chills, hypotension, skin erythema, somnolence, confusion, and lethargy. Myelosuppression was minimal. Among these extensively pretreated patients, there was one partial responder and one additional patient who showed improvement (less than a partial response); both responses occurred in soft tissue sites.     

Phase II study of sirolimus in treatment-naive patients with advanced hepatocellular carcinoma

BackgroundRapalogs are emerging as promising targeted anticancer drugs. Activation of the PI3K/Akt/mTOR pathway has been observed in 15–50% of hepatocellular carcinomas.MethodsIn this phase II study, patients with advanced hepatocellular carcinoma and underlying cirrhosis received sirolimus (20 mg/week for 1 month then 30 mg/week). Tumour response was assessed every 8 weeks. The primary endpoint was the objective tumour response rate according to the Response Evaluation Criteria in Solid Tumours criteria. Secondary endpoints included the objective response according to the modified Response Evaluation Criteria in Solid Tumours criteria, safety, and pharmacokinetic parameters.ResultsTwenty-five patients received sirolimus for a median of 20.6 weeks. Two patients had an objective response (8%, 95CI: 0.98–26.03), including one complete response, and 8 patients had stable disease. There were 2 cases of grade 5 toxicity (infections) and 5 cases of grade 3 toxicity. The main grade 1/2 toxicity was mild transient fatigue (76%). Median time to radiological progression and overall survival were 15.3 weeks (range: 8.2–173.9) and 26.4 weeks (range: 8.2–173.9) respectively. Use of the modified Response Evaluation Criteria in Solid Tumours criteria did not identify any further responders.ConclusionThese data suggest that first-line sirolimus shows antitumoural efficacy in advanced hepatocellular carcinoma. Larger trials with Child A patients are needed.