Phase II trial of echinomycin in advanced soft tissue sarcomas

Summary Thirty-four patients with advanced soft tissue sarcomas were entered in a phase II trial of echinomycin. Patients received 1.2 mg/m² intravenously (i.v.) weekly times four followed by a two week rest period. There were no objective responses. Dose limiting toxicity was gastrointestinal. Echinomycin given on this weekly schedule is inactive in treating previously treated patients with advanced soft tissue sarcomas.Southwest Oncology Group (SWOG-8505), Operations Office, 5430 Fredericksburg Road, Suite #618, San Antonio, TX 78229-6197, USA     

Elliptinium: Phase II study in advanced measurable breast cancer

Summary Eighteen patients with advanced measurable breast cancer were treated with elliptinium acetate 100 mg/m² × 3 days every 3 weeks. Fourteen of these patients had failed prior chemotherapy. Two patients had an objective tumor response of greater than 4 weeks. Myelosuppression, renal insufficiency and thrombophlebitis were rarely encountered and alopecia was not seen at all. This study demonstrates that elliptinium has minimal activity in recurrent breast cancer with a favorable toxicity profile.     

Phase II study of ionidamine in patients with metastatic breast cancer

Summary The Eastern Cooperative Oncology Group conducted a phase II study of lonidamine in patients with metastatic breast cancer. The drug was given orally to a maximum daily dose of 340 mg/m². Forty-two patients were entered on study. One partial response was observed; there were no life-threatening toxicities. The results of this study are compared to two similar phase II trials.Other participating institutions include: Fox Chase Cancer Center, Philadelphia, PA (CA-18281); Medical College of Ohio, Toledo, OH; Rush-Presbyterian-St. Luke's Medical Center, Chicago, IL (CA-25988), Evanston Hospital (CCOP), Evanston, IL.     

Phase II trial of echinomycin for the treatment of advanced renal cell carcinoma

Summary Forty-nine patients with metastatic or recurrent renal cell carcinoma were treated on a phase II trial of Echinomycin. Treatment consisted of Echinomycin 1.25 mg/m² intravenously every 28 days. Among the 47 evaluable patients there were no complete responses and only one partial response for an overall response rate of 2% (95% confidence interval, 0–11%). Eighteen patients (38%) experienced toxicity of grade 3 or worse. The most common toxicities were nausea and vomiting. The results of this study indicate that Echinomycin is not sufficiently active to warrant further trials for the treatment of renal cell carcinoma.     

Phase II trial with oral idarubicin in advanced breast cancer

Summary Idarubicin, a new analogue of daunorubicin, was administered to 27 patients with advanced breast cancer in a phase II trial. The drug was given orally at a dose of 30–35 mg/m² every 3 weeks. Twenty-two patients were evaluable for response. All evaluable patients were previously treated with one or more chemotherapeutic regimens, including an anthracycline in more than 50% of the cases. Partial remissions were obtained in 5 patients, for a response rate of 23%. The median duration of response was 191 days. Mild nausea and vomiting were common. Diarrhea, which occurred in less than 50% of the patients, was usually short-lived. Alopecia was generally minimal. Myelosuppression was the dose-limiting toxic effect. Leukopenia was frequently seen, with full recovery by day 28 in 81 % of the courses. Thrombocytopenia was less common than leukopenia. Four cases of grade 1 acute cardiac toxicity were recorded. This study suggests that idarubicin can induce regressions in advanced carcinoma of the breast, and justifies further studies in combination with other agents.     

Phase II trial of dolastatin-10 in patients with advanced breast cancer

Summary Purpose: Phase II multicenter cooperative group study investigated the efficacy and toxicity of the novel anti-microtubule agent dolastatin-10 in patients with advanced breast cancer.Patient and methods: Twenty-one patients with measurable metastatic breast cancer were treated with dolastatin-10 at a dose of 400 mcg/m² by intravenous bolus once every 3 weeks. Patients must have received a total of 1 or 2 prior chemotherapy regimens and have an Eastern Cooperative Oncology Group performance status of 0–2. Patients received this treatment as either a first (n = 11) or second-line (n = 10) chemotherapy for metastatic disease. Eighteen patients (86%) had received a prior anthracycline. The National Cancer Institute provided the dolastatin-10.Results: One out of 21 patients (5%; 95% CI: 0–24%) achieved a partial remission for a duration of 113 days. Four patients maintained stable disease for a median of 87 days. A total of 58 courses of dolastatin-10 were administered. Patients received a median of two cycles of dolastatin-10. Hematologic toxicity was moderate, with 8 patients developing grade 4 neutropenia, and 5 with grade 3 neutropenia; one grade 3 febrile neutropenia was observed. These episodes of grade 3 and 4 neutropenia were experienced on 36% of the treatment cycles. Non-hematologic toxicity was uncommon.Conclusion: While the toxicity profile of dolastatin-10 was acceptable, it had minimal activity in this advanced breast cancer study. We are not pursuing further clinical trials of this agent in the setting of advanced breast cancer.     

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.     

Phase II study of echinomycin in the treatment of renal cell carcinoma ECOG study E2885

Summary Seventeen patients were treated with echinomycin for metastatic renal cell carcinoma. Echinomycin is a bifunctional DNA intercalating agent with broad preclinical antitumor activity. It was given at 1200 mg/m² by intravenous infusion over 30–60 min weekly for 4 weeks. The treatment was repeated every 6 weeks. There were no responses observed in the study. No life threatening or lethal toxicity was documented in 13 eligible patients. The median survival of these patients was 13.7 months. We conclude that echinomycin is not active against metastatic renal cell carcinoma at the dose and schedule tested.     

Phase II study of vincristine,mitomycin-C and mitoxantrone in advanced breast cancer: a preliminary report of response and toxicity

Summary Nineteen patients with advanced, previously treated breast cancer received treatment with vincristine 2 mg i.v., mitomycin-C 6 mg/m² and mitoxantrone (Novantrone®; dihydroxyanthracenedione) 12 mg/m² i.v. every three weeks. Thirteen patients are evaluable for response and toxicity. Partial remission was seen in six patients, with soft tissue, bone and visceral metastases and static disease in a further four patients. Median duration of response has not yet been reached (8+ months). Toxicity was mild and predictable, with no patient experiencing severe nausea and vomiting, and only four of the patients requiring a wig for alopecia. Malaise and lethargy were common in those patients receiving more than three courses, and an increase in the mean corpuscular volume (MCV) together with a fall in haemoglobin were seen in patients receiving multiple courses of treatment. The study suggests that this combination is active, and may prove useful with other agents in the treatment of breast cancer.     

Phase II study of mitozolomide (M & B 39,565) in colorectal and breast cancer

Summary Twenty-two patients with advanced colorectal cancer (CRC) (12 without prior chemotherapy) and fourteen with pretreated breast cancer (BC) were given mitozolomide (MTZ), IV infusion, every six weeks. The starting dose was 90 mg/m². When it was well-tolerated, dose escalation was done up to 100–115 mg/m². Toxicity was mild, limited to thrombocytopenia with a median nadir of 1.27 × 10⁵ (0.20–4.86). No response was observed in these patients. MTZ, according to these schedule and dosage, does not show activity in human CRC and pretreated BC.     

Phase I–II study of high-dose etoposide in patients with refractory breast cancer

Address for offprints: G. Fraschini, The University of Texas M.D. Anderson Cancer Center, Box 56, 1515 Holcombe Boulevard, Houston, TX, 77030, USA     

Phase II study of flutamide in patients with metastatic breast cancer. A National Cancer Institute of Canada Clinical Trials Group study

Summary The National Cancer Institute of Canada (NCIC) Clinical Trials Group conducted a phase II study of the oral antiandrogen flutamide in 33 patients with metastatic breast cancer. Eight patients had received no prior systemic therapy for their metastatic disease and 13 had only one site of metastasis. Toxicity occurred in 18 of the 33 patients and was primarily gastrointestinal. It ranged in severity from mild to severe with 4 patients discontinuing treatment early because of nausea, vomiting, diarrhea or stomatitis. One response, of 8 weeks duration, was noted in 29 evaluable patients. We conclude that flutamide does not have meaningful anti-tumour activity in breast cancer and plan no further trials of the drug in this disease.     

Phase II study of didemnin B in advanced colorectal cancer

Summary Didemnin B is a depsipeptide derived from a Caribbean tunicate (sea squirt) that has demonstrated antineoplastic activity against a variety of murine tumor models, including the L1210 and P388 leukemia, the B16 melanoma, and M5076 sarcoma cell lines. Based on these data, we designed a phase II trial in which 15 patients with measureable, unresectable colorectal cancer were treated with Didemnin B at an initial dosage of 3.47 mg/m² over 30 minutes administered by intravenous infusion every 28 days; the dosage was altered in accordance with the toxicity observed, with only one patient requiring a dosage reduction for pronounced nausea and vomiting. No hematologie or nonhematologic toxicity developed. No complete or partial responses were observed. These results do not compare favorably with results of treatments using other single agents or combinations that are currently available for the treatment of advanced colorectal cancers. However, because of the tolerable levels of toxicity experienced by in our patients, it is possible that an insufficient dose of the medication was delivered. We concluded that Didemnin B is not active against of colorectal cancers at the dosage and schedule at which it was administered in this study.     

A phase II clinical trial of echinomycin in metastatic soft tissue sarcoma

Summary Echinomycin, a cyclic peptide in the family of quinoxaline antibiotics, was evaluated in patients with metastatic, soft tissue sarcoma not previously treated for metastatic disease. The starting dose of echinomycin was 1,200 mcg/m² administered intravenously, once weekly × 4, followed by a two-week break. The protocol design called for dose escalation on subsequent cycles of therapy, but because of significant toxicity, dose escalation occurred in only 5 of 25 treatment cycles. Severe nausea and vomiting was the most common toxicity. No clinical responses were observed in the 12 evaluable patients. Echinomycin at this dose and schedule is inactive in metastatic soft tissue sarcoma.     

Phase II study of Fenretinide (N-[4-Hydroxyphenyl]retinamide) in advanced breast cancer and melanoma

Summary Retinoids, the natural and synthetic analogs of vitamin A, are growth-inhibiting and differentiation-inducing agents and show clinical promise as chemopreventive and antineoplastic agents. Fenretinide, a new synthetic retinoid, has antitumor activity in certain in vitro and in vivo model systems and was relatively nontoxic in phase I trials. Based on these data, we designed a phase II study of Fenretinide involving 31 patients with advanced breast cancer [15] and melanoma [16], two cancers shown to be responsive to this agent in preclinical models. Fenretinide was inactive in patients with advanced disease. Toxicity was mild, and reversible. Mucocutaneous side effects occurred in 16 (52%) patients. Nyctalopia developed in three patients one of whom developed decreased B-wave amplitude of the scotopic electroretinogram. The minimal toxicity and significant activity in preclinical studies make this an attractive agent for future breast cancer chemoprevention studies.     

Phase II trial of trimetrexate in advanced esophageal cancer: A southwest oncology group study

Trimetrexate (TMQ) is a synthetic folate antagonist that has demonstrated non-cross resistance with methotrexate in preclinical screens. A phase II trial was performed with TMQ given to patients with advanced squamous cell carcinoma of the esophagus. TMQ was administered as an i.v. bolus on a daily × 5 schedule, every 3 weeks; a starting dose of 12 mg/m² was used for patients with no prior irradiation, and of 8 mg/m² for patients with prior irradiation. Twenty-four patients were entered onto study, with 23 patients eligible, and a median of 2 courses of TMQ administered per patient. Twenty-three patients were evaluable for toxicity. Toxicities of SWOG grade 3 included granulocytopenia (9 patients), leukopenia (7 patients), thrombocytopenia (4 patients), anemia (3 patients), mucositis (3 patients), nausea and vomiting (2 patients), dermatitis (1 patient), diarrhea (1 patient), and fever (1 patient). Fifteen patients had some hematologic toxicity, and eleven patients had hematologic toxicity of grade 3. Two treatment related deaths occurred in association with myelosuppression. One patient achieved a complete response and one patient achieved a partial response, with response durations of 8.5 months and 6 months, respectively. The overall response rate was 8% [95% confidence interval of 1 to 28%], with a median survival for the 23 eligible patients of 5.1 months.     

Recombinant gamma interferon in advanced breast cancer: A phase II trial

Fifteen patients with advanced carcinoma of the breast who had failed prior chemotherapy, were treated with recombinant gamma interferon at a dose of 2mg/m² (1mg = 2.4 × 10⁷ international units) intravenously for five consecutive days every other week. The median patient age was 51 and all patients had a performance status of 0–2 (Karnofsky 50). Thirteen patients had two or three sites of metastatic disease and seven were estrogen receptor positive. No complete or partial responses were noted. Although some patients had brief periods of stable disease, almost all patients progressed after one or two courses. Only one patient was able to receive six courses of induction therapy and a brief course of maintenance. Flu-like symptoms and nausea were seen in all patients; vomiting and anorexia were frequent. Hepatic toxicity manifested by enzyme elevation was common and was most severe in patients with liver metastases. In this study a highly purified biologically active gamma interferon was not associated with anti-tumor activity in previously treated women with metastatic breast cancer.