Phase II trial of piroxantrone in metastatic gastric adenocarcinoma

Summary Piroxantrone, a synthetic intercalating agent, was studied in patients with advanced, measurable gastric adenocarcinoma who had not received prior chemotherapy. The starting piroxantrone dose was 150 mg/m² given intravenously over 1 hour on day 1 and repeated every 21 days. Response and toxicity could be evaluated in 15 patients. No complete, partial, or minor responses were observed. Toxic effects included granulocytopenia, anemia, vomiting, nausea, anorexia, fatigue, stomatitis, alopecia, hyperbilirubinemia, and increased alkaline phosphatase levels. At the stated dose and schedule, piroxantrone does not possess significant activity against advanced gastric cancer.     

Phase II trial of piroxantrone for advanced or metastatic soft tissue sarcomas

Summary Piroxantrone is an anthrapyrazole compound undergoing phase II testing in a variety of diseases. The anthrapyrazoles are a series of compounds synthesized with the intent of maintaining the broad antitumor activity of anthracyclines, but with lessened cardiac toxicity. The Southwest Oncology Group (SWOG) conducted a phase II trial of piroxantrone in advanced soft tissue sarcoma. Treatment consisted of piroxantrone 150 mg/M² administered intravenously over 1 hour every 21 days. Twenty-five eligible patients were registered to the trial. Twenty-three patients received treatment and are fully evaluable for response and toxicity. Two partial responses were seen for an overall response rate of 9% (95% confidence limit 1%–28%). Abnormal cardiac ejection fraction occurred in five patients, and fatal congestive heart failure developed in one patient on study. Toxicities other than cardiac were tolerable. Based on the observed response rate and cardiac toxicity, further trials of piroxantrone in the treatment of soft tissue sarcoma do not appear warranted.     

Phase II trial of piroxantrone in gastric carcinoma

Summary Twenty-one evaluable patients with advanced gastric adenocarcinoma were treated with piroxantrone at a dose of 150 mg/m² intravenously every 21 days. One objective response was seen for an overall response rate of 5% (95% confidence interval 0–24%). Toxicities of grade 3 were primarily hematologie and seen in 13/21 patients. Piroxantrone has minimal activity against gastric adenocarcinoma and no further investigation of this agent on this schedule in this disease is recommended.     

Phase II trial of piroxantrone in patients with recurrent and metastatic squamous cell carcinoma of the head and neck

Summary Twenty-two patients with recurrent or metastatic squamous cell carcinoma of the head and neck were treated with piroxantrone 150 mg/m² intravenously every 21 days. There were no objective responses. The 95% upper confidence bound for response is 15%. Primary toxicity was hematologic.     

Phase II trial of doxorubicin and trifluoperazine in metastatic breast cancer

Summary Pre-clinical and clinical studies have shown that trifluoperazine (TFP) can modulate multidrug resistance. We have performed a Phase II trial of TFP and doxorubicin in doxorubicin-naive patients with metastatic breast cancer. We hypothesized that TFP would inhibit the development of doxorubicin resistance, resulting in an increased rate of complete response or a prolongation in response duration. Twenty patients with metastatic breast cancer were treated every 3 weeks with TFP 5 mg by mouth every 6 hours on days 0–5 and doxorubicin 60 mg/m²/96 hr on days 1–4 by continuous intravenous infusion. The first 5 patients were treated with TFP 15 mg by mouth every 6 hours, but the dose was reduced to 5 mg every 6 hours when grade 3–4 extrapyramidal toxicity was noted in 3 of the first 5 patients. Thereafter, neurologic toxicity was grade 0–2. No complete and 9 partial responses were produced in 20 patients (45%). The median response duration was 17 weeks (range 7–112). The combination of trifluoperazine and doxorubicin did not seem to produce a response rate or duration markedly different than that expected for doxorubicin alone in patients with metastatic breast cancer. Alternative trial designs may be necessary in future clinical trials investigating the inhibition of acquisition of drug resistance.     

Phase II evaluation of piroxantrone in renal cell carcinoma

Summary The Southwest Oncology Group (SWOG) studied the response rate and toxicity of piroxantrone (150 mg/m² q 21 days) in patients with advanced metastatic renal cell carcinoma. Among 32 eligible patients, there were no partial nor complete responses. There were two mixed responses. Significant white cell toxicity, anemia, nausea, and vomiting were observed. Mild or moderate degrees of fever, malaise, and stomatitis occurred. No significant cardiac toxicity was noted. Piroxantrone does not have significant activity as a single agent in advanced renal cell carcinoma.     

A phase II trial of piroxantrone in disseminated malignant melanoma

Summary Piroxantrone is one of the anthrapyrazoles developed in an effort to combine the broad antitumor activity of the anthracyclines with decreased myocardial toxicity. It has shown activity in metastatic melanoma during phase I trials. The Southwest Oncology Group (SWOG) conducted a phase II trial in disseminated malignant melanoma with piroxantrone administered at 150 mg/m² intravenously over 1 h every 21 days, based upon the phase I experience. Forty-six eligible patients were registered to the trial and 44 were evaluable for response. Two partial responses, Wayne of 6 and 9 months duration were observed for an overall response rate of 5% (95% confidence interval 1%–15%). Thirty-six of 46 eligible patients have died with an estimated median survival of 5 months (95% confidence interval 3–8 months). Toxicities were tolerable with granulocytopenia being the predominant toxicity. Based upon the observed response rate, it is concluded that piroxantrone administered at this dose and schedule has detectable but minimal activity, and does not warrant further investigation in this disease.     

A phase II trial of piroxantrone in adenocarcinoma of the pancreas

Summary Thirty-five evaluable patients with advanced adenocarcinoma of the pancreas were treated with piroxantrone at a dose of 150 mg/m² intravenously every 21 days. No objective responses were observed (95% confidence interval 0% –10%). Toxicities of grade 3 were primarily hematologic and were seen in 28 patients. Piroxantrone is inactive in pancreatic cancer and no further investigation of this agent in this tumor is recommended.     

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 recombinant Beta (IFN-Betaser) interferon in the treatment of metastatic breast cancer

Summary Nine patients with metastatic breast cancer received 30 × 10⁶ I.U. of Interferon — Beta_ser (Betaseron) intravenously daily times five for two consecutive weeks followed by a two week rest period. Only one patient received more than one such cycle of Betaseron. The drug was well tolerated in eight of these patients. One patient, with liver metastases and liver dysfunction, developed hepatic decompensation during therapy. Toxicity consisted of anorexia, chills, fever, fatigue and nausea with an occasional patient having emesis. One patient developed severe thrombocytopenia, two, significant leukopenia and nine, mild elevations of serum transaminase. Two patients developed beta interferon binding antibodies but none developed neutralizing antibodies. No anti-tumor responses were seen and disease progression occurred rapidly during the four week cycle in eight of nine patients.     

Phase II trial of fazarabine (ARA-AC,arabinosyl-5-azacytosine) in metastatic breast cancer

Fourteen consecutive female patients with metastatic breast cancer received a total of 31 courses of fazarabine at a dose of 2 mg/m²/hour×72 hours (48 mg/m²/day×3) as a continuous infusion. There were no responses seen, although one patient achieved stability of her disease for five courses. Because of encouragingin vitro results and the primarily hematologic dose-limiting toxicity, further study in combination with colony stimulating growth factors might be of interest.     

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 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.     

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 teniposide (VM-26) in metastatic breast carcinoma

The Southeastern Cancer Study Group performed a Phase II study of teniposide in previously treated patients with metastatic breast cancer. No responses were observed in 11 evaluable patients who received teniposide 60 mg/m² by IV infusion for five consecutive days every three weeks. Toxicity was primarily gastrointestinal and hematologic and was frequently severe. This study demonstrated no therapeutic activity for teniposide when given in this dose and schedule to patients with heavily pretreated metastatic breast cancer.     

Phase II study of a combination of elliptinium and vinblastine in metastatic breast cancer

Thirty nine patients with metastatic breast cancer, all previously treated with chemotherapy including anthracycline, were given Elliptinium acetate (80 mg/m²/day) and a continous infusion of Vinblastine (2 mg/m²day) for 3 consecutive days every 4 weeks. Twenty nine patients had measurable metastatic disease. Nine (31%) achieved a partial response. No complete response was observed. Median duration of response was 6 months. The response rate was dependent on the number of metastatic sites and independent of the number of previous chemotherapy regimes. Side effects were dry mouth (27 patients), vomiting (9), neutropenia (3 patients with grade IV, 2 with grade III), muscle cramps (5) and thrombosis (3). Xerostomia and vomiting contributed to weight loss and fatigue (8 patients). We conclude that Elliptinium-Vinblastine combination has moderate activity as second line treatment in metastatic breast cancer. This combination causes xerostomia and fatigue with moderate myelosuppression.     

Phase II trial of edatrexate in patients with metastatic colorectal cancer

Summary Edatrexate is an analog of methotrexate whichin vitro demonstrated activity against human colon cancer xenografts grown in nude mice. In a phase II trial, 12 patients with metastatic colorectal cancer and no prior chemotherapy were treated with Edatrexate 80 mg/m²/week for an initial period of 8 weeks. No objective responses were observed. Edatrexate is inactive against colon cancer at the dose and schedule used in this trial.     

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 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.     

Emerging drugs in metastatic breast cancer

Background: Breast cancer is the most common cancer among women and comprises 26% of all cancers diagnosed in women in the United States. Among presenting patients, 3 – 6% already have metastatic disease, and 50 – 70% of the remaining patients develop systemic relapse. Recently many new drugs, particularly molecular targeted therapies, have been developed in the field. Objective: To review the current and emerging data on the treatment of metastatic breast cancer, with emphasis on novel therapies that show promise. Methods: PubMed and ASCO annual meeting abstracts were used for a literature search. Results/conclusions: Despite improved response rates, conventional treatments still result only in transient remission in most cases. New therapeutic alternatives and new strategies to overcome drug resistance are needed to improve these results.