Phase I study of VRCTC-310, a purified phospholipase A2 purified from snake venom, in patients with refractory cancer: safety and pharmacokinetic data.

A phase I study was performed to evaluate the maximum tolerated dose (MTD), safety profile and pharmacokinetic data with VRCTC-310, a natural product derived from purified snake venom fractions, with phospholipase A2 activity and inhibitory effects against human and murine tumor cell lines. Fifteen patients with refractory malignancies were entered after providing written informed consent. VRCTC-310 was administered as an intramuscular injection daily for 30 consecutive days. Doses were escalated from 0.0025 to 0.023 mg/kg. Toxicities included local pain at the injection site, eosinophilia, reversible diplopia and palpebral ptosis. Dose escalation was stopped at 0.023 mg/kg, when two patients had developed anaphylactoid reactions. Both cases had high VRCTC-310-specific IgG by EIA. MTD was 0.017 mg/kg and the recommended dose for phase II studies is 0.017 mg/kg. Stabilization was found in six patients.

Treatment of non-small cell lung cancer with ifosfamide (IFO)+ 4'-epiadriamycin (EPI)+platinum vs. IFO+EPI: a GETLAC Study. Grupo de Estudio y Tratamiento Latinoamericano del Cáncer Study.

203 patients with inoperable non-small cell lung cancer (NSCLC) were randomized to receive ifosfamide (IFO) 2.5 g/m2 days 1-2 + epirubicin (EPI) 70 mg/m2 day 1 with cisplatin (DDP) 70 mg/m2 day 1 (arm IEP), or without cisplatin (arm IE). For uroprophylaxis, mesna i.v. 20% of IFO dose, hour 0 and 3, and oral, 40% of IFO dose, hour 6 and 9, days 1-2 was given. Cycles were repeated every 28 days. Four cycles were required for evaluation purposes. After completion of chemotherapy, external beam irradiation 40 Gy was given over 4 weeks for stage III B responders. Most of the patients with stable disease, partial response or complete response (CR) received 6 cycles. The median follow-up of the trial is 30 months. There were no differences in overall response rates: arm IEP: 52% (2% CR); arm IE: 51% (13.5% CR). Median time to progression was 6 months (arm IEP) and 4 months (arm IE) (p = 0.4844). Toxicity ranged from mild to moderate. Nephrotoxicity was not seen; only 6 patients had neurotoxic side effects of short duration. Median survival according to treatment was 12 months for IEP arm (12% at 2 years) and 10 months for IE arm (21% at 2 years). IFO/mesna+EPI or IFO/mesna, EPI plus DDP appeared to be an active and well tolerated combination for the treatment of NSCLC, with a good survival time.

Cisplatin and ifosfamide in patients with advanced squamous cell carcinoma of the uterine cervix. A phase II trial.

Thirty patients with advanced squamous cell carcinoma of the cervix were included in a phase II study with cisplatin (DDP) and ifosfamide (IF)/mesna. They received a median of 4 courses of chemotherapy and were all evaluable for response and toxicity. Each cycle consisted of 2,500 mg/m2 IF i.v. days 1-5; mesna 500 mg/m2 i.v. at hours 0 and 2, and 1,000 mg/m2 per os at hours 6 and 10, days 1-5; DDP 20 mg/m2 i.v., days 1-5. Cycles were repeated every 4 weeks. One patient obtained CR and 14 PR giving an overall response rate of 50%. Mean duration of response was 21 months. Anemia grade 3 developed in 7 patients, leukopenia grade 3 in 9 patients and grade 4 in one patient; thrombopenia grade 3 in 2; creatinine clearance grade 3 in one; CNS grade 3 in one and cystitis grade 3 in one patient. Overall median survival time was about 25+ months (3-63+); after a follow-up of 70 months, 11 patients (37%) are still alive with a median survival of 31+ months. IF plus DDP seems to be a good combination for treatment of advanced cervical cancer, with acceptable tolerance and response rate.

Chemotherapy with high dose ifosfamide/mesna plus cisplatin for the treatment of ovarian cancer: a study of the Grupo de Estudio y Tratamiento Latino-Americano del Cancer.

Twenty-one evaluable patients with FIGO stages II-IV epithelial ovarian cancer, median age 57 (range 47-75 years), were treated with ifosfamide (IF), 3 g/m2 diluted in 500 ml saline solution, 8 hour intravenous (i.v.) infusion on days 1-5; mesna 20% of IF dose, i.v. bolus injection, was given at hours 0 and 4; mesna 40% of IF dose by oral route at hours 8 and 12, days 1-5; plus cisplatin 20 mg/m2 diluted in 500 ml saline solution, 2 hour i.v. infusion, days 1-5. Cycles were repeated every 4 weeks. All patients had metastatic lesions (mesentery, pleura, colon, cervix, abdominal wall, lung, liver, bladder, and nodes). Toxicity ranged from mild to moderate. All patients experienced alopecia, nausea, and vomiting. Neutropenia and anemia ranged from mild to moderate. One patient experienced mild brain confusion and two patients microscopic hematuria. Ten clinically complete responses (47%) and five clinically partial responses (23%) were registered, for an overall 70% objective response. However, after a second look performance in 10 patients with clinically complete response, six of 10 patients showed a pathological complete response and four showed pathological partial response. The median duration of complete response is about 33 months, and median partial response duration is 14 months. Although the numbers are small, these data indicate that combination chemotherapy with high dose ifosfamide/mesna plus cisplatin may be an active treatment for advanced ovarian carcinoma.

Ifosfamide and mesna for the treatment of advanced squamous cell head and neck cancer. A GETLAC study.

High-dose ifosfamide/mesna was administrated to 28 mostly pretreated patients with locally advanced and metastatic head and neck cancer who failed conventional surgery/radiation treatment. Primary sites include tongue (5), salivary gland (3), floor of mouth (5), oropharynx (2), hypopharynx (5) and larynx (8). The dose and schedule of ifosfamide (IF) was 3.5 g/m2 8 h, i.v. infusion, days 1-5, every 28 days, and mesna was given as 20% of IF dose intravenous bolus injection at 0, 2, 4, 6 and 8 h; mesna 40% of IF dose was given by oral route at 10 and 12 h, days 1-5, every 28 days. All patients were evaluable for both toxicity and response. 14 patients had received prior treatment with surgery plus radiation therapy and 14 patients radiation therapy. Following chemotherapy, 4 patients (14.2%) achieved complete remission and 8 patients (28.5%) achieved partial remission, with an overall response rate of 42.7%. Toxicity was reported for 186 cycles and ranged from mild to moderate: anemia 4, leukopenia 6, thrombopenia 1, nausea and vomiting 12, alopecia 28, microscopic hematuria 3, increased transaminase 1. No CNS symptoms and renal toxicity were registered. Median duration of survival is 11+ months (range 3+ to 18+ months). Nine patients died. We conclude that ifosfamide/mesna at this dose and schedule has a significant activity in recurrent head and neck cancer, and produces minimal toxicity.

Combined hormonal therapy with high-dose diethylstilbestrol diphosphate (DES-DP) intravenous infusion plus vindesine (VND) for the treatment of advanced prostatic carcinoma: a controlled study.

Fifty-one patients with stage D prostate cancer, who had failed primary hormone treatment, were treated with diethylstilbestrol diphosphate (DES-DP) 1.5 g 24 hr intravenous infusion from day 1 to day 7 (group A). In group B, patients were treated with DES-DP as in A, plus vindesine (VND) 3 mg/m2 intravenously on days 8, 15, and 22. Cycles were repeated every 28 days for six consecutive cycles. All 51 patients were evaluable for response, toxicity, time to progression, and survival. Pretreatment clinical and laboratory characteristics were comparable. The National Prostatic Cancer Project Criteria were used for evaluation. A minimum of two cycles were required for evaluation of response. No complete response was seen. In group A, 9 "partial response" and 7 "no change" (80%), and in group B, 11 "partial response" and 12 "no change" (74%) were registered. Median survival time was 40 weeks. Toxicity ranged from mild to moderate. DES-DP + VND seemed to improve duration of objective response compared to DES-DP alone, but the difference was not significant.

Ifosfamide and mesna at high doses for the treatment of cancer of the cervix: a GETLAC study.

This study was carried out to assess the efficacy of high-dose ifosfamide/mesna (HDIFM) in the treatment of advanced or recurrent cancer of the cervix. In all, 18/21 evaluable patients with advanced or inoperable cervical cancer were included. The mean age was 42 years (range, 31-58 years); and the International Federation of Gynecology and Obstetrics (FIGO) stage was III in 10 patients and IV in 11. The Karnofsky performance status ranged between 70 and 90, with a median of 77. Ten patients had previously been treated with surgery, radium and cobalt (8) or cobalt alone (2). Therapy consisted of 3.5 g/m2, ifosfamide (IFO) given in an 8-h i.v. infusion on days 1-5 and mesna at 20% of the IFO dose, given i.v. at 0, 2, 4, 6 and 8 h, followed by mesna at 40% of the IFO dose by the oral route at 10 and 12 h on days 1-5. For evaluation purposes, patients received at least two cycles. Toxicity was registered in 137 cycles and was mild to moderate. Three complete (16.6%) and six partial (33.3%) responses were observed (50%), but 66% of them occurred in areas that had not previously been irradiated. The median duration of response was 14 months and the overall median survival was 15+ months (18+ months for responders). The Karnofsky scale after treatment ranged from 90 to 100. The results of this study indicate that HDIFM is well tolerated, giving a high percentage of remission (50%) and significantly improving the quality of life.

Sequential versus alternating regimens in the treatment of advanced breast cancer. Argentine Breast Cancer Cooperative Group.

With the object of proving whether sequential or alternate forms of chemotherapy would be advantageous one over the other in treating advanced breast cancer and with the purpose of evaluating two different anthracyclines at equimolecular doses in the above-mentioned alternating regimens, 250 patients who had received no prior chemo- or hormonotherapy were entered in a prospective randomized trial. Group A was administered 4-epiadriamycin and cyclophosphamide for 8 courses, followed by 6 cycles of CMF, and medroxyprogesterone acetate (MPA) from the beginning of therapy until progression. In group B, adriamycin + cyclophosphamide were alternated with CMF every two courses until 14 cycles were completed. Group C received 4'-epiadriamycin + cyclophosphamide alternated with CMF for 14 courses. In groups B and C, MPA was administered as in group A. Two hundred and twenty-four patients were evaluated. CR + PR were observed in 55.8% of group A, 43.4% of group B, and 46.4% of group C. Median duration of responses was 16 months (m) in group A, 13 m in group B and 20 m in group C, and median survival (CR + PR) was 16.5 m in group A, 16 m in group B and 24 m in group C. There were no statistically significant differences among the three groups in terms of response rate, duration of response and survival; furthermore, toxicity was moderate in all groups. At equimolecular doses there were no differences between adriamycin and epirubicin in the alternating schedules.