Phase I and pharmacokinetic study of CCI-779, a novel cytostatic cell-cycle inhibitor, in combination with 5-fluorouracil and leucovorin in patients with advanced solid tumors

CCI-779 is a novel ester of the immunosuppressive agent sirolimus that exerts cytostatic effects by the inhibition of the translation of cell-cycle regulatory proteins. We investigated the maximum tolerated dose (MTD) and pharmacokinetics (PK) of CCI-779 in combination with leucovorin (LV) and 5-fluorouracil (5-FU) in patients with advanced solid tumors. Patients were treated with LV at 200 mg/m(2) as a 1-h i.v. infusion directly followed by continuous 24-h i.v. infusion of 5-FU, in the first patient at 2000 mg/m(2) and in subsequent patients at 2600 mg/m(2). CCI-779 was administered directly prior to LV as a 30-min i.v. infusion at a starting dose of 15 mg/m(2) beginning at day 8 and escalated in subsequent cohorts of patients. One cycle consisted of six weekly administrations followed by 1 week of rest. Blood samples were drawn to assess PK of CCI-779 as well as its effect on steady-state 5-FU exposures. Twenty-eight patients entered the study, the majority having tumor types for which 5-FU is used as a treatment. CCI-779 doses of 15, 25, 45 and 75 mg/m(2) were investigated. Skin toxicity (rash) was prominent at all dose levels examined. Stomatitis was the dose-limiting toxicity (DLT) for 75 mg/m(2) doses of CCI-779. Subsequently the cohort at 45 mg/m(2) was expanded to a total of 15 patients, and at this dose level two treatment-related deaths occurred due to mucositis with bowel perforation. Based on the toxicities observed, it was decided to discontinue the study. Partial responses were observed in three patients with gastrointestinal tumors. No pharmacokinetic interaction between CCI-779 and 5-FU was observed. The safety profiles of CCI-779 and 5-FU/LV suggest an overlap of drug-related toxicities, and the administration of these drugs at these doses and schedule resulted in unacceptable toxicity and therefore cannot be recommended. If CCI-779 is to be used in combination with 5-FU/LV, other doses or schedules of administration will need to be explore

Phase II trial of diaziquone (AZQ) in advanced malignant melanoma

Forty-two evaluable patients with malignant melanoma received AZQ 27 mg/m2 i.v. every 4 weeks. In 5 patients with poor marrow reserve this dose was reduced to 20 mg/m2. Doses were rapidly escalated when no significant myelosuppression was encountered in previous courses. Twenty-five patients had received no prior chemotherapy. A single partial response was obtained for 3 months. Inconsistent myelosuppression was the main toxic effect in this trial. The median WBC and platelet nadirs were 3200/mm3 (900-19,500) and 105,000/mm3 (33,000-530,000) respectively. In 2 patients leukopenia was complicated by a transient episode of infection. One-third of the patients did not experience significant myelosuppression. Non-hematologic adverse reactions were generally mild to moderate and consisted of nausea and vomiting in 26 patients and alopecia in 1. It is concluded that at this dose schedule AZQ is ineffective against malignant melanoma. © 1983.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Phase II study of 5' deoxy 5 fluorouridine (doxifluridine) in advanced malignant melanoma

Forty-two patients with malignant melanoma were treated with doxifluridine, 4000 mg/m2 daily ×5, repeated every 3 weeks. The daily dose was reduced to 3000 mg/m2 in patients who had experienced severe myelosuppression with prior chemotherapy. A total of 35 patients were evaluable for response, and 25 of these received two or more courses. Two responses were observed. Toxicity mainly took the form of nausea, vomiting, stomatitis, dizziness, ataxia, and fatigue. Mild leukopenia was frequent (43%). Nadir counts <1.5×109/l leukocytes or 50×109/l platelets were seen in 7% and 2% of the courses respectively. Doxifluridine has no useful activity against malignant melanoma. © 1986 Springer-Verlag.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

The EORTC Early Clinical Trials Cooperative Group experience with 5 aza 2' deorycytidine (NSC 1227716) in patients with colorectal, head and neck, renal carcinomas and malignant melanomas

The Early Clinical Trials Cooperative Group of the EORTC conducted several phase II studies with a pyrimidine analogue of deoxycytidine, 5-aza-2′-deoxycytidine (DAC). The drug was given as three consecutive 1 h i.v. infusions of 75 mg/m2, separated by intervals of 7 h; courses were repeated every 5 weeks. A total of 101 eligible patients were studied: 42 with colo-rectal adenocarcinoma, 27 with squamous cell carcinoma of the head and neck, 18 with malignant melanoma and 14 with renal cell carcinoma. Drug-induced toxicities consisted of moderate myelosuppression, and nausea and vomiting. One single partial remission was seen in a patient with malignant melanoma. DAC given in this dose and schedule is devoid of antitumour activity in adult patients with these refractory types of carcinomas. © 1987.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Primary resistance of renal adenocarcinoma to 1,2,4 triglycidylurazol (TGU, NSC 332488), a new triexpoxide cytostatic agent phase II study of the EORTC Early Clinical Trials Group

Fourteen patients with metastatic renal adenocarcinoma without prior chemotherapy were treated with 1,2,4-triglycidylurazol (TGU, NSC-332488), a new triepoxide alkylating agent. TGU was chosen for this study among other triepoxides because of its high antitumour activity in animal models, its relatively good water solubility and the expected favourable therapeutic index. The starting dose was 800 mg/m2 i.v. (600 mg/m2 for patients with prior extensive radiotherapy) every 4 weeks. No objective tumour regression was seen in this favourable group of patients. Leuko- and thrombocytopenia were the most important side-effects. Severe cumulative and prolonged thrombocytopenia was seen. Other toxicities observed were nausea with or without vomiting in all patients and local phlebitis in some. © 1986.SCOPUS: ar.jinfo:eu-repo/semantics/publishe