Phase I study of DMP 840 in pediatric patients with refractory solid tumors

The bis-naphthalimide DMP 840 has demonstrated high level antitumor activity in a number of preclinical models and has been evaluated in several Phase I studies in adults. We enrolled 10 patients with refractory pediatric solid tumors to this Phase I study of DMP 840 given intravenously by short infusion daily for 5 days. The most frequent and dose-limiting toxicity was myelosuppression. The maximum tolerated dose on this schedule was 8.6 mg/m² daily for 5 days. One patient had a complete response; there were no measurable tumor responses among the remaining 9 patients.     

Phase I study of DMP 840 in pediatric patients with refractory solid tumors

The bis-naphthalimide DMP 840 has demonstrated high level antitumor activity in a number of preclinical models and has been evaluated in several Phase I studies in adults. We enrolled 10 patients with refractory pediatric solid tumors to this Phase I study of DMP 840 given intravenously by short infusion daily for 5 days. The most frequent and dose-limiting toxicity was myelosuppression. The maximum tolerated dose on this schedule was 8.6 mg/m² daily for 5 days. One patient had a complete response; there were no measurable tumor responses among the remaining 9 patients.     

Phase I study of mitonafide in solid tumors

Summary Mitonafide was the first synthetized compound of a new series of 3-nitronaphthalimides with intercalative properties. A phase I study with a conventional escalation scheme was developed. The schedule of drug administration was a daily ×5 days by short (1h) intravenous (i.v.) infusion, every 21 days. Thirty evaluable patients were treated at doses from 15.4 mg/m²/d×5 days to 138.6 mg/m²/d×5 days. The study was interrupted due to appearance of central nervous system toxicity in 5 patients treated at doses above 118 mg/m²×5 days. This toxicity consisted firstly of loss of memory in all patients. It was irreversible and progressed in 3 patients to disorientation and confusion, leading to dementia in one of them. This was considered to be dose-limiting toxicity, and since it appeared to be related to the administration schedule, no further studies with short i.v. infusions of mitonafide are recommended. A phase I study utilizing a more desirable administration schedule over longer periods of time is ongoing in other centers.     

Phase I study of temsirolimus in combination with EKB-569 in patients with advanced solid tumors

Purpose Activation of EGFR can stimulate proliferative and survival signaling through mTOR. Preclinical data demonstrates synergistic activity of combined EGFR and mTOR inhibition. We undertook a phase I trial of temsirolimus (T, an mTOR inhibitor) and EKB-569 (E, an EGFR inhibitor) to determine the safety and tolerability. Methods The primary aim was to determine the maximally tolerated dose (MTD) of this combination in adults with solid tumors. Following the dose-escalation phase, (Cohort A), two subsequent cohorts were used to assess any pharmacokinetic (PK) interaction between the agents. Results Forty eight patients were enrolled. The MTD of this combination was E, 35 mg daily and T, 30 mg on days 1-3 and 15-17 using a 28-day cycle. The most common toxicities were nausea, diarrhea, fatigue, anorexia, stomatitis, rash, anemia, neutropenia, thrombocytopenia, and hypertriglyceridemia. Sixteen patients (36%) had at least one grade 3 toxicity. The most frequent grade 3/4 toxicities were diarrhea, dehydration, and nausea and vomiting (19% each). No grade 5 events were seen. Four patients had a partial response and 15 had stable disease. Clinical benefit was seen across a range of tumor types and in all cohorts. PK analysis revealed no significant interaction between E and T. Conclusions This combination of agents is associated with tolerable toxicities at doses that induced responses. PK studies revealed no interaction between the drugs. Further investigations of this targeting strategy may be attractive in renal cell carcinoma, non-small cell lung cancer, alveolar sarcoma, and carcinoid tumor.     

A Phase I study of acivicin in refractory pediatric solid tumors

Forty-two patients with progressive solid tumors and brain tumors were entered in this Phase I study of the glutamine antagonist acivicin given intravenously over thirty minutes daily for five days. The major toxicities encountered were myelosuppression and central nervous system toxicity (nightmares and somnolence). The maximum tolerated dosage on this schedule was 26 mg/M² daily for five days. Six patients including three patients with brain tumor had stable disease.     

Phase I and pharmacokinetic study of the orally administered farnesyl transferase inhibitor R115777 in patients with advanced solid tumors

R115777 is a novel selective inhibitor of farnesyl transferase, an enzyme that is involved in the proliferation of the malignant cell type. This study was designed to determine the toxicity, maximal tolerated dose and pharmacokinetics of R115777 when given orally b.i.d. for 28 days followed by 1-2 weeks of rest. Patients with advanced solid tumors for whom no standard therapy was available could enter the study. The starting dose of R115777 was 200 mg/dose and inter- as well as intra-patient dose escalations were performed with increments of 100 mg/dose. Nine patients entered the study and received in total 23 treatment cycles. A dose of 300 mg b.i.d. proved feasible with grade 4 neutropenia occurring in one of six patients who completed the first treatment cycle. Other toxicities were infrequent. Pharmacokinetic analysis demonstrated that peak plasma concentrations of 881+/-393 ng/ml were reached within 1-5 h. No accumulation of R115777 was observed over a 28-day period. The study was terminated based on these results together with the observation from a related phase I study in which higher doses of R115777 were associated with the frequent occurrence of grade 3-4 myelosuppression. We conclude that the recommended dose of R115777 given for 28 days followed by 1-2 weeks of rest is 300 mg b.i.d. Myelosuppression is the dose-limiting toxicity.     

Phase I clinical and pharmacokinetic study of bisantrene in refractory pediatric solid tumors

Summary Fourteen patients with pediatric malignant solid tumors, median age 15 years, received 22 courses of bisantrene in a Phase I study. Dosage escalations ranged from 10 to 120 mg/m² daily for 5 consecutive days. Toxicity included myelosuppression and phlebitis. A sensitive (detection limit of 2 ng/ml) and specific HPLC method was developed to quantitate bisantrene in patient's plasma and urine. Peak plasma concentrations at the end of 60 minute infusions ranged from 568 ng/ml at 10 mg/m² to 6800 ng/ml at the 100 mg/m² dosage. The elimination half life (T 1/2) averaged about 10 hours but increased to 20 hours in a patient with liver disease. Only 2.4–10% of the bisantrene dose was eliminated in the urine suggesting that the liver may be the major route of elimination for this antineoplastic anthracene derivative.