adozelesin and Neoplasms

Adozelesin, a synthetic analog of the antitumor antibiotic CC-1065, is a novel cytotoxic agent which inhibits DNA synthesis by binding to the minor groove of the DNA helix. Preclinical studies have shown a broad spectrum of activity against a variety of murine and human tumor xenograft models. We conducted a phase I study of adozelesin to (i) determine a recommended dose for phase II testing using a 10 min i.v. infusion, (ii) characterize the toxic effects of the drug using this schedule and (iii) document any antitumor activity observed. Adozelesin was administered as an i.v. infusion every 6 weeks. CBC and biological parameters were performed weekly. The starting dose of 10 microg/m2, corresponding to 1/30 the mouse equivalent lethal dose, was escalated, according to a modified Fibonacci scheme, until dose-limiting toxicity was encountered. Forty-seven adult patients with solid malignancies were entered in the study. Successive dose levels used were 10, 20, 33, 50, 70, 105, 120, 150 and 180 microg/m2. The main toxic effect was myelosuppression, which was dose limiting. The maximally tolerated dose was defined as 180 microg/m2. A minor response with a 4 month duration was reported in one previously treated patient with melanoma. We conclude that the recommended phase II dose of adozelesin given as a 10 min infusion is 150 microg/m2, repeated every 4 weeks.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Benzofurans; Blood; Cyclohexanecarboxylic Acids; Cyclohexenes; Dose-Response Relationship, Drug; Duocarmycins; Female; Humans; Hyperglycemia; Indoles; Infusions, Intravenous; Liver; Male; Middle Aged; Neoplasms; Neutropenia; Treatment Outcome

CC-1065 is a unique alkylating agent that preferentially binds in the minor groove of double-stranded DNA at adenine-thymine-rich sites. Although it has broad antitumor activity in preclinical models its development was discontinued because of deaths observed during preclinical toxicology studies. Adozelesin is a potent synthetic analog that was chosen for clinical development because it had a similar preclinical antitumor spectrum, but did not produce deaths similar to CC-1065 at therapeutic doses. Phase I evaluations using a variety of Adozelesin treatment schedules have been conducted. This report describes our experience using a multiple dose treatment schedule. Endpoints including antitumor response, maximum tolerated dose, dose limiting toxicity as well as other toxicities and the recommended Phase II starting dose were determined. Adozelesin was given as a 10 minute IV infusion for 5 consecutive days every 21 days or upon recovery from toxicity. The dose range evaluated was 6-30 mcg/m2/day. All patients had refractory solid tumors and had received prior cytotoxic treatment. Thirty-three patients (22 men: 11 women) were entered onto the study and 87 courses were initiated. Dose limiting toxicity was cumulative myelosuppression (leucopenia, thrombocytopenia). The maximum tolerated dose was 30 mcg/m2/day. The only other significant toxicity was an anaphylactoid syndrome that occurred in 2 patients. A partial response was observed in a patient with refractory soft tissue sarcoma. The recommended Phase II starting dose of Adozelesin using a 10 minute IV infusion for 5 consecutive days is 25 mcg/m2/day to be repeated every 4-6 weeks to allow recovery from myelotoxicity, based on our experience. Additional Phase I and II studies with Adozelesin are recommended.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Benzofurans; Cyclohexanecarboxylic Acids; Cyclohexenes; Dose-Response Relationship, Drug; Drug Administration Schedule; Duocarmycins; Female; Humans; Indoles; Infusions, Intravenous; Male; Middle Aged; Neoplasms

During a phase I clinical and pharmacologic trial, 26 patients with refractory solid tumors were treated with increasing doses of adozelesin by brief intravenous infusion every 3 weeks. Overall, adozelesin was well tolerated. The dose-limiting toxicity was myelosuppression, mainly thrombocytopenia and leukopenia. Nonhematologic toxicity was generally mild, with fatigue (36%), local reaction at the infusion site (24%), nausea or vomiting (20%) and hypersensitivity reaction (16%) being the most common adverse effects. There were no objective clinical responses. The maximally tolerated dose on this schedule was 188 micrograms/m2 with the recommended phase II starting dose being 150 micrograms/m2 on an every 3 week schedule. Adozelesin merits broad investigation at the phase II level.

Topics: Adult; Aged; Antineoplastic Agents; Benzofurans; Cyclohexanecarboxylic Acids; Cyclohexenes; Drug Resistance; Duocarmycins; Female; Humans; Indoles; Infusions, Intravenous; Male; Middle Aged; Neoplasms

Adozelesin, a synthetic analogue of the antitumor antibiotic CC-1065, is the first of a class of potent sequence-specific alkylating agents to be brought to clinical trial. In preclinical in vitro testing, it has demonstrated antitumor activity at picomolar concentrations.. We conducted a phase I study of adozelesin to (a) determine a recommended dose for phase II testing using a 24-hour intravenous infusion, (b) characterize the toxic effects of the drug using this schedule, and (c) document any antitumor activity observed.. Adozelesin was given as a 24-hour continuous intravenous infusion. Treatments were initially scheduled every 3 weeks, but the prolonged myelosuppression observed necessitated a final dosing interval of every 6 weeks. The starting dose of 30 micrograms/m2 was escalated using a modified Fibonacci scheme until dose-limiting toxicity was encountered.. Twenty-nine patients were entered in the study. Successive dose levels used were 30, 60, 100, 150, 120, and 100 micrograms/m2. Prolonged thrombocytopenia and granulocytopenia were dose limiting. No antitumor responses were observed.. We recommend that the phase II dose of adozelesin given as a continuous 24-hour intravenous infusion be 100 micrograms/m2, repeated every 6 weeks. Other potentially less myelosuppressive schedules could be pursued.

Topics: Adult; Aged; Antineoplastic Agents; Benzofurans; Cyclohexanecarboxylic Acids; Cyclohexenes; Drug Administration Schedule; Duocarmycins; Female; Hematologic Diseases; Humans; Indoles; Infusions, Intravenous; Male; Middle Aged; Neoplasms; Treatment Outcome