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Phase I clinical trial of (NPAz2)2NSOAz: 'SOAz'
Abstract:
(NPAz2)2NSOAz ('SOAz') is the first of a new class of cytotoxic agents containing an inorganic heterocyclic ring system to enter clinical trial. It was used to treat 31 patients with advanced cancer by IV infusion over 30 min on days 1, 2, 3, and 4 of a 21-day cycle, which was postponed if necessary to allow for hematological recovery. A total of 46 courses evaluable for toxicity was given and the tumor response was evaluable in 21 patients. Seven dose levels, ranging from 25 mg/m2 to 300 mg/m2, were studied, with three to six patients at each level. The only major toxicity was myelosuppression, especially thrombocytopenia, which was dose-limiting. Platelets decreased from the 14th day onward, with a nadir 4-5 weeks after administration. Leukopenia was less predictable and reached a nadir 3-5 weeks after administration. In most patients recovery was complete after 6-9 weeks. Myelosuppression was clearly cumulative in succeeding courses and proved irreversible in three patients. Anemia also occurred, but otherwise SOAz was remarkably well tolerated. There were no responses and no therapy-related deaths. The highest tolerated dose for patients who had received no or only minor chemotherapy prior to treatment with SOAz was 300 mg/m2, and that for heavily pretreated patients, 175 mg/m2. Because of cumulative myelotoxicity phase II studies with SOAz are not recommended.
Insights
The novel cytotoxic agent SOAz, a new class of inorganic heterocyclic compounds, showed dose-limiting myelosuppression in advanced cancer patients. Cumulative toxicity suggests against further Phase II studies.
Area of Science:
- Oncology
- Pharmacology
- Medicinal Chemistry
Background:
- Introduction of SOAz (NPAz2)2NSOAz, a novel cytotoxic agent with an inorganic heterocyclic ring system.
- SOAz represents a new class of anticancer agents entering clinical trials.
Purpose of the Study:
- To evaluate the safety and tolerability of SOAz in patients with advanced cancer.
- To determine the dose-limiting toxicity and maximum tolerated dose (MTD) of SOAz.
Main Methods:
- Phase I clinical trial involving 31 patients with advanced cancer.
- SOAz administered via IV infusion over 30 minutes on days 1-4 of a 21-day cycle.
- Dose escalation from 25 mg/m2 to 300 mg/m2 across seven levels.
Main Results:
- Myelosuppression, particularly dose-limiting thrombocytopenia and leukopenia, was the primary toxicity.
- Platelet nadir occurred 4-5 weeks post-administration; leukopenia nadir at 3-5 weeks.
- Cumulative myelotoxicity was observed, leading to irreversible effects in three patients.
- Highest tolerated dose was 300 mg/m2 for minimally pretreated patients and 175 mg/m2 for heavily pretreated patients.
- No tumor responses were observed.
Conclusions:
- SOAz exhibits significant cumulative myelotoxicity, which is dose-limiting.
- Due to cumulative toxicity, Phase II studies with SOAz are not recommended.
- SOAz was generally well-tolerated apart from myelosuppression, with no therapy-related deaths.