Spirohydantoin mustard (
spiromustine,
NSC 172112) is a classical bifunctional
alkylating agent synthesized in an effort to develop
antitumor agents effective against CNS
tumors. The rationale was to combine the reactive moiety of an active
antitumor agent with the
hydantoin part of the molecule, which might serve as a carrier to cross the blood brain barrier. Thirty-eight patients with refractory solid
tumors received
spiromustine as part of a phase I trial at the Johns Hopkins Oncology Center. Three schedules were investigated: intravenously (IV) daily for three consecutive days, IV every other day for 3 days, and IV on a weekly basis for three doses, all cycled every 28 days. Hematologic toxicity was infrequently seen. Mild to moderate
nausea and
vomiting occurred on all schedules. The dose limiting toxicity was CNS toxicity characterized by
mydriasis,
xerostomia,
lethargy,
confusion, and
hallucinations. This CNS toxicity was dose related, cumulative, and reversible. IV
physostigmine appeared to diminish the neurotoxicity if administered before
spiromustine and at frequent intervals following the
drug. The maximum tolerated dose of
spiromustine (without concomitant
physostigmine) on the three times a week schedule is 6 mg/m2. With
physostigmine pretreatment, 8 mg/m2 can be administered. The three times daily and every other day for three days schedules are not recommended for further study due to the severity of neurotoxicity. It is recommended that 6 mg/m2 be used as the starting dose for any phase II studies using the three times weekly schedule, and that
physostigmine be used as needed to minimize neurotoxicity. Dose escalation above this level can be considered when individual tolerance has been established. Phase II trials to investigate the activity of this agent against primary and metastatic CNS
malignancies appear indicated on the basis of three transient radiographic responses in refractory
malignancies metastatic to the CNS.