Intrathecal mafosfamide: a preclinical pharmacology and phase I trial.
OBJECTIVE
Preclinical studies of mafosfamide, a preactivated cyclophosphamide analog, were performed to define a tolerable and potentially active target concentration for intrathecal (IT) administration. A phase I and pharmacokinetic study of IT mafosfamide was performed to determine a dose for subsequent phase II trials.


METHODS
In vitro cytotoxicity studies were performed in MCF-7, Molt-4, and rhabdomyosarcoma cell lines. Feasibility and pharmacokinetic studies were performed in nonhuman primates. These preclinical studies were followed by a phase I trial in patients with neoplastic meningitis. There were five dose levels ranging from 1 mg to 6.5 mg. Serial CSF samples were obtained for pharmacokinetic studies in a subset of patients with Ommaya reservoirs.


RESULTS
The cytotoxic target exposure for mafosfamide was 10 micromol/L. Preclinical studies demonstrated that this concentration could be easily achieved in ventricular CSF after intraventricular dosing. In the phase I clinical trial, headache was the dose-limiting toxicity. Headache was ameliorated at 5 mg by prolonging the infusion rate to 20 minutes, but dose-limiting headache occurred at 6.5 mg dose with prolonged infusion. Ventricular CSF mafosfamide concentrations at 5 mg exceeded target cytotoxic concentrations after an intraventricular dose, but lumbar CSF concentrations 2 hours after the dose were less than 10 micromol/L. Therefore, a strategy to alternate dosing between the intralumbar and intraventricular routes was tested. Seven of 30 registrants who were assessable for response had a partial response, and six had stable disease.


CONCLUSIONS
The recommended phase II dose for IT mafosfamide, administered without concomitant analgesia, is 5 mg over 20 minutes.
Blaney
Susan M
SM
Texas Children's Cancer Center, 6621 Fannin St, CC 1410 00, Houston, TX 77030-2399, USA. sblaney@txccc.org
Balis
Frank M
FM
Berg
Stacey
S
Arndt
Carola A S
CA
Heideman
Richard
R
Geyer
J Russell
JR
Packer
Roger
R
Adamson
Peter C
PC
Jaeckle
Kurt
K
Klenke
Renee
R
Aikin
Alberta
A
Murphy
Robert
R
McCully
Cynthia
C
Poplack
David G
DG
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics* / Q000633:toxicity; D002675:Child, Preschool; D003520:Cyclophosphamide / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics* / Q000633:toxicity; D005240:Feasibility Studies; D006801:Humans; D007278:Injections, Spinal; D008253:Macaca mulatta; D008577:Meningeal Neoplasms / Q000188:drug therapy / Q000378:metabolism; D008581:Meningitis / Q000188:drug therapy / Q000378:metabolism; D009369:Neoplasms; D016896:Treatment Outcome
D000970:Antineoplastic Agents; C048341:mafosfamide; D003520:Cyclophosphamide