Cyclophosphamide and ifosfamide are nitrogen mustard alkylating agents that act by crosslinking DNA strands at the guanine N-7 position, resulting in cell death. Both of these are prodrugs that are metabolised in the liver to phosphoramide mustard active metabolites, but their use is limited by toxic side-effects. They are also prone to tumour resistance, which results from numerous mechanisms, including DNA repair.
In an attempt to overcome some of these problems, Ziopharm Oncology has developed palifosfamide tromethamine, which is a salt formulation of isophosphoramide mustard, the active metabolite of isofosfamide.1
In a Phase I trial, it was given in combination with doxorubicin to 13 patients with advanced refractory tumours – eight with soft tissue sarcoma and the remainder with small cell lung cancer – for whom there was no available standard therapy.2 It was given on the first three days of a three-week cycle, with a starting dose of 150mg/m2, and doxorubicin given on the first day at a starting dose of 60mg/m2. The doses were escalated to a maximum tolerated dose of 150mg/m2 for palifosfamide and 75mg/m2 for doxorubicin. It was well tolerated, and three of the 12 assessable patients had a partial response, two of whom were from the sarcoma group, and the median progression free survival was 20 weeks.
The drug has also been investigated in a Phase II trial in patients with soft tissue sarcoma.3 A total of 67 patients were given doses of 150mg/m2 drug plus 75mg/m2 of doxorubicin or the doxorubicin alone for up to six cycles, until either progression or toxicity occurred.
After six cycles, all patients were eligible for palifosfamide treatment. The median progression-free survival for the palifosfamide group was 7.8 months, and 4.4 months for the control group. There were no significant differences in toxicities between the two groups, and it was well tolerated as an outpatient treatment.
Enrolment into the trial was halted early because of the positive results.
references
1. S. Jung and B. Kasper, IDrugs 2010, 13, 38
2. L.J. Camacho et al. J. Clin. Oncol. 2009, 27 (Suppl.), Abst. 10577
3. C.F. Verschraegen et al. J. Clin. Oncol. 2010, 28 (Suppl.), A