(Zymafos; ZIO-201) is a cytotoxic, active metabolite of the alkylating agent ifosfamide, which causes irreparable DNA interstrand cross-linking in cancer cells. This prevents DNA replication and cell division, leading to cell death.

In contrast to ifosfamide, palifosfamide is not metabolised to the toxins acrolein and chloracetaldehyde, which are associated with haemorrhagic cystitis, and neuro- and nephro-toxicities respectively. Also, palifosfamide is not a substrate for aldehyde dehydrogenase (ALDH), an important mediator of drug resistance

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

isofosamide

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.

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

Palifosfamide (Zymafos™ or ZIO-201) references a novel composition (tris formulation) that is the functional active metabolite of ifosfamide (IFOS), a bi-functional DNA alkylator being investigated as a potential therapy for the treatment of soft tissue sarcoma (STS). Palifosfamide is formulated by combining the tris (hydroxymethyl) amino methane (tris) salt of palifosfamide and a number of excipients to create the final drug product. Preclinical development of palifosfamide has included in vitro and in vivo studies demonstrating activity against various sarcomas, breast cancers, other solid tumors and leukemias, including several that are resistant to IFOS. Several clinical studies have been initiated in a variety of cancer types. A Phase I study in advanced cancers, using the original lysine formulation, has been completed. A two-stage Phase I/II Study in advanced sarcomas, introducing the tris salt formulation, has completed enrollment and data retrieval is ongoing. A Phase I study in combination with doxorubicin evaluating patients with advanced, refractory solid tumors for whom treatment with doxorubicin is considered medically acceptable, has completed enrollment and data retrieval is ongoing. Based on the result of the Phase I combination study, an international randomized Phase II study comparing palifosfamide in combination with doxorubicin versus doxorubicin alone in 1st and 2nd line patients with advanced STS has been completed. phase 3 on now also

What is Soft Tissue Sarcoma, and what are the currently available treatments?

Soft-tissue sarcomas (STS) represent a rare and diverse group of tumors that are not very well understood. Although soft-tissue sarcomas account for <1% of all cancers, they represent a high percentage of cancer-related deaths worldwide (Ref. 3, Ref. 4, Ref. 5). STS tumors can occur anywhere within the body, originating in various soft tissues including fat, smooth or striated muscle, nerve/nerve sheath, vascular tissue, and other connective tissues; the extremities are the most common site of origin, accounting for approximately 50% of cases