Phase I-II Trial of Sorafenib in Combination With Ifosfamide in Soft Tissue Sarcoma
Status:
Unknown status
Trial end date:
2010-04-01
Target enrollment:
Participant gender:
Summary
Soft tissue sarcomas (STS) are an uncommon group of malignant tumors of mesenchymal origin.
For most advanced STS types, chemotherapy is currently the only available treatment.
Unfortunately, a very limited number of useful drugs are active against this disease.
Doxorubicin is widely considered the standard first-line treatment. Ifosfamide has also a
well-established activity (1,2) and is often administered either associated with Doxorubicin
or alone as a second-line chemotherapy treatment. Other drugs such as DTIC, Gemcitabine and
Temozolomide showed modest activity as a second-line agents (3,4). Thus, there is a necessity
to identify new agents with activity to improve therapy for patients with advanced STS. In
some studies, most STS showed VEGF expression, and elevated serum VEGF levels were found to
correlate with higher histologic tumor grade (5,6). Additionally, inhibition of VEGFR was
associated with tumor activity in preclinical models of sarcoma (7,8). For these reasons,
inhibition of VEGFR seems to be a reasonable approach to explore in the treatment of STS.
Sorafenib (BAY 43-9006) is an orally available, small molecule multi-kinase inhibitor of
VEGFR, PDGFR and RAF with demonstrated activity in the treatment of renal cell cancer (9).
Preclinical studies suggest that the combination of Sorafenib with cytotoxic agents results
in additive anti-tumor activity (10), initiating justification for combination studies. A
recent trial, however, reported an unexpected incidence of cardiac toxicity in patients with
STS treated with Bevacizumab, a monoclonal antibody that binds VEGF, in combination with
Doxorubicin (11). This finding suggest that the possibility of potentiation of the
cardiotoxicity of Doxorubicin when inhibiting the VEGF pathway cannot be ruled out. The
association of Sorafenib with Ifosfamide, the other established active agent against STS,
could improve the efficacy of single-agent Ifosfamide minimizing the risk of cardiac toxicity
.