Randomized phase II trial of pegylated liposomal doxorubicin (PLD) with or without anti-platelet-derived growth factor receptor-alpha (PDGFR-alpha) monoclonal antibody IMC-3G3 in platinum-refractory/resistant advanced ovarian cancer.

Abstract

TPS256 Background: Single-agent PLD is an established therapy for platinum-refractory/resistant advanced ovarian cancer with response rates of approximately 20%. This ongoing study will assess antitumor activity and safety of PLD with or without IMC-3G3 in this population. IMC- 3G3 is an IgG1-type recombinant human monoclonal antibody which specifically targets PDGFRα with high affinity, blocks ligand-induced cell mitogenesis and receptor autophosphorylation, and inhibits phosphorylation of the downstream signaling molecules Akt and MAP kinase (Mol Cancer Ther 2005;4:369). PDGFRα is expressed in 52% of ovarian cancers, including in 89% with clear cell histology (Oncogene. 2002;21:6289). PDGF and PDGFRα are often co-expressed in ovarian cancers, suggesting an autocrine mechanism of tumor growth, and PDGFRα expression is associated with shorter survival in patients (Ca Res 1993; 53: 4550). Ovarian cancer-associated ascites fluid contains PDGF, and can stimulate ovarian cancer growth through PDGFRα signaling, highlighting a potential mechanism of intraperitoneal disease spread (Oncogene. 2006;25:2060). IMC-3G3 inhibits proliferation and growth of several human tumor cell lines in vitro and in vivo and enhances the antitumor effect of doxorubicin in xenograft models (ImClone Systems, data on file). Methods: One hundred ten patients with platinum- refractory/resistant ovarian cancer will be enrolled at 13-15 North American and European centers. Progression-free survival is the primary endpoint. Potential associations between clinical outcomes and tumor PDGFRα expression and serum vascular endothelial growth factor (VEGF)/PDGF levels, and the relationship between IMC-3G3 treatment and serum VEGF/PDGF levels will be assessed. Patients will be randomized to receive IMC-3G3 (20 mg/kg) every two weeks with PLD (40 mg/m2) every 4 weeks (Arm A), or doxorubicin alone (Arm B) until disease progression or other withdrawal criteria. Patients in Arm B may receive IMC-3G3 monotherapy upon disease progression. As of January 2010, 25 patients have been enrolled at 6 sites. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration ImClone Systems ImClone Systems ImClone Systems