Evaluation of response is critical and early signals of benefit are compelling for the development of novel drug therapies. FDG-PET was utilized in early trials of imatinib (IM), an oral tyrosine kinase inhibitor with activity against KIT and PDGFRA, in patients with advanced gastrointestinal stromal tumors (GISTs). Treatment with IM led to dramatic metabolic responses that proved to be predictive of long term disease control. GISTs lacking mutations in c-KIT or PDGFRA, the usual oncologic drivers of GISTs, are less responsive to IM therapy. Our group has demonstrated that the insulin-like growth factor 1 receptor (IGF- 1R) is over-expressed and constitutively activated in GISTs, particularly those that lack mutations in c-KIT and PDGFRA. IGF1R and the IGF signaling pathway have been shown to play a role in malignant cell growth, metastasis, and resistance to chemotherapeutic drugs. Numerous studies focusing mainly on insulin growth factor-1 and -2 (IGF-1 and IGF-2) and IGF-1R have demonstrated that these genes are expressed, or over-expressed in numerous cancers as compared to normal tissue. Our preclinical studies in GIST cell lines have demonstrated decreased proliferation of cells with an IGF-1R inhibitor alone or in combination with IM. It is therefore rational to test the efficacy of an anti-IGF-1R antibody alone and in combination with IM in patients with advanced GIST. This proposal seeks to evaluate, in a preliminary fashion, the role of FDG-PET in the evaluation of the anti- IGF-1R antibody BIIB022 alone and in combination with IM in patients with advanced GISTs. A primary toxicity of anti-IGF1R antibody therapy is hyperglycemia, suggesting there is a perturbation of normal insulin homeostasis. Limited published data do not exist on the reliability of FDG-PET imaging for the assessment of response to therapy with an IGF-1R inhibitor therapy, nor is there information on the impact of IGF-1R antibodies on circulating levels of insulin family ligands. It is possible that perturbations in the levels of circulating IGF family members may affect the reliability of FDG-PET imaging. We will conduct a phase I/II study incorporating FDG-PET along with conventional imaging and measurements of serum glucose, insulin and circulating levels of the IGF-1R ligands IGF-1 and IGF-2, and their inhibitors the IGF binding proteins (IGFBPs). We will explore correlations between changes in tumor metabolic activity by FDG-PET and tumor size, serum levels of glucose, insulin, IGF-1R ligands or IGFBPs in patients with advanced GIST treated with an anti-IGF1R inhibitor BIIB022 alone or in combination with IM.
The incorporation of functional imaging in clinical trials is becoming an important tool to minimize the time of drug development. This proposal seeks to evaluate the effectiveness of FDG-PET scanning to measure biological effects and predict clinical benefit in a phase I/II clinical trial of an antibody targeting IGF-1R alone or in combination with IM in patients with advanced GIST. The results of this proposal would be applicable to all cancer types and extend our understanding the role of FDG-PET in assessing drug effect generally and in particular, the effects of IGF-1R targeted therapeutics, which are undergoing clinical development at this time in multiple challenging and refractory malignancies.
|von Mehren, Margaret; Britten, Carolyn D; Pieslor, Peter et al. (2014) A phase 1, open-label, dose-escalation study of BIIB022 (anti-IGF-1R monoclonal antibody) in subjects with relapsed or refractory solid tumors. Invest New Drugs 32:518-25|
|Corless, Christopher L; Ballman, Karla V; Antonescu, Cristina R et al. (2014) Pathologic and molecular features correlate with long-term outcome after adjuvant therapy of resected primary GI stromal tumor: the ACOSOG Z9001 trial. J Clin Oncol 32:1563-70|
|Belinsky, Martin G; Rink, Lori; Flieder, Douglas B et al. (2013) Overexpression of insulin-like growth factor 1 receptor and frequent mutational inactivation of SDHA in wild-type SDHB-negative gastrointestinal stromal tumors. Genes Chromosomes Cancer 52:214-24|
|Vadakara, Joseph; von Mehren, Margaret (2013) Gastrointestinal stromal tumors: management of metastatic disease and emerging therapies. Hematol Oncol Clin North Am 27:905-20|