Abstract
BackgroundIn advanced cancers, transforming growth factor-beta (TGFβ) promotes tumor growth and metastases and suppresses host antitumor immunity. GC1008 is a human anti-TGFβ monoclonal antibody that neutralizes all isoforms of TGFβ. Here, the safety and activity of GC1008 was evaluated in patients with advanced malignant melanoma and renal cell carcinoma.MethodsIn this multi-center phase I trial, cohorts of patients with previously treated malignant melanoma or renal cell carcinoma received intravenous GC1008 at 0.1, 0.3, 1, 3, 10, or 15 mg/kg on days 0, 28, 42, and 56. Patients achieving at least stable disease were eligible to receive Extended Treatment consisting of 4 doses of GC1008 every 2 weeks for up to 2 additional courses. Pharmacokinetic and exploratory biomarker assessments were performed.ResultsTwenty-nine patients, 28 with malignant melanoma and 1 with renal cell carcinoma, were enrolled and treated, 22 in the dose-escalation part and 7 in a safety cohort expansion. No dose-limiting toxicity was observed, and the maximum dose, 15 mg/kg, was determined to be safe. The development of reversible cutaneous keratoacanthomas/squamous-cell carcinomas (4 patients) and hyperkeratosis was the major adverse event observed. One malignant melanoma patient achieved a partial response, and six had stable disease with a median progression-free survival of 24 weeks for these 7 patients (range, 16.4–44.4 weeks).ConclusionsGC1008 had no dose-limiting toxicity up to 15 mg/kg. In patients with advanced malignant melanoma and renal cell carcinoma, multiple doses of GC1008 demonstrated acceptable safety and preliminary evidence of antitumor activity, warranting further studies of single agent and combination treatments.Trial RegistrationClinicaltrials.gov NCT00356460
Highlights
Transforming growth factor-beta (TGFb) is a pleiotropic cytokine that is a member of a superfamily of ligands that includes bone morphogenetic proteins and activins [1,2]
Chronic exposure of transformed mouse keratinocytes to transforming growth factor-beta (TGFb) causes a change in morphology and engenders these cells with the ability to form spindle cell carcinomas when transplanted into mice [6]
We report our results on the safety and antitumor activity of repeated doses of GC1008 administered to patients with advanced malignant melanoma (MM) and renal cell carcinoma (RCC)
Summary
Transforming growth factor-beta (TGFb) is a pleiotropic cytokine that is a member of a superfamily of ligands that includes bone morphogenetic proteins and activins [1,2]. In the transition of premalignant lesions into malignant neoplasms, TGFb can suppress cell growth; in advanced cancers these effects are typically lost. TGFb will directly promote tumor growth and metastases [2,4,5]. Chronic exposure of transformed mouse keratinocytes to TGFb causes a change in morphology and engenders these cells with the ability to form spindle cell carcinomas when transplanted into mice [6]. TGFb induces epithelial-to-mesenchymal transition, which is characterized by a morphological change to a spindle cell shape, downregulation of E-cadherin and cytokeratin expression, loss of cell-cell junctions, remodeling of the cytoskeleton, and increased cell motility [2,4,7]. In advanced cancers, transforming growth factor-beta (TGFb) promotes tumor growth and metastases and suppresses host antitumor immunity. The safety and activity of GC1008 was evaluated in patients with advanced malignant melanoma and renal cell carcinoma
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