Phase I Study of GC1008 (Fresolimumab): A Human Anti-Transforming Growth Factor-Beta (TGFβ) Monoclonal Antibody in Patients with Advanced Malignant Melanoma or Renal Cell Carcinoma

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

Targeting TGF-β Signaling for Therapeutic Gain

“…The other drug class that has received considerable attention in the clinic (Table 2) is the TGF-b ligand-and receptor-blocking antibodies, including the pan-TGF-b1/2/3 blocking antibody, fresolimumab (Genzyme/Sanofi) (Morris et al 2014), the TGF-b1-specific blocking antibody LY2382770 (Eli Lilly) (Cohn et al 2014;Tampe and Zeisberg 2014), and the TbRII blocking antibody LY3022859, also called IMC-TR1 (Eli Lilly, NCT01646203) (Zhong et al 2010). Other companies followed their lead with the development of alternative TGF-b ligand blocking antibodies, such as an anti-TGF-b1/2 antibody that is not cross reactive with TGF-b3, developed by Xoma/ Novartis (Bedinger et al 2016).…”

“…There have also been preclinical reports of the ability of TGF-b blockade drugs to awaken dormant metastatic breast tumor cells within the bone marrow, with the supposition that TGF-b2 plays a major role in breast tumor cell dormancy (Bragado et al 2013). During a clinical trial of the pan anti-TGF-b antibody, fresolimumab, for the treatment of endstage drug-refractile metastatic melanoma and RCC, grade 1 or 2 skin rashes that improved or resolved by the end of study were reported in 10 of 29 patients, and nonmalignant keratoacanthomas (KA) appeared de novo in four of these patients (Morris et al 2014), whereas a lowgrade SCC appeared in another individual (Lacouture et al 2015). Notably, KAs are commonly seen in response to other targeted therapies such as consequent to treatment with the multikinase inhibitor, sorafenib, or the B-Raf enzyme inhibitor, vemurafinib (Arnault et al 2012;Lacouture et al 2012), and these KAs are considered a manageable side effect of cancer therapy.…”

“…Two phase I trials of fresolimumab monotherapy have been completed, one focusing on metastatic melanoma (Morris et al 2014) and another on high-grade glioblastoma patients (Den Hollander et al 2015). Fresolimumab is a highaffinity fully humanized monoclonal antibody that neutralizes the active forms of human TGFb1, TGF-b2, and TGF-b3 (K D s of 2.3 nM, 2.8 nM, and 1.3 nM, respectively) .…”

Loss of TGF-β signaling drives cSCC from skin stem cells – More evidence

“…Convincing reports include the genotypephenotype correlation between inactivating TGFBR1 mutation and familial multiple self-healing squamous epithelioma (MSSE), 4 as well as reports of spontaneous cSCC arising secondary to systemic treatment with the pan-TGF-b ligand antibody (GC1008). 5 In addition, TGF-b receptor mutations have also been detected in RAF-kinase induced skin tumors 6 ; which is where our study began.…”

Overview of Transforming Growth Factor β Superfamily Involvement in Glioblastoma Initiation and Progression

“…Fresolimumab is a human monoclonal antibody that can neutralize all TGFβ's isoforms with high-affinity in several cancer cell lines. This antitumor property led to its clinical translation in several cancers including GBM, malignant melanoma and renal cell carcinoma attesting to its safety and potential therapeutic effect (Morris et al, 2014). Nonetheless, fresolimumab can induce skin lesions, which require caution (Lacouture et al, 2015).…”