Abstract A1: Phase 1 study of PF-03446962, a fully human mAb against activin receptor-like kinase 1 (ALK 1), a TGFβ receptor involved in tumor angiogenesis.
Authors: de Braud Filippo , Cohen Roger , Berlin Jordan , Noberasco Cristina , Borghaei Hossein , Stampino Corrado Gallo , Wang Erjan , Hu-Lowe Dana D. , Levin Wendy J. , Abbattista Antonello , Goff Laura 
Published: June 2012

Background: Transforming Growth Factor β (TGF β) is a cytokine able to regulate many biological processes in cancer.

At the vascular level, the activity of TGFβ is exerted by selectively binding to its receptor, activin receptor like kinase 1 (ALK-1), triggering a downstream signaling involving intracellular and nuclear proteins (SMADs and Id1) and leading to transcriptional upregulation of proangiogenic factors. ALK-1 deficiency is related to a clinical syndrome called hereditary hemorrhagic telangectasia.

PF-03446962 is a fully human mAb against ALK-1 with dose dependent antiangiogenic activity as demonstrated preclinically in human tumour xenografts. Mechanistic studies indicated that ALK 1 and VEGF signalling pathways may promote angiogenesis in a collaborative manner.

Methods: We conducted a Phase 1 trial in patients (pts) with solid tumors. Primary objectives: identify MTD and a recommended phase 2 dose (RP2D); secondary objectives included safety profile, PK, antitumor activity, soluble proteins TGFβ related and blood flow by contrast enhanced ultrasound (CE-US).

Results: 44 pts have been enrolled on 8 dose levels (0.5–15 mg/kg).

PF-03446962 is administered iv on Day 1, 29 and then q 2 weeks. 15 mg/kg was defined as maximum administered dose, with DLTs represented by G3 thrombocytopenia and increase in pancreatic enzymes in 2/6 pts.

Noteworthy 3 pts developed telangectasia suggesting an in vivo knock-out of the ALK-1 function.

The dose of 6.75 mg/kg was defined as RP2D and PK data support the proposed regimen with drug concentration above the estimated therapeutic concentrations during each cycles. 3 PRs were observed, one hepatocellular carcinoma (HCC) resistant to anti-VEGF therapy, one NSCLC and one RCC (both NSCLC and RCC still ongoing). SD lasting for at least 16 weeks was observed in 7/44 pts, with 2 patients (adrenocortical ca. and mesothelioma) lasting for approximately 12 months from treatment start.

2/5 HCC pts showed a TTP of 5.5–6 months similar to those observed with sorafenib in first line. Of note all patients with PR and most of SDs were treated with prior antiangiogenic therapy. In preclinical models, PF-03446962 exerted antitumor activity in tumors resistant to VEGFRTKIs thus suggesting ALK 1 as potential mechanism of escape from VEGF blockade. CE-US showed changes consistent with reduced blood flow in 2/3 pts assessed at this time.

Conclusions: PF-03446962 is a first in class mAb anti ALK-1, safe and with manageable toxicities, mainly characterized by asymptomatic elevation of pancreatic enzymes and transient platelet decreases. Based on clinical activity, anti ALK 1 may be a promising novel antiangiogenic strategy with particular interest for pts who failed anti VEGF/VEGFRTKI in clinic.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A1.