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• W2232291427 abstract "3034 Background: Transforming growth factor β (TGF β) is a cytokine able to regulate many biological processes, including tissue development and remodeling, cellular proliferation and survival. At the vascular level, the activity of TGFβ is exerted by selectively binding to its receptor, activin receptor like kinase 1 (ALK-1), through TGFβRII, which triggers a downstream signaling involving intracellular and nuclear proteins (SMADs and Id1) and leading to transcriptional upregulation of pro-angiogenic factors. PF-03446962 is a fully human mAb against ALK-1 with dose dependent antiangiogenic activity as demonstrated in nonclinical studies in a chimera mouse model bearing human tumors xenograft. Methods: A phase 1 trial in patients with solid tumors is ongoing. Primary objective is to identify the MTD; secondary end points include safety profile, PK, antitumor activity, circulating endothelial cells (CEC), soluble proteins related to TGFβ and blood flow evaluation by contrast enhanced ultrasound (CE-US). Results: 23 patients (13 M/ 10 F, ECOG 0-1), have been enrolled. Five dose levels (0.5 to 4.5 mg/kg) have been explored. The sixth cohort is ongoing at 6.75 mg/kg. PF-03446962 is administered IV on day 1, 29 and then q 2 weeks. PK data support the proposed regimen to maintain drug levels over the EC50 over cycles. The t1/2 is 325 hrs at the dose of 4.5 mg/kg. With the exception of asymptomatic pancreatic enzyme elevation and platelets decrease in a single patient treated at 2.0 mg/kg, no grade 3 or 4 adverse events related to the drug have been reported so far. One PR lasting 13 weeks in a patient with hepatocellular carcinoma resistant to anti-VEGF therapy, and SD (27 and 21 weeks) in a thymic carcinoma and pseudomixoma peritonei were observed. CE-US data are suggestive of a reduction in blood flow in metastatic hepatic lesions between screening and day 15 post therapy. Conclusions: PF-03446962 is a first in class mAb targeting ALK-1. Treatment with PF-03446962 has been safe and is well tolerated in the first 5 dose levels. CE-US suggests potential vascular changes in liver metastasis and preliminary evidence of clinical activity was also observed. The study is ongoing and updated results will be presented at the meeting. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Pfizer Pfizer Pfizer" @default.
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• W2232291427 date "2010-05-20" @default.
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• W2232291427 title "Phase I study of PF-03446962, a fully human mab against ALK 1, a TGFβ receptor involved in tumor angiogenesis." @default.
• W2232291427 doi "https://doi.org/10.1200/jco.2010.28.15_suppl.3034" @default.
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