Safety, Pharmacokinetics, Pharmacodynamics, and Antitumor Activity of Dalantercept, an Activin Receptor–like Kinase-1 Ligand Trap, in Patients with Advanced Cancer

Bendell, Johanna C.; Gordon, Michael; Hurwitz, Herbert I.; Jones, Suzanne F.; Mendelson, David S.; Blobe, Gerard C.; Agarwal, Neeraj; Condon, Carolyn H.; Wilson, Dawn; Pearsall, Amelia E.; Yang, Yijun; McClure, Ty; Attie, Kenneth M.; Sherman, Matthew L.; Sharma, Sunil

doi:10.1158/1078-0432.ccr-13-1840

Cited by 53 publications

(70 citation statements)

References 50 publications

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“…A similar finding of treatment-related telangiectasia has been reported in clinical studies of an ALK-1 receptor fusion protein (dalantercept) and an endoglin-neutralizing antibody (TRC105) in patients with advanced cancer (13)(14)(15)(16). Of note, hyponatremia was reported following treatment with dalantercept, but not with PF-03446962 (13,15). Peripheral edema, observed with dalantercept, was not dose limiting for treatment with PF-03446962, and it was noted only in a minority of PF-03446962-treated patients (13,15).…”

Section: Discussionsupporting

confidence: 79%

“…Of note, hyponatremia was reported following treatment with dalantercept, but not with PF-03446962 (13,15). Peripheral edema, observed with dalantercept, was not dose limiting for treatment with PF-03446962, and it was noted only in a minority of PF-03446962-treated patients (13,15). Furthermore, hypertension, proteinuria, and bleeding, known to be associated with administration of the VEGF inhibitor bevacizumab, were not frequently observed with PF-03446962 (17).…”

Section: Discussionmentioning

confidence: 95%

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A Phase I Study of the Anti-Activin Receptor-Like Kinase 1 (ALK-1) Monoclonal Antibody PF-03446962 in Patients with Advanced Solid Tumors

Goff

Cohen

Berlin

et al. 2016

Clinical Cancer Research

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Purpose: Objectives of this dose-finding study were to determine the MTD and recommended phase II dose (RP2D) of the first-in-class anti-activin receptor-like kinase 1 (ALK-1) monoclonal antibody PF-03446962, and assess safety and antitumor activity in patients with advanced solid tumors.Experimental Design: This open-label, multicenter study was based on a 3þ3 design. PF-03446962 was administered biweekly by intravenous infusion, at doses ranging from 0.5 to 15 mg/kg.Results: Forty-four patients received treatment with PF-03446962. Dose-limiting toxicities observed during dose escalation included grade 3 increased amylase, grade 3/4 increased lipase, and grade 3/4 thrombocytopenia. The MTD was determined to be 10 mg/kg. The RP2D was set at 7 mg/kg for patients with advanced solid tumors, based on the observed safety, pharmacokinetics, and antitumor activity. The most-frequent treatment-related, all-grade adverse events included thrombocytopenia (20.5%), fatigue (15.9%), and nausea, increased amylase, and increased lipase (each 11.4%). Treatment-related telangiectasia was noted in 7% of patients, suggesting in vivo inhibition of the ALK-1 pathway.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 95%

A Phase I Study of the Anti-Activin Receptor-Like Kinase 1 (ALK-1) Monoclonal Antibody PF-03446962 in Patients with Advanced Solid Tumors

Goff

Cohen

Berlin

et al. 2016

Clinical Cancer Research

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“…Dalantercept (ACE-041), the human counterpart of RAP-041, is an ALK1 ligand trap comprising the extracellular domain of ALK1 fused to the Fc portion of IgG. Phase I clinical trials demonstrate the safety and tolerability of dalantercept; the most common and dose-limiting side effects include peripheral edema and fluid retention (24). Likewise, the fully human ALK1-neutralizing antibody PF-03446962 has concluded phase I clinical trials with grade 3 thrombocytopenia and increase in pancreatic enzymes as the dose-limiting toxicities (25).…”

Section: Discussionmentioning

confidence: 99%

“…Likewise, the fully human ALK1-neutralizing antibody PF-03446962 has concluded phase I clinical trials with grade 3 thrombocytopenia and increase in pancreatic enzymes as the dose-limiting toxicities (25). Both compounds show evidence for on-target effects on the neoangiogenic vasculature in functional imaging modalities, such as 18 FDG-PET and contrast-enhanced ultrasound imaging (24,25). Notably, the side effect profile of the ALK1 targeting agents is distinct from that of anti-VEGF compounds, such as bevacizumab, sunitinib, and sorafenib, indicating a unique mechanism of action.…”

Section: Discussionmentioning

confidence: 99%

Endothelial ALK1 Is a Therapeutic Target to Block Metastatic Dissemination of Breast Cancer

et al. 2015

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Exploration of new strategies for the prevention of breast cancer metastasis is justifiably at the center of clinical attention. In this study, we combined a computational biology approach with mechanism-based preclinical trials to identify inhibitors of activin-like receptor kinase (ALK) 1 as effective agents for blocking angiogenesis and metastasis in breast cancer. Pharmacologic targeting of ALK1 provided long-term therapeutic benefit in mouse models of mammary carcinoma, accompanied by strikingly reduced metastatic colonization as a monotherapy or part of combinations with chemotherapy. Gene-expression analysis of breast cancer specimens from a population-based nested casecontrol study encompassing 768 subjects defined endothelial expression of ALK1 as an independent and highly specific prognostic factor for metastatic manifestation, a finding that was corroborated in an independent clinical cohort. Overall, our results suggest that pharmacologic inhibition of endothelial ALK1 constitutes a tractable strategy for interfering with metastatic dissemination of breast cancer. Cancer Res; 75(12); 2445-56. Ó2015 AACR.

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“…ACE-041 (Dalantercept), another ALK1 blocker, was tested in squamous cell carcinoma, non-small cell lung cancer, and intestinal adenocarcinoma and displayed antitumor activity in phase II clinical trial (113). No responses or PR to PF-03446962, an antibody targeting ALK1, was observed in hepatocellular carcinoma, urothelial cancer, colorectal cancer, malignant pleural mesothelioma, and other solid tumors (114)(115)(116).…”

Section: Alk1 Blockersmentioning

confidence: 99%

Hey Factors at the Crossroad of Tumorigenesis and Clinical Therapeutic Modulation of Hey for Anticancer Treatment

Liu

Sanders

Liang

et al. 2017

Molecular Cancer Therapeutics

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Hairy and Enhancer-of-split related with YRPW motif (Hey) transcription factors are important regulators of stem cell embryogenesis. Clinical relevance shows that they are also highly expressed in malignant carcinoma. Recent studies have highlighted functions for the Hey factors in tumor metastasis, the maintenance of cancer cell self-renewal, as well as proliferation and the promotion of tumor angiogenesis. Pathways that regulate Hey gene expression, such as Notch and TGFb signaling, are frequently aberrant in numerous cancers. In addition, Hey factors control downstream targets via recruitment of histone deacetylases (HDAC). Targeting these signaling pathways or HDACs may reverse tumor progression and provide clinical benefit for cancer patients. Thus, some small molecular inhibitors or monoclonal antibodies of each of these signaling pathways have been studied in clinical trials. This review focuses on the involvement of Hey proteins in malignant carcinoma progression and provides valuable therapeutic information for anticancer treatment.

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Safety, Pharmacokinetics, Pharmacodynamics, and Antitumor Activity of Dalantercept, an Activin Receptor–like Kinase-1 Ligand Trap, in Patients with Advanced Cancer

Abstract: Purpose: The angiogenesis inhibitor dalantercept (formerly ACE-041) is a soluble form of activin receptor-like kinase-1 (ALK1) that prevents activation of endogenous ALK1 by bone morphogenetic protein-9 (BMP9) and BMP10 and exhibits antitumor activity in preclinical models.

Cited by 53 publications

References 50 publications

A Phase I Study of the Anti-Activin Receptor-Like Kinase 1 (ALK-1) Monoclonal Antibody PF-03446962 in Patients with Advanced Solid Tumors

A Phase I Study of the Anti-Activin Receptor-Like Kinase 1 (ALK-1) Monoclonal Antibody PF-03446962 in Patients with Advanced Solid Tumors

Endothelial ALK1 Is a Therapeutic Target to Block Metastatic Dissemination of Breast Cancer

Hey Factors at the Crossroad of Tumorigenesis and Clinical Therapeutic Modulation of Hey for Anticancer Treatment

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