title: The DART Study: Results from the Dose-Escalation and Expansion Cohorts Evaluating the Combination of Dalantercept plus Axitinib in Advanced Renal Cell Carcinoma.
abstract: Purpose:Activin receptor-like kinase 1 (ALK1) is a novel target in angiogenesis. Concurrent targeting of ALK1 and VEGF signaling results in augmented inhibition of tumor growth in renal cell carcinoma (RCC) xenograft models. Dalantercept is an ALK1-receptor fusion protein that acts as a ligand trap for bone morphogenetic proteins 9 and 10. The DART Study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of dalantercept plus axitinib in patients with advanced RCC and determined the optimal dose for further testing.Experimental Design:Patients received dalantercept 0.6, 0.9, or 1.2 mg/kg subcutaneously every 3 weeks plus axitinib 5 mg by mouth twice daily until disease progression or intolerance.Results:Twenty-nine patients were enrolled in the dose escalation (n= 15) and expansion (n= 14) cohorts. There were no dose-limiting toxicities or grade 4/5 treatment-related adverse events. In addition to common VEGFR tyrosine kinase inhibitor effects, such as fatigue and diarrhea, commonly seen treatment-related adverse events were peripheral edema, epistaxis, pericardial effusion, and telangiectasia. The objective response rate by RECIST v1.1 was 25% with responses seen at all dose levels. The overall median progression-free survival was 8.3 months.Conclusions:The combination of dalantercept plus axitinib is well tolerated and associated with clinical activity. On the basis of safety and efficacy results, the 0.9 mg/kg dose level was chosen for further study in a randomized phase II trial of dalantercept plus axitinib versus placebo plus axitinib.Clin Cancer Res; 23(14); 3557-65. ©2016 AACR.
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York. vossm@mskcc.org.|Department of Medicine, Weill Medical College of Cornell University, New York, New York.
authors.forename: Martin H
authors.initials: MH
authors.lastname: Voss
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors.forename: Rupal S
authors.initials: RS
authors.lastname: Bhatt
authors.affiliation: Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Plimack
authors.affiliation: Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio.
authors.forename: Brian I
authors.initials: BI
authors.lastname: Rini
authors.affiliation: John Theurer Cancer Center Hackensack UMC, Hackensack, New Jersey.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Alter
authors.affiliation: Highlands Oncology Group, Fayetteville, Arkansas.
authors.forename: J Thaddeus
authors.initials: JT
authors.lastname: Beck
authors.affiliation: Acceleron Pharma, Cambridge, Massachusetts.
authors.forename: Dawn
authors.initials: D
authors.lastname: Wilson
authors.affiliation: Acceleron Pharma, Cambridge, Massachusetts.
authors.forename: Xiaosha
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Acceleron Pharma, Cambridge, Massachusetts.
authors.forename: Musa
authors.initials: M
authors.lastname: Mutyaba
authors.affiliation: Acceleron Pharma, Cambridge, Massachusetts.
authors.forename: Chad
authors.initials: C
authors.lastname: Glasser
authors.affiliation: Acceleron Pharma, Cambridge, Massachusetts.
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Attie
authors.affiliation: Acceleron Pharma, Cambridge, Massachusetts.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Sherman
authors.affiliation: Acceleron Pharma, Cambridge, Massachusetts.
authors.forename: Shuchi S
authors.initials: SS
authors.lastname: Pandya
authors.affiliation: Georgetown University Medical Center, Washington, DC.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Atkins
mesh_terms: D030301:Activin Receptors, Type II / Q000008:administration & dosage* / Q000009:adverse effects / Q000037:antagonists & inhibitors / Q000235:genetics*; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects; D000077784:Axitinib; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000009:adverse effects; D007141:Immunoglobulin Fc Fragments / Q000008:administration & dosage* / Q000009:adverse effects; D007191:Indazoles / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000009:adverse effects; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: D020533:Angiogenesis Inhibitors; D007093:Imidazoles; D007141:Immunoglobulin Fc Fragments; D007191:Indazoles; D047428:Protein Kinase Inhibitors; D011993:Recombinant Fusion Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000077784:Axitinib; C425364:ACVRL1 protein, human; D030301:Activin Receptors, Type II; C000591618:ALK1-Fc fusion protein, human