Phase 1 study of aflibercept administered subcutaneously to patients with advanced solid tumors Journal Article


Authors: Tew, W. P.; Gordon, M.; Murren, J.; Dupont, J.; Pezzulli, S.; Aghajanian, C.; Sabbatini, P.; Mendelson, D.; Schwartz, L.; Gettinger, S.; Psyrri, A.; Cedarbaum, J. M.; Spriggs, D. R.
Article Title: Phase 1 study of aflibercept administered subcutaneously to patients with advanced solid tumors
Abstract: Purpose: To determine the maximum tolerated dose or maximal administered dose and pharmacokinetic and safety profiles of s.c. administered vascular endothelial growth factor Trap (aflibercept), a novel antiangiogenic agent. Experimental Design: In this open-label, dose-escalation study, patients with advanced solid tumors were treated with subcutaneous doses of aflibercept at seven dose levels. Patients received a single dose of aflibercept and then underwent safety and pharmacokinetic assessments over the next 4 weeks. Patients then received weekly or biweekly treatment over the subsequent 6 weeks. Patients tolerating and benefiting could continue on aflibercept at the same dose and schedule until progression of disease. Results: Thirty-eight patients received at least one dose of aflibercept. Maximum tolerated dose was not reached. Due to solubility/dosing limits with the subcutaneous formulation, 1,600 μg/kg/week was the maximal administered dose. The most common toxicities were proteinuria (37%), fatigue (32%), injection site reactions (18%), nausea (17%), myalgia and anorexia (16% each), hypertension (13%), and voice hoarseness (11%). Drug-related grade 3 to 4 toxicity was uncommon (7%) and reversible: dehydration, cerebral ischemia, proteinuria, hypertension, leukopenia, and pulmonary embolism. We identified dose-proportional increases in plasma concentrations of aflibercept bound to vascular endothelial growth factor with a t1/2 of 18 days. No antiaflibercept antibodies were detected. Stable disease was maintained for at least 10 weeks in 18 patients (47%), and 2 patients maintained on study for >1 year. Conclusion: Subcutaneous aflibercept was well tolerated and had manageable side effects. Its favorable pharmacokinetic profile and potential antitumor activity warrants further evaluation. ©2010 AACR.
Keywords: vasculotropin; adult; cancer chemotherapy; clinical article; controlled study; treatment outcome; aged; middle aged; vascular endothelial growth factor a; clinical trial; constipation; drug tolerability; fatigue; neutropenia; paresthesia; advanced cancer; area under the curve; cancer growth; diarrhea; drug safety; drug withdrawal; hypertension; side effect; solid tumor; antineoplastic agents; cancer patient; nuclear magnetic resonance imaging; endometrium carcinoma; anorexia; neoplasms; melanoma; controlled clinical trial; drug eruption; breast cancer; anemia; leukopenia; nausea; dehydration; myalgia; clinical assessment; fluid therapy; orthostatic hypotension; weight reduction; drug effect; kidney carcinoma; abdominal pain; backache; colorectal carcinoma; dizziness; drug dose escalation; drug fever; injection site reaction; sarcoma; syncope; lung embolism; chemotherapy induced emesis; confusion; drug induced headache; recombinant fusion proteins; head and neck cancer; multicenter study; immunogenicity; aflibercept; ovary carcinoma; mesothelioma; single drug dose; carcinoid; antihypertensive agent; thyroid carcinoma; optimal drug dose; maximum plasma concentration; time to maximum plasma concentration; drug blood level; maximum tolerated dose; phase 1 clinical trial; lung carcinogenesis; thymoma; dyspepsia; diplopia; angiogenesis inhibitors; brain ischemia; proteinuria; musculoskeletal disease; drug protein binding; drug formulation; anticoagulant agent; hemoptysis; appendix tumor; hoarseness; eructation; vagina cancer; hypodermoclysis
Journal Title: Clinical Cancer Research
Volume: 16
Issue: 1
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2010-01-01
Start Page: 358
End Page: 366
Language: English
DOI: 10.1158/1078-0432.ccr-09-2103
PUBMED: 20028764
PROVIDER: scopus
PMCID: PMC4211604
DOI/URL:
Notes: --- - "Cited By (since 1996): 6" - "Export Date: 20 April 2011" - "CODEN: CCREF" - "Source: Scopus"
Altmetric Score
MSK Authors
  1. Jakob Dupont
    64 Dupont
  2. Lawrence H Schwartz
    281 Schwartz
  3. Paul J Sabbatini
    199 Sabbatini
  4. William P Tew
    122 Tew
  5. David R Spriggs
    312 Spriggs