A Phase I First-in-Human Study of Nesvacumab (REGN910), a Fully Human Anti-Angiopoietin-2 (Ang2) Monoclonal Antibody, in Patients with Advanced Solid Tumors.
OBJECTIVE
Nesvacumab (REGN910) is a fully human immunoglobulin G1 (IgG1) monoclonal antibody that specifically binds and inactivates the Tie2 receptor ligand Ang2 with high affinity, but shows no binding to Ang1. The main objectives of this trial were to determine the safety, tolerability, dose-limiting toxicities (DLT), and recommended phase II dose (RP2D) of nesvacumab.


METHODS
Nesvacumab was administered intravenously every two weeks with dose escalations from 1 to 20 mg/kg in patients with advanced solid tumors.


RESULTS
A total of 47 patients were treated with nesvacumab. No patients in the dose escalation phase experienced DLTs, therefore a maximum tolerated dose (MTD) was not reached. The most common nesvacumab-related adverse events were fatigue (23.4%), peripheral edema (21.3%), decreased appetite, and diarrhea (each 10.6%; all grade ≤ 2). Nesvacumab was characterized by linear kinetics and had a terminal half-life of 6.35 to 9.66 days in a dose-independent manner. Best response by RECIST 1.1 in 43 evaluable patients included 1 partial response (adrenocortical carcinoma) of 24 weeks duration. Two patients with hepatocellular carcinoma had stable disease (SD) > 16 weeks, with tumor regression and >50% decrease in α-fetoprotein. Analyses of putative angiogenesis biomarkers in serum and tumor biopsies were uninformative for treatment duration.


CONCLUSIONS
Nesvacumab safety profile was acceptable at all dose levels tested. Preliminary antitumor activity was observed in patients with treatment-refractory advanced solid tumors. On the basis of cumulative safety, antitumor activity, pharmacokinetic and pharmacodynamic data, the 20 mg/kg dose was determined to be the RP2D.
South Texas Accelerated Research Therapeutics (START), San Antonio, Texas. Kyri.Papadopoulos@start.stoh.com.
Kyriakos P
KP
Papadopoulos
Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California.
Robin Kate
RK
Kelley
South Texas Accelerated Research Therapeutics (START), San Antonio, Texas.
Anthony W
AW
Tolcher
Princess Margaret Cancer Centre, Toronto, Ontario.
Albiruni R Abdul
AR
Razak
Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California.
Katherine
K
Van Loon
South Texas Accelerated Research Therapeutics (START), San Antonio, Texas.
Amita
A
Patnaik
Princess Margaret Cancer Centre, Toronto, Ontario.
Philippe L
PL
Bedard
Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California.
Ariceli A
AA
Alfaro
South Texas Accelerated Research Therapeutics (START), San Antonio, Texas.
Muralidhar
M
Beeram
Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
Lieve
L
Adriaens
Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
Carrie M
CM
Brownstein
Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
Israel
I
Lowy
Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
Ana
A
Kostic
Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
Pamela A
PA
Trail
Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
Bo
B
Gao
Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
A Thomas
AT
DiCioccio
Princess Margaret Cancer Centre, Toronto, Ontario.
Lillian L
LL
Siu
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D042702:Angiopoietin-2 / Q000037:antagonists & inhibitors*; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015415:Biomarkers; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D016896:Treatment Outcome; D055815:Young Adult
D042702:Angiopoietin-2; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D015415:Biomarkers