Annual Meeting Proceedings Part 1 - American Society of Clinical ...

172s Developmental Therapeutics—Clinical Pharmacology and Immunotherapy
TPS2621 General Poster Session (Board #11F), Mon, 8:00 AM-12:00 PM
Safety, pharmacokinetics, and antitumor activity of MEDI3617, a selective
angiopoietin inhibitor, in adult patients with advanced solid tumors.
Presenting Author: Ronald B. Natale, Cedars-Sinai Outpatient Cancer
Center, Los Angeles, CA
Background: MEDI3617 is an investigational monoclonal antibody that
inhibits angiogenesis by preventing the interaction of angiopoietin-1 and
angiopoietin-2 (Ang2) ligands with the Tie2 receptor. Methods: This is an
ongoing phase 1 dose-escalation and dose-expansion study in patients with
advanced solid tumors, Karnofsky performance status �70, and adequate
organ function. Patients were treated with escalating IV doses of MEDI3617
on day 1 of each 21 day cycle in cohorts of 3-6 patients. The objectives are
to evaluate the safety profile and determine the maximum tolerated dose,
dose-limiting toxicities (DLT), pharmacokinetics, pharmacodynamics, and
clinical activity of MEDI3617. Results: Preliminary data are presented for
21 patients (14M/7F), median age 65 yrs, evaluable for DLT. One DLT
occurred: grade 4 neutropenia lasting more than 7 days. The most
frequently reported drug-related adverse events (% of patients) were
fatigue (24%), diarrhea (19%), nausea (19%), dysgeusia (14%), and
headache (14%), all of which were � grade 2. All monotherapy dose levels
have completely enrolled patients without exceeding the maximum tolerated
dose. The exposure of MEDI3617 after the first dose showed a more
than dose-proportional increase. Suppression of free Ang2 was dosedependent.
Maximum accumulation of total Ang2 was observed at the
lowest administered dose. No anti-MEDI3617 neutralizing antibodies were
detected. Of the 21 patients, 4 continue on treatment (maximum of 6�
months in a patient with carcinoid tumor of the jejunum) as of the data
cut-off date. Of the 17 patients for whom response data are available, 5 had
stabilization of disease of 12 weeks or greater. Conclusions: Preliminary
safety and activity signals warrant continued evaluation of MEDI3617. This
study was funded by MedImmune, LLC.
TPS2622 General Poster Session (Board #11G), Mon, 8:00 AM-12:00 PM
Clinical pharmacokinetics (PK) of BMS-936558, a fully human anti-PD-1
monoclonal antibody. Presenting Author: Shruti Agrawal, Bristol-Myers
Squibb, Princeton, NJ
Background: BMS-936558 is a fully human IgG4 monoclonal antibody
targeted against human Programed Death-1 (PD1) receptor on activated T
and B lymphocytes. Blocking of PD-1 prevents these activated cells from
becoming anergic, thereby maintaining anti-tumor immunologic activity.
Methods: The PK of BMS-936558 was characterized with data from a
single ascending dose (SAD) and a multiple ascending dose (MAD) study in
subjects with advanced solid malignancies. Subjects received a single IV
infusion of 0.3 to 10 mg/kg BMS-936558 in the SAD study (MDX-1106-01
Study) and 0.1 to 10 mg/kg BMS-936558 every two weeks in the MAD
study (MDX-1106-03/CA209003 Study). The PK of BMS-936558 was
characterized by non-compartmental analysis of intensively sampled PK
data from a SAD study, as well as by population PK analysis of available
intensive and sparse PK data from the SAD and MAD studies, respectively.
Results: The PK of BMS-936558 is linear in the studied dose range with
dose-proportional increase in Cmax and AUC with low to moderate
(20-44%) inter-subject variability. Geometric mean clearance ranged from
0.13 - 0.19 mL/h/kg, whereas mean volume of distribution ranged from 83
-113 mL/kg. The range of mean terminal elimination half-life of BMS-
936558 is 17 to 25 days which is consistent with half-life of endogenous
IgG4. BMS-936558 PK was adequately described by a linear twocompartment
model, and there was no evidence of a contribution of target
mediated drug disposition to drug elimination within tested dose range.
Body weight and gender are potentially clinically significant covariate for
both clearance and volume of distribution (� 20% effect); and baseline
CRP, LDH, and albumin are potentially clinically significant covariates for
CL. The body weight normalized dosing employed produces trough concentrations
that are approximately constant over a wide range of body weights.
Conclusions: The pharmacokinetics of BMS-936558 is dose-proportional
and body weight normalized dosing is appropriate to ensure consistent
exposure over a wide range of body weights.
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