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

Developmental Therapeutics—Clinical Pharmacology and Immunotherapy
2512 Clinical Science Symposium, Sat, 1:15 PM-2:45 PM
Phase I study of MK-3475 (anti-PD-1 monoclonal antibody) in patients
with advanced solid tumors. Presenting Author: Amita Patnaik, South
Texas Accelerated Research Therapeutics, LLC, San Antonio, TX
Background: Programmed death-1 (PD-1) is an inhibitory T-cell coreceptor that
may lead to suppression of antitumor immunity. MK-3475 is a humanized
monoclonal IgG4 antibody against PD-1. Preclinically, MK-3475 has shown
antitumor activity in multiple tumor types. This first-in-human phase I trial
explored safety, PK, PD, and antitumor activity of MK-3475. Methods: An
open-label, dose escalation study was conducted in patients with advanced
malignancy refractory to standard therapy. Cohorts of 3-6 patients were
enrolled (3�3 design) at escalating IV doses of 1, 3, and 10 mg/kg. Following
an initial dose and 28-day Cycle 1, patients were allowed to subsequently
receive multiple doses given every 2 wks. Radiographic assessment was
conducted every 8 wks using RECIST 1.1 guidelines. Results: Nine patients, 3
at each dose level, completed the dose-limiting toxicity (DLT) period (28 d).
Patients had non–small cell lung cancer (NSCLC, n�3), rectal cancer (n�2),
melanoma (MEL, n�2), sarcoma (n�1), or carcinoid (n�1). To date, a total of
63 doses were administered (median 7/patient; max 12) without DLT.
Drug-related adverse events (AEs) across all doses included Grade 1 fatigue
(n�3), nausea (n�2), diarrhea (n�1), dysgeusia (n�1), breast pain (n�1),
and pruritus (n�1). One drug-related Grade 2 AE of pruritus was reported. No
drug-related AEs � Grade 3 were observed. PK data are shown in the table.
Based on RECIST, 1 patient with MEL on therapy �6 mths had a partial
response, and preliminary evidence of tumor size reduction (stable disease)
was observed in 3 additional patients with advanced cancer. Conclusions:
MK-3475 was well-tolerated without DLT across 3 tested dose levels.
Evidence of antitumor activity was observed. Enrollment continues to obtain
additional safety, PK, and efficacy data; updated data will be presented at the
meeting.
Mean (CV%) PK parameter values of MK-3475 following single IV dose of
1, 3, or 10 mg/kg in cycle 1.
Dose (mg/kg) N Cmax (·g/mL) AUC (0-28day) (�g·day/mL) a t1/2 (day)
1 4 6.8 (23) 163 (20) b 15.1 (41) b
3 3 109 (26) 990 (23) 21.7 (11)
10 2 337 (8) 2,640 (30) 13.6 (28)
aPK sampling up to 28 days following first IV administration; therefore t1/2 not
fully characterized.
bN�3 due to subject discontinuation.
2515 Poster Discussion Session (Board #3), Sat, 8:00 AM-12:00 PM and
12:00 PM-1:00 PM
Radiotherapy plus the anti-EGFR mAb nimotuzumab or placebo for the
treatment of high-grade glioma patients. Presenting Author: Maria Teresa
Solomon, Calixto García Hospital, Havana, Cuba
Background: Despite remarkable advances in multimodal therapy, high
grade glioma (HGG) patients still face a poor prognosis. EGFR is well
validated as a primary contributor of HGG initiation and progression.
Nimotuzumab is a humanized monoclonal antibody (mAbs) that recognizes
the EGFR extracellular domain. While it has similar preclinical and clinical
activity when compared to other anti-EGFR mAbs, it does not induce skin
toxicity or hypomagnesemia. Methods: A randomized, double blind, multicentric
clinical trial was conducted in 70 anaplastic astrocytoma (AA) and
glioblastoma multiforme (GBM) patients that received radiotherapy (RT)
plus nimotuzumab or placebo. Patients received 6 weekly doses of
nimotuzumab or placebo together with radiotherapy. Treatment was maintained
every 3 weeks, until completing 1 year of treatment. GBM patients
did not receive temozolomide since the drug cannot be sold to Cuba. The
objectives of this study were to assess the overall survival, progression free
survival (PFS), response rate, immunogenicity and safety in both treatment
groups. Results: Seventy patients were included in the study: 41 AA and 29
GBM. The median cumulative dose was 3600 mg of nimotuzumab and the
median antibody number of doses was 16. The combination of nimotuzumab
and radiotherapy was very safe. The most prevalent related adverse
events included grade 1-2 nausea, fever, tremors and anorexia. There was
no increasing toxicity with repeated drug exposure. No anti-idyotipic
response was detected. The mean and median survival time for subjects
treated with nimotuzumab and RT was 31.06 and 17.76 months while the
mean and median survival time for controls was 21.07 and 12.63 months,
respectively. For the evaluable patients of the AA stratum, the median
survival time was 44.56 months (active drug) vs. 14.6 months (control).
For the evaluable patients in the GBM cohort, the median survival time was
16.06 months (nimotuzumab arm) vs. 8.36 months (placebo arm). Median
PFS was 18.23 vs. 6.25 months. Conclusions: In this randomized trial,
nimotuzumab continues showing an excellent safety profile and positive
efficacy results in patients with high grade glioma in combination with
irradiation.
145s
2514 Poster Discussion Session (Board #2), Sat, 8:00 AM-12:00 PM and
12:00 PM-1:00 PM
Effect of stimulation of natural killer cells with an anti-CD137 mAb on the
efficacy of trastuzumab, cetuximab, and rituximab. Presenting Author:
Holbrook Edwin Kohrt, Stanford Cancer Center, Stanford, CA
Background: Antibody-dependent cell-mediated cytotoxicity (ADCC), mediated
by natural killer (NK) cells, plays an important role in the efficacy of
monoclonal antibodies (mAb)s. CD137 is a costimulatory molecule expressed
on immune cells following activation, including NK cells. We
hypothesize that as the antitumor efficacy of mAbs is due to ADCC, their
activity can be enhanced by stimulation of NK cells with an anti-CD137
agonistic mAb. Methods: Upregulation of CD137 on NK cells was assessed
using CD20�lymphoma, HER2�breast, and EGFR�head and neck cell
lines and primary patient samples. NK cell degranulation, cytokine release
and cytotoxicity were assessed by CD107a mobilization, IFN-� secretion,
and chromium release. Mechanism of synergy was explored by cell
depletion in an immune competent mouse model. Xenotransplanted
models were used to demonstrate anti-tumor activity and sufficiency of an
innate immune response. Results: NK cells in human primary patient
samples do not express CD137 at baseline, however CD137 is highly
upregulated when encountering mAb-coated tumor cells. MAb-induced NK
cell degranulation and cytotoxicity are enhanced by anti-CD137 agonistic
mAb. In a murine lymphoma model, anti-CD137 mAb significantly enhances
anti-tumor activity of anti-CD20 mAb leading to complete tumor
resolution and prolonged survival. NK cell depletion completely abrogates
the therapeutic effect. In seven xenotransplant models, sequential administration
of rituximab, trastuzumab or cetuximab plus anti-CD137 mAb
provided superior reduction in tumor burden and prolonged overall survival.
In a phase 0 biomarker study, level of CD137 expression on circulating and
intratumoral NK cells was influenced by disease burden, prior treatment,
Fc�RIII polymorphism, and time since mAb therapy. Conclusions: Our
results demonstrate the synergy of anti-CD137 mAb and a tumor-targeting
mAb by stimulation of mAb-activated NK cells with anti-CD137 mAb to
enhance ADCC. These results support a novel, sequential antibody approach
against CD20�B cell, HER2�breast, and EGFR�head and neck
malignancies by targeting first the tumor and then the host immune system.
2516 Poster Discussion Session (Board #4), Sat, 8:00 AM-12:00 PM and
12:00 PM-1:00 PM
Safety of the antimyostatin monoclonal antibody LY2495655 in healthy
subjects and patients with advanced cancer. Presenting Author: Gayle S.
Jameson, Virginia G. Piper Cancer Center/Translational Genomics Research
Institute, Scottsdale, AZ
Background: Skeletal muscle wasting (cachexia) is a prevalent and not
readily managed condition in advanced cancer patients. LY2495655 is a
humanized monoclonal antibody to myostatin, which has demonstrated
positive effects on cachexia measures in animal models. We present phase
I trial data on use of LY2495655 in healthy volunteers (Study 1) and
interim data from an ongoing phase I study in patients with advanced
cancer (Study 2). Methods: Study 1 was a randomized, placebo-controlled,
blinded, single-dose, parallel, dose-escalation study evaluating the safety
and tolerability of IV or SC LY2495655 (0.7 mg-700 mg). Study 2 is an
ongoing nonrandomized, open-label study evaluating the safety and pharmacokinetics
(PKs) of LY2495655 in patients with advanced cancer not
receiving chemotherapy. Dose cohorts (2 mg-700 mg, �3 patients per
cohort) were to be treated until the maximum tolerated dose (MTD) was
met, or the highest dose (700 mg) cohort was completed. Final locked data
from Study 1 and interim data from the dose escalation phase of Study 2
were used in the analyses. Results: In Study 1, 64 healthy volunteers were
enrolled (48 LY2495655, 16 placebo). In Study 2, 22 patients had
received treatment with LY2495655 at the time of the analysis. In both
studies, all doses of LY2495655 were well tolerated (no DLTs were
observed and MTD was not reached), and nonlinear PKs were observed
(most evident in lower dose levels). In Study 1, thigh muscle volume
generally increased with LY2495655. In Study 2, increased muscle
volume was observed only at 21-mg and 70-mg doses. Consistent increases
in hand grip strength and improvements in functional tests were observed
at doses �21 mg. Conclusions: There were no unusual safety concerns in
healthy subjects or cancer patients. PK results were consistent between the
2 studies. Increases in muscle volume were observed in both studies, with
concomitant improvement in functional measures. However, there is no
clear trend in dose-dependent efficacy, possibly due to extremely small
sample sizes and patient heterogeneity. Enrollment in Study 2 continues
with dose expansion cohorts. A Phase 2 study is ongoing in pancreatic
cancer patients.
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