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

170s Developmental Therapeutics—Clinical Pharmacology and Immunotherapy
TPS2613 General Poster Session (Board #10F), Mon, 8:00 AM-12:00 PM
An exploratory study to investigate the immunomodulatory activity of
BMS-936558 in patients with metastatic clear-cell renal cell carcinoma.
Presenting Author: Charles G. Drake, Sidney Kimmel Comprehensive
Cancer Center at Johns Hopkins University, Baltimore, MD
Background: With the enhanced understanding of the immune response to a
tumor, new immunotherapeutic agents may expand treatment options for
metastatic renal cell carcinoma (mRCC). The programmed death-1 (PD-1)
receptor is upregulated by activated lymphocytes, and upon binding to its
ligands, inhibits lymphocyte function. In a phase 1 study of the anti-PD-1
monoclonal antibody BMS-936558, encouraging antitumor activity has
been observed in patients with previously treated mRCC. Responses
occurred in extensive mRCC and were durable in many patients. Here we
describe an exploratory study to investigate the immune-regulatory activity
of various doses of BMS-936558 in patients with metastatic clear-cell
RCC. Methods: Eighty patients with metastatic clear-cell RCC will be
enrolled in this open-label, parallel group, randomized study. Patients who
have received prior treatment with �3 therapies, including �1 antiangiogenic
therapy, will be enrolled in Arms 1-3 (~20 patients per arm); 20
treatment-naïve patients will be enrolled in Arm 4. BMS-936558 will be
administered every 3 weeks until disease progression or unacceptable
toxicity at 0.3 mg/kg (Arm 1), 2 mg/kg (Arm 2), and 10 mg/kg (Arms 3 and
4). Patients in the 0.3-mg/kg group may escalate to 2 mg/kg if not
responding. Tumor assessments will occur every 6 weeks for the first 12
months then every 12 weeks for the remainder of the study. The primary
objective is to evaluate the effects of BMS-936558 on the frequency of
circulating immune cell subsets, levels of soluble factors associated with
immune responses, and tumor infiltrating lymphocyte populations (based
on pre-treatment and week 5 paired biopsies). Secondary objectives are to
assess the safety, tolerability, antitumor activity, and immunogenicity of
BMS-936558. Exploratory objectives include the association of clinical
activity and safety with selected biomarkers in peripheral blood and tumor
microenvironment and the characterization of the pharmacokinetics of
BMS-936558. As of February 1, 2012, 30 patients were enrolled.
TPS2615 General Poster Session (Board #10H), Mon, 8:00 AM-12:00 PM
A phase I study of BMS-936558 in combination with gemcitabine/
cisplatin, pemetrexed/cisplatin, or carboplatin/paclitaxel in patients with
treatment-naive, stage IIIB/IV non-small-cell lung cancer. Presenting
Author: Scott N. Gettinger, Yale University School of Medicine, New Haven,
CT
Background: Lung cancer is the leading cause of cancer-related mortality
worldwide and non-small-cell lung cancer (NSCLC) accounts for ~85% of
all cases. Platinum-based chemotherapy alone or in combination with
bevacizumab is considered first-line standard of care for advanced NSCLC.
Despite such therapy, most patients (pts) will experience disease progression
within 6 months and die from their disease within 1 year. Programmed
death-1 (PD-1) is a coinhibitory receptor that negatively regulates T-cell
activation; PD-1 expression by tumor infiltrating lymphocytes is associated
with poor prognosis in NSCLC. BMS-936558 is a fully human anti-PD-1
monoclonal antibody that blocks ligand interaction with PD-L1 and PD-L2.
In a phase 1 trial, BMS-936558 had antitumor activity at doses of 1-10
mg/kg in pts with advanced tumors, and impressive tumor responses in
heavily pre-treated pts with NSCLC. Here we describe a phase 1 study
planned to evaluate the safety and tolerability of BMS-936558 in combination
with 3 standard, platinum-based doublet chemotherapy regimens in
pts with NSCLC. Methods: Treatment-naïve pts with stage IIIB/IV NSCLC
will be enrolled. Treatment arms will include: A) gemcitabine 1250 mg/M2 on day 1 (D1) and day 8 (D8)/cisplatin 75 mg/M2 D1/BMS-936558 D1; B)
pemetrexed 500 mg/M2 D1/cisplatin 75 mg/M2 D1/BMS-936558 D1; and
C) carboplatin AUC 6 D1/paclitaxel 200 mg/M2 D1/BMS-936558 D1. The
starting dose of BMS-936558 will be 10 mg/kg for each treatment arm. A
decision to de-escalate to a lower dose (2 or 0.3 mg/kg) will be guided by
the number of dose-limiting toxicities reported per treatment arm. Chemotherapy
will be given for 4 cycles (1 cycle � 3 weeks). BMS-936558 will be
administered every 3 weeks until disease progression, intolerable toxicity,
or withdrawal of consent. The primary objectives are to assess safety and
tolerability by measuring the frequency of adverse events (AEs), serious
AEs, and laboratory abnormalities; secondary objectives are to determine
the overall response rate and disease control rates based on RECIST 1.1. As
of February 1, 2012, 2 patients were enrolled.
TPS2614 General Poster Session (Board #10G), Mon, 8:00 AM-12:00 PM
A phase I study of BMS-936558 plus sunitinib or pazopanib in patients
with metastatic renal cell carcinoma. Presenting Author: Hans J. Hammers,
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University,
Baltimore, MD
Background: Standard treatments for metastatic renal cell carcinoma
(mRCC) block the vascular endothelial growth factor pathway (eg, sunitinib,
pazopanib) or mammalian target of rapamycin pathway (e.g., temsirolimus,
everolimus). However, most patients (pts) develop resistance and complete
responses are rare. Upregulation of programmed death-1 (PD-1) in tumor
infiltrating lymphoctyes, and its ligand PD-L1 in tumors, is associated with
more aggressive disease and poor prognosis. Blocking the PD-1/PD-L1
interaction is a novel immunotherapeutic approach for mRCC. In preliminary
results of a phase I trial, the anti-PD-1 monoclonal antibody BMS-
936558 had antitumor activity in pts with advanced tumors, including
objective responses (ORs) in 6 of 18 pts with mRCC. Here we describe a
phase I study planned to evaluate the safety, tolerability, and maximum
tolerated dose (MTD) of BMS-936558, when combined with sunitinib or
pazopanib in pts with mRCC. Methods: This open-label study will have two
parallel treatment arms (BMS-936558 plus sunitinib and BMS-936558
plus pazopanib) conducted in two parts (dose escalation and dose expansion).
Pts must have received �1 prior systemic therapy to be eligible for
dose escalation. Only treatment-naïve pts will be eligible for dose expansion.
Up to 36 pts (18 per arm) will be treated in the dose-escalation phase.
After determining the MTD of BMS-936558, treatment-naïve pts will be
enrolled to expansion cohorts allowing 24 pts to be treated at the MTD of
each arm. Each treatment cycle will be 6 weeks, with BMS-936558 dosed
on Days 1 and 22 and sunitinib or pazopanib given according to product
label. Adverse events will be graded according to NCI CTCAE v4.0. Disease
will be assessed every 6 weeks for the first four assessments and then every
12 weeks until disease progression. Pts will be treated until unacceptable
toxicity, disease progression, or withdrawal of consent. The safety profile in
pts treated at the MTD will be used to determine the recommended phase II
study dose of BMS-936558 in each combination arm. Secondary objectives
will include OR rate and duration of response based on RECIST 1.1.
Exploratory analyses will investigate predictive biomarkers of BMS-
936558.
TPS2616 General Poster Session (Board #11A), Mon, 8:00 AM-12:00 PM
A phase Ib/II study testing the safety and efficacy of combined inhibition of
the AKT/PI3K and AR signaling pathways in castration-resistant prostate
cancer: GDC-0068 or GDC-0980 with abiraterone acetate versus abiraterone
acetate. Presenting Author: Roel Peter Funke, Genentech, South
San Francisco, CA
Background: Loss of PTEN, leading to activation of the AKT/PI3K pathway is
frequent and associated with poor prognosis in prostate cancer. In addition,
AR and AKT/PI3K cross-regulate by reciprocal feedback and combined
inhibition of both pathways resulted in improved preclinical efficacy. This
study is designed to evaluate the effect of combined inhibition of AR
pathway (with abiraterone) and AKT/PI3K pathway (with either GDC-0068
or GDC-0980). GDC-0068 is a potent, selective ATP-competitive inhibitor
of AKT1, 2, and 3. Preclinical studies showed that cell and tumor models
with PTEN loss are more likely to be sensitive to GDC-0068. GDC-0068
was generally well tolerated in phase I and a MTD of 600 mg daily was
identified. GDC-0980 is a potent pan-inhibitor of Class I PI3K and inhibits
wild-type and mutated p110� isoforms, as well as mTOR kinase. The
recommended phase II dose (RP2D) for single-agent GDC-0980 is 40 mg
daily. Methods: This study will enroll CRPC patients previously treated with
docetaxel. In phase Ib, the RP2D will be determined separately for
GDC-0068 and GDC-0980 in combination with abiraterone 1000 mg qd
and prednisone 5mg bid. In phase II, patients will be randomized 1:1:1 to
receive GDC-0068 � abiraterone, GDC-0980 � abiraterone, or placebo �
abiraterone. The primary endpoint of phase II is PFS measured by PCWG2
in all patients and in patients with PTEN loss. Secondary endpoints include
OS, PSA response rate, ORR, safety, Pharmacokinetics and biomarker
analyses. The effect of each treatment on the number of circulating tumor
cells will be assessed. Primary and secondary analyses will include all
randomized patients and will be conducted according to assigned treatment
arm. Kaplan-Meier methodology will be used to estimate median PFS
for each arm. Up to 24 patients are planned to be enrolled in phase Ib; 240
patients (80 per arm) are planned for phase II. This study is open for
accrual; to date 2 patients have been enrolled in phase Ib.
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