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

320s Genitourinary Cancer
TPS4674 General Poster Session (Board #14A), Sun, 8:00 AM-12:00 PM
Vinflunine maintenance therapy versus best supportive care (BSC) after
platinum combination in advanced bladder cancer: A phase II, randomized,
open-label study (MAJA study)—SOGUG 2011-02. Presenting Author:
Sonia Maciá, Hospital General de Elda, Elda, Spain
Background: Vinflunine is a novel microtubule inhibitor currently approved
by EMA as treatment after platinum progression, in metastasic bladder
cancer. It is distinguished from the other vinca-alkaloids because it binds
relatively weakly to tubulin, suggesting an improved tolerance profile as a
result of less neuropathy. Based on the fact that no cumulative toxicity is
expected and the results reported in second-line, we aim to test the role of
vinflunine in first line therapy, as maintenance treatment for patients who
obtain clinical benefit after platinum. Methods: This is a multicenter,
randomized, open label, proof-of-concept study that will be performed in
20 institutions members of the Spanish Oncology Genitourinary Group
(SOGUG). Subjects will be randomized in a 1:1 ratio to receive vinflunine
320 mg/m2 every 21 days plus BSC vs BSC alone until disease progression.
Vinflunine dose will be 280mg/m2 for patients with PS�1, age � 75 years,
prior pelvic radiotherapy or creatinine clearance Cr �60ml/min. Stratification
factors are: 1) Scheduled dose at randomization (320 vs 280mg/m2)
2) Liver metastasis (Y/N). Main inclusion criteria are: Subjects �18 and�
80 years of age with histological diagnosis of transitional cell carcinoma of
the urothelial tract and measurable disease with radiological response or
stabilization after 6 cycles of a platinum containing doublet for metastasic/
advanced disease. Primary objective will be progression free survival (PFS),
considering as clinically relevant 6 months in experimental arm. To
guarantee an overall type-1 � error (one side) no greater than 0.05 and a
type II (�) error 0.1 for the primary endpoint of PFS, a sample size of 86
patients allocated in a 1:1 ratio is planned. Recruitment is scheduled to
start by February 2012. A pharmacogenomic translational study will also
be conducted.
TPS4676 General Poster Session (Board #14C), Sun, 8:00 AM-12:00 PM
Phase II trial of gemcitabine and cisplatin plus ipilimumab as first-line
treatment for metastatic urothelial carcinoma. Presenting Author: Benjamin
Adam Gartrell, Division of Hematology and Medical Oncology, The
Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY
Background: While metastatic urothelial carcinoma is a chemosensitive
neoplasm, current therapeutic approaches are inadequate. Preclinical and
clinical data suggests that bladder cancer is immunogenic. For example,
CD8� tumor infiltrating lymphocytes correlate with survival in patients
with muscle-invasive disease (Sharma, PNAS, 2007). However, immunotherapeutic
approaches have been rarely investigated for advanced urothelial
cancer. CTLA4 blockade with ipilimumab is a novel approach to
immunotherapy that interrupts T-cell pathways responsible for immune
down-regulation or tolerance. In a proof of concept study, ipilimumab was
administered to 12 patients with muscle-invasive disease preoperatively
(Carthon, Clin Can Res, 2010). Treatment resulted in perivascular infiltration
of cells positive for CD3, CD8, CD4, and granzyme and intriguing
evidence of antitumor activity. In the current trial, we will explore a
“phased” schedule of chemotherapy and ipilimumab with the goal of
“autovaccinating” patients to tumor antigen with chemotherapy prior to
introduction of immune checkpoint blockade. Methods: We have initiated a
phase II clinical trial of gemcitabine (G), cisplatin (C), plus ipilimumab in
chemonaive patients with unresectable and/or metastatic urothelial cancer
within the Hoosier Oncology Group network. During cycles 1 and 2, G
(1000 mg/m2 D day 1 � 8) and C (70 mg/m2 D 1) will be administered
every 21 days without ipilimumab. During cycles 3-6, GC plus ipilimumab
(10 mg/kg day 1) will be administered every 21 days. Patients without
evidence of disease progression after completion cycle 6 will continue
single-agent ipilimumab “maintenance” every 3 months. The primary
objective is to determine the 1-year overall survival. The trial will enroll 36
patients and is powered to detect an improvement in 1-year survival from
60% to 80%. Secondary objectives include progression-free survival,
disease control rate, safety, and immunologic outcomes. Correlative
studies will include serial measurements of the global composition of
immune cells in the blood by polychromatic flow cytometry, whole blood
transcriptional profiling, and tumor-antigen specific CD8� T cells assays.
TPS4675^ General Poster Session (Board #14B), Sun, 8:00 AM-12:00 PM
Randomized phase II study of docetaxel with or without ramucirumab
(IMC-1121B) or icrucumab (IMC-18F1) in patients with urothelial transitional
cell carcinoma (TCC) following progression on first-line platinumbased
therapy. Presenting Author: Daniel Peter Petrylak, Columbia
University Medical Center, New York, NY
Background: The vascular endothelial growth factor (VEGF) pathway may
play an important role in the pathogenesis of bladder cancer. Two
antibodies (ramucirumab or icrucumab) in combination with docetaxel are
being tested in this clinical study. Ramucirumab is a fully human IgG1
monoclonal antibody (MAb) that specifically binds with high affinity to
VEGF receptor-2 (VEGFR-2), thereby blocking the interaction of VEGF
ligands. Ramucirumab inhibits VEGF-mediated proliferation of human
endothelial cells and migration of human leukemia cells. Icrucumab is a
fully human IgG1 MAb that specifically binds with high affinity to VEGFR-1
and blocks the binding of VEGF-A, VEGF-B, and placental growth factor
(PlGF) to the receptor, thereby inhibiting subsequent signaling. Blockage
of VEGFR-1 and VEGFR-2 by antibodies demonstrates antiangiogenic and
antitumor activity and prevents dissemination and growth of lung metastases
in several tumor xenograft models. Methods: This study includes
patients (pts) with TCC with progressive disease after prior platinum-based
therapy. Pts are randomized equally to 1 of 3 open-label treatments given
on a 21-day cycle: docetaxel (75 mg/m2 ) on Day 1 (Arm A); docetaxel on
Day 1 and ramucirumab (10 mg/kg) on Day 1 (Arm B); or docetaxel on Day
1 and icrucumab (12 mg/kg) on Days 1 and 8 (Arm C). Randomization is
stratified by the absence/presence of visceral metastases and receipt of
prior antiangiogenic therapy. The primary endpoint is progression-free
survival (PFS). Secondary outcome measures include response rate and
duration of response, overall survival, and pharmacodynamic markers,
including circulating levels of PlGF, VEGF-A, VEGF-B, soluble VEGFR-1,
and soluble VEGFR-2. Exploratory analyses of VEGF, VEGFR-1, and
VEGFR-2 genetic polymorphisms will be performed. As of 12 January
2012, approximately 20% of 138 planned pts were randomized in the US
and Canada. The sample size will allow differentiation of an expected
increase in median PFS from 3.0 months to 4.5 months with a one-sided
alpha of 0.1 and a power of 71%. ClinicalTrials.gov identifier:
NCT01282463.
TPS4677 General Poster Session (Board #14D), Sun, 8:00 AM-12:00 PM
Phase II study of everolimus (E) in refractory germ cell tumors (GCTs).
Presenting Author: Michal Mego, Department of Medical Oncology, School
of Medicine, Comenius University, National Cancer Institute, Bratislava,
Slovakia
Background: GCTs represent a model for the cure of cancer. Nonetheless, a
small proportion of patients (pts) develop disease recurrence. Because of
insufficient results in the treatment of relapsed GCTs, evaluation of new
treatments is a priority. Loss of the tumor suppressor gene PTEN (phosphatase
and tensin homolog) marks the transition from intratubular germ cell
neoplasias (ITGCN) to invasive GCTs. In the testis, PTEN was abundantly
expressed in germ cells whereas it was virtually absent from 56% of
seminomas as well as from 86% of embryonal carcinomas and virtually all
teratomas. On the contrary, ITGCN intensely expressed PTEN, indicating
that loss of PTEN expression is not in early event in GCTs development, but
is associated with disease progression. PTEN inactivation is associated
with dysregulation of PI3K/Akt pathway and increased mTOR signalling.
We hypothesize that dysregulation of PI3K/Akt pathway due to PTEN
inactivation in GCTs suggests that these pts could have greater benefit from
mTOR inhibition. Methods: In December 2011, National Cancer Institute of
Slovakia launched an one arm, two-staged phase II study aimed to evaluate
the efficacy and toxicity of E in pts with refractory GCTs. The primary
objective is to determine the efficacy of E in patients with refractory GCTs.
Secondary objectives includes favourable response rate, time to progression
and safety. The pts with radiological and/or serological proof of
relapsed GCTs, who were not amenable to be cured by chemotherapy or
surgery and who failed at least two platinum-based regimens or one
platinum regimen in case of platinum-refractory disease or primary mediastinal
non-seminomatous GCTs were eligible. All other standard inclusion
and exclusion criteria for study of salvage treatment in refractory GCTs pts
were applied. E will be administered at a dose of 10mg daily until
progression or unacceptable toxicity. Assuming a response rate of clinical
interest of �40%, a minimal response rate of 20%, a probability of 5% for
rejecting an active drug, and a probability of 20% to further evaluate an
ineffective drug, 18 pts will be enrolled into the first cohort. If �4
responses will be observed, the study will be terminated, otherwise, it will
be continued with a second cohort of 20 pts.
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