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

566s Melanoma/Skin Cancers
TPS8604 General Poster Session (Board #39F), Sun, 8:00 AM-12:00 PM
OPTiM: A randomized phase III trial to evaluate the efficacy and safety of
talimogene laherparepvec (T-VEC) compared with subcutaneously (sc)
administered GM-CSF for the treatment (tx) of unresectable stage IIIb, IIIc,
and IV melanoma. Presenting Author: Howard Kaufman, Rush University
Medical Center, Chicago, IL
Background: T-VEC (formerly OncoVEXGM-CSF ) is an oncolytic HSV1 that
selectively replicates in tumors. The proposed MOA includes lytic destruction
of injected tumors and induction of a systemic anti-tumor immune
response enhanced by local GM-CSF expression. Intratumoral T-VEC tx in a
50-patient (pt) ph II study in advanced melanoma (Stage IIIc-IVM1c) was
well tolerated and achieved a high rate and duration of response, including
20% CR (Senzer et al., JCO 2009; 27: 5763-71). As immune effects may
be delayed, progressive disease (PD) often occurred before response.
Based on the ph II data, a randomized ph III trial of T-VEC in unresectable
melanoma (the OPTiM study; clinical trials registry NCT00769704) was
designed taking into account the response patterns seen with T-VEC and
other immunotherapeutic agents. T-VEC is the first �armed� oncolytic agent
to enter pivotal testing worldwide. Methods: OPTiM compares the efficacy
and safety of intratumoral T-VEC to sc GM-CSF in 430 pts with treated or
untreated unresectable Stage IIIb-IVM1c melanoma stratified by typical
prognostic factors. Pts are randomized 2:1 to T-VEC (priming dose of up to
4x106pfu intratumorally then 3 wks later by up to 4x108pfu Q2W) or
GM-CSF 125 �g/m2 qd sc x 14 days every 28 days. Key eligibility criteria
are � 18 yrs old, ECOG 0-1, and at least 1 injectable cutaneous, sc, or
nodal tumor. The primary endpoint is durable response rate (DRR: CR or PR
continuously maintained for � 6 mo initiating within 12 mo of starting tx;
secondary endpoints include OS. Responses are subject to independent
review. Pts are treated until wk 24, even with PD. Thereafter pts are treated
until clinically significant PD, CR, or for 1 yr. The study has 90% power to
show a 10% difference in DRR with 2-sided Fisher Exact Test (� � 5%).
Enrollment closed in July 2011 with 439 pts randomized in the US, UK, S
Africa, and Canada. Interim analysis in Dec 2010 on 75 pts on study � 9
mo concluded that the study should continue. Results are expected during
2012. Conclusions: T-VEC provides a novel potential tx for melanoma. This
pivotal ph III study is expected to report during 2012.
TPS8606 General Poster Session (Board #39H), Sun, 8:00 AM-12:00 PM
Pilot evaluation of sulforaphane in melanoma patients with multiple
atypical nevi: Tissue STAT1 and STAT3 as risk markers. Presenting Author:
David Lobur, University of Pittsburgh Medical Center, Pittsburgh, PA
Background: Increasing incidence and the poor prognosis of advanced
melanoma argue for prevention efforts. Primary prevention and ultraviolet
radiation (UVR) reduction have failed to gain traction in the population,
making chemoprevention increasingly attractive. Sulforaphanes (SFN) are
bioactive cruciferous compounds rich in the Brassica family, especially
broccoli sprouts. Topical broccoli sprout extracts (BSE) decrease UVR
erythema response in human skin, and may protect against UVR DNA
damage. We have shown SFN inhibition of STAT3, which is constitutively
activated in melanoma. We have therefore initiated a pilot study to evaluate
BSE SFN in relation to melanoma progression biomarkers, and expression
of STAT proteins of atypical melanocytic nevi. Methods: Melanoma patients
with �2 atypical nevi are eligible for this trial, which aims to define the
safety and clinico-pathological response to oral BSE-SFN. Secondary
objectives are documentation of pharmacokinetics and pharmacodynamics
of BSE-SFN, and the modulation of STAT 1/3 expression in atypical nevi
and normal skin. Baseline photo-documentation and atypical nevus biopsy
is performed to assess histopathological atypia and STAT 1/3 expression.
Adjacent normal skin biopsies will establish baseline skin SFN levels. Six
subjects per group will be accrued at daily dosages of 50, 100, and 200
�M. Subjects must abstain from dietary glucosinolates and isothiocyanates
for the study duration and maintain food diaries. Following 27 days of
BSE-SFN, blood samples, photography of index atypical nevi, and biopsies
of selected atypical nevi and normal skin will be obtained. The three dosage
groups will be analyzed for changes in atypia, SFN localization histopathology,
and STAT 1/3 expression in the nevi and skin harvested at baseline and
at study completion. This trial, UPCI 10-114, has received an IND and is
IRB-approved. Accrual is planned to be completed during 2012-13.
TPS8605 General Poster Session (Board #39G), Sun, 8:00 AM-12:00 PM
A randomized phase II study of sunitinib versus dacarbazine in the
treatment of patients with metastatic uveal melanoma. Presenting Author:
Ernie Marshall, Clatterbridge Centre for Oncology, Wirral, United Kingdom
Background: Metastatic uveal melanoma represents an orphan disease area
with a median survival of less than 6 months. There is currently no effective
systemic therapy for metastatic uveal melanoma and few clinical trials have
been conducted. In the absence of phase III data, many patients in the UK
continue to receive single agent dacarbazine or best supportive care outside
of the context of clinical trials. Uveal melanoma is characterized by
activation of the MAP kinase pathway via functionally activating mutations
in Gnaq/11. Evidence also suggests that dysfunctional c-Kit signalling and
angiogenesis may both play a role in disease progression and a small
single-arm phase II trial recently reported preliminary activity using the
multi-targeted receptor tyrosine kinase inhibitor, sunitinib (Tijani et al,
ASCO 2010). Methods: The SUAVE trial aims to evaluate the Progression
Free Survival (PFS) of good performance status patients treated with
sunitinib or dacarbazine. Secondary objectives include: Overall Survival
(OS), Overall Response Rate (ORR), safety, crossover PFS and response
and biomarker analyses. SUAVE is a CR-UK-funded, open-label, randomised,
phase II trial that will include 124 patients. Patients will be
stratified according to their Helsinki Prognostic Index (ALP, largest
diameter of largest metastasis, ECOG). Inclusion Criteria: good performance
status patients with confirmed unresectable metastatic uveal
melanoma, with at least one target lesion measurable by RECIST 1.1.
Patients must not have received previous systemic therapy. At confirmed
progression, good performance status patients may crossover to the other
study treatment. The trial opened in Oct 2010 and as of 23 January 2012,
had randomized 49 patients with at least 1 recruited from each of the 12
recruiting sites. There will be a total of 13 sites. Completion of the
recruitment phase is expected within 36 months. Prospective tissue and
blood sample collection for translational biomarker analyses is also
ongoing. The SUAVE trial represents one of the largest randomised trials in
this rare disease area (Clinical trial registry number: 2008-008794-55).
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