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

TPS5600 General Poster Session (Board #33B), Sat, 1:15 PM-5:15 PM
A phase III study of standard fractionation radiotherapy with concurrent
high-dose cisplatin versus accelerated fractionation radiotherapy (RT) with
panitumumab in patients with locally advanced stage III and IV squamous
cell carcinoma of the head and neck (SCCHN) (NCIC Clinical Trials Group
HN.6). Presenting Author: John N. Waldron, Princess Margaret Hospital,
Toronto, ON, Canada
Background: Standard treatment for locally advanced SCCHN, chemoradiotherapy
(CRT), leads to significant acute and long-term morbidity. The
demonstration that EGFR antibody (Ab) therapy improves outcome when
added to standard RT (Bonner NEJM 2006) and that altered fractionation
RT improves outcome compared to standard RT that is of similar magnitude
as CRT (Bourhis Lancet 2006), led to the hypothesis that the combination
of the two treatment strategies will improve efficacy compared to standard
CRT with good tolerability. Methods: HN.6 is a Canadian phase III
randomized study comparing standard RT 70Gy/35 over 7 weeks �
cisplatin 100mg/m2 d 1, 22, 43 to accelerated RT 70Gy/35 over 6 weeks �
panitumumab (anti EGFR Ab)) 9mg/kg 1 week prior to RT, d15, 36. Key
eligibility criteria are: SCC of oral cavity, oropharynx, larynx or hypopharynx;
TanyN�M0 or T3-4N0M0; adequate organ function and PS. Primary
endpoint is progression free survival (PFS). Secondary endpoints include
OS, local PFS, regional PFS, distant metastases, swallowing related QOL,
functional swallowing outcomes, and economic evaluation (healthcare
utilization, health utilities, indirect costs). Tissue and blood collection will
allow biomarker evaluation including HPV status. Real time quality review
of RT plans with plan data and radiology archiving will allow future analysis
of RT parameters relative to toxicity and patterns of failure. Clinical
epidemiological data will be prospectively collected and correlated with
biomarkers and outcome. Planned sample size is 320 patients over 3.2
years with 3 more years of follow-up and target hazard ratio � 0.7 (absolute
difference in control arm 2 year PFS of 12%, power 80%, 2-tail type 1 error
0.05). If superiority is not demonstrated, noninferiority will be tested. One
interim analysis is planned. Conduct to Date: Study activation: Dec 2008
and completed accrual in Nov 2011. In Oct 2011, the DSMC recommended
trial continuation. Supported by CCSRI grant 021039 and Amgen
Inc. ClinicalTrials.gov: NCT00820248.
TPS5602 General Poster Session (Board #33D), Sat, 1:15 PM-5:15 PM
A pilot study of raltegravir and cisplatin in head and neck squamous cell
carcinoma (HNSCC). Presenting Author: Julie E. Bauman, University of
New Mexico, Albuquerque, NM
Background: Metnase is a recently characterized DNA repair component
present in anthropoid primates. Metnase, the fusion of a SET histone
methylase domain and a Transposase nuclease (Tn) domain, enhances
DNA double-stranded break (DSB) repair. The Tn domain trims free DNA
ends for optimal end-joining, and is required to re-start stalled replication
forks. The SET domain di-methylates H3K36 at the DSB, recruiting
non-homologous end-joining repair components. Cisplatin (CDDP), the
central chemotherapy in HNSCC, covalently binds DNA leading to intraand
interstrand crosslinks (ICL). In addition to blocking strand transcription
and segregation, the ICL stalls DNA replication fork progression
leading to collapse and DSB. The role of Metnase in DNA repair, including
overcoming the stalled replication fork, makes it a potential therapeutic
target. We hypothesize that Metnase inhibition may be a useful adjunct to
CDDP. 3D modeling of the Metnase Tn domain identified significant
homology with human immunodeficiency virus 1 (HIV-1) integrase. A
virtual screen of the Chem Div library identified the HIV-1 integrase
inhibitor, raltegravir, as a lead compound for inhibiting the Metnase Tn
domain. We designed a pilot study in HNSCC to evaluate potentiation of
CDDP DNA damage by raltegravir. Methods: The primary objective of this
window-of-opportunity study is to analyze biomarkers of DNA damage, fork
arrest, and apoptosis in serial tumor biopsies from patients (pts) with
HNSCC undergoing CDDP, with and without raltegravir. Eligible pts: 1)
have HNSCC with tumor site amenable to repeat, awake biopsy; 2) are
appropriate candidates for CDDP. Pts are treated with 2 doses of CDDP 30
mg/m2 . One CDDP dose is administered with raltegravir 400 mg bid for 5
days, starting the day before CDDP. Pts undergo 3 research biopsies, at
baseline and 48-72 hours after each CDDP. Serial biopsies will be
evaluated for expression changes in �H2AX, Annexin V, pChk1, pChk2, and
p53BP1 by immunohistochemistry. Numerical increase in biomarker
expression in tumors exposed to CDDP-raltegravir vs. CDDP will justify
development of a phase I/II study. Four of 12 pts have enrolled and
completed all biopsies. Supported by a grant from the American Cancer
Society.
Head and Neck Cancer
381s
TPS5601 General Poster Session (Board #33C), Sat, 1:15 PM-5:15 PM
Phase II trial of neoadjuvant chemotherapy for HPV-associated squamous
cell carcinoma of the oropharynx followed by reduced-dose radiotherapy/
chemoradiotherapy for responders or standard dose chemoradiotherapy for
nonresponders. Presenting Author: Bhoomi Mehrotra, Hofstra North Shore-
LIJ School of Medicine, New Hyde Park, NY
Background: Recent studies have established an improved outcome for HPV
associated oropharyngeal squamous cell cancers with 3 year OS rates
approaching 90%. Given that current aggressive treatment modalities for
HNC include IMRT and chemotherapy (CT), they adversely affect the long
term QOL of these patients who are considered highly curable. The primary
objective of our study is to confirm the activity (CR � PR at 3 months post
completion RT/CRT) of induction TPF followed by dose reduced IMRT �/concurrent
CT, in nonsmokers with HPV associated, locally advanced SCC
of H&N. Secondary objectives include: to define objective tumor RR to
induction chemotherapy and to subsequent RT based treatment, per
RECIST version 1.1 criteria, assess PFS and OS at 2 years,assess
locoregional disease and distant disease control at 2 years, and monitoring
of QOL instruments for HNC. Methods: Institutional IRB approval has been
obtained for this study. Eligibility criteria include p16 expressing or ISH �
SCC of the oropharynx, T1-3, N1-2, age � 17 years, adequate marrow and
organ function and adequate PS. Exclusion criteria include T4 or N3
disease, significant smoking history � 10 pack year lifetime exposure.
Patients would be treated with standard TPF induction for 3 cycles followed
by risk assessment. Pts. achieving locoregional CR or CR/PR at primary site
would receive dose reduced RT (66 Gy) �/- CT, while those with SD/PD
would receive standard CRT with full dose XRT. Post therapy assessments
include serial evaluation of functional quality-of-life, including M. D.
Anderson Dysphagia Inventory (MDADI) and Oropharyngeal swallowing
efficiency (OPSE) measures of swallowing function, treatment related
symptoms, dietary status assessments and formal sialometric measurement
of parotid function. Interim analysis would include RR assessment at
3 months post treatment in the first 12 patients who received dose reduced
RT and compared with historical controls. Early stopping rules are built into
the protocol. This study is currently open and patient accrual is ongoing.
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