Squamous Cell Carcinoma Clinical Trial
Official title:
A Phase I/II Study of BYL719, Cetuximab, and Cisplatin in Transorally Resectable, HPV-Associated Oropharyngeal Squamous Cell Carcinoma
This study evaluates the combination of BYL719, cisplatin and cetuximab as induction chemotherapy prior to minimally-invasive transoral surgery (TORS or TLM) and selective lymph node dissection (SLND), followed by risk-adapted intensity-modulated radiation therapy (IMRT) in patients with transorally resectable, Stage III-IVa, HPV-associated oropharyngeal squamous cell carcinoma (OPSCC).
HPV status and tobacco use are the major independent prognostic factors for patients with
OPSCC. Patients with HPV-associated OPSCC have a favorable prognosis when treated with
chemotherapy, radiation, and/or surgery. This has resulted in national trials investigating
de-intensification strategies for good-risk patients with HPV-associated OPSCC, where current
multimodality paradigms may represent overtreatment.
The PI3K/Akt/mTOR signaling network, a mitogenic pathway regulating cellular metabolism,
proliferation and survival, plays a major role in HPV biology. Starting with early infection,
activation of PI3K suppresses autophagy and induces functional protein translational
machinery. Activation of the pathway is a nearly universal aspect of mammalian viral
infection, and is of particular importance for dsDNA viruses such as HPV. The oncoproteins
E5, E6 and E7 also have direct roles in pathway activation. Moreover, HPV-associated OPSCC
demonstrates a strikingly high prevalence of genomic activation of the PI3K pathway,
including activating PIK3CA mutations (27-31%), PIK3CA amplification (20%), and loss of PTEN
(30%), the negative regulator of PI3K. Overall genomic events hypothesized to result in PI3K
pathway activation are present in approximately 45-60% of HPV-transformed OPSCC.
BYL719 is an oral, small molecule, alpha-specific inhibitor of PI3-Kinase. Because
HPV-associated OPSCC demonstrates a high rate of both genomic and non-genomic PI3K pathway
activation, we hypothesize that adding BYL719 to platinum-taxane induction chemotherapy in
HPV-associated OPSCC will increase clinico-radiologic complete response relative to
historical control. In this phase I/II trial, eligible patients wiht HPV-associated OPSCC
will be treated with 3 cycles of induction BYL719, cisplatin and paclitaxel. Induction will
be followed by minimally-invasive, transoral surgery (TORS or TLM) then risk-adapted IMRT.
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