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OSU 09120 – Phase I Trial of Vorinostat in the Treatment of Advanced Oropharyngeal Squamous Cell Carcinoma (OPSCC)

HYPOTHESIS: The addition of vorinostat to a standard chemo-radiation therapy protocol for the treatment of unresectable or border-line resectable OPSCC will improve the toxicity of this effective regimen; improve tumor immune surveillance by activating adaptive and innate immune responses, especially in human papilloma virus (HPV)- positive tumors; and improve the methylation status of commonly methylated genes in OPSCC.

STUDY DESIGN: Phase I clinical trial

RATIONALE: Despite aggressive therapy that can include chemotherapy and concurrent chemoradiation, the overall five-year survival rate for advanced- stage OPSCC is less than 50 percent. Better treatment options are needed for this functionally and aesthetically sensitive area.

It has become evident in recent years that there exists an aggressive subtype of OPSCC characterized by female gender, a history of smoking, an anti-apoptotic phenotype and poor survival; and a subtype that is HPV-positive with low EGFR expression that is associated with good treatment response and survival.

In both cases, chemoradiation therapy protocols are very toxic, with radiation-related complications that include soft tissue fibrosis, muscle fibrosis and atrophy, dysphagia, and osteoradionecrosis and chondroradionecrosis. Improving therapeutic efficacy while minimizing toxicity to normal tissues is the over-riding rationale for the use of vorinostat in this investigation.

Vorinostat (SAHA) inhibits the enzymatic activity of several histone deacetylases at nanomolar concen-trations. These enzymes catalyze the removal of acetyl groups from proteins such as histones and transcription factors, altering gene expression.

Elevated histone deacetylase (HDAC) levels have been observed in head and neck cancer. HDAC inhibitors, such as vorinostat, regulate gene transcription, inhibit growth and induce apoptosis. Evidence indicates that these agents also preferentially induce both intrinsic and extrinsic apoptotic pathways in head and neck squamous cell carcinoma while sparing normal oral mucosa.

These characteristics—along with targeted cell-cycle disruption, inhi-bition of angiogenesis, inhibition of cell proliferation in tumor cells but not normal cells—is why vorinostat has been shown to sensitize head and neck cancer to radiotherapy while minimizing radiation-related damage. Vorinostat also suppresses the cutaneous radiation syndrome by decreasing production of TNF-alpha and TGF-beta.

Research has shown that vorinostat can be safely combined with platinum-based chemotherapy, and that it may sensitize head and neck cancer to this cytotoxic agent. Finally, evidence from our laboratories suggests that this agent modulates the immune system to better recognize virally induced tumors. Thus, the multiple effects of vorinostat indicate that this agent should improve the response rates of HPV-positive and HPV-negative OPSCC to organ-preservation therapy, while reducing treatment toxicity.

AT A GLANCE
Clinical trial OSU 09120

PI: Theodoros N. Teknos, MD, professor of Otolaryngology

Phone: 614-293-8074

Email: Ted.Teknos@osumc.edu

Eligibility: Histologically confirmed unresectable or borderline resectable OPSCC; Oropharyngeal sites of tumor include tonsil, soft palate, base of tongue, lateral and posterior pharyngeal wall; Must be AJCC Stage III or Stage IVa and be either unresectable or borderline resectable; No prior therapy for the tumor, including extensive surgery, radiation therapy, chemotherapy, immunotherapy, targeted therapy or any other investigational agents; ECOG 0-2; Age greater than 18 years old; Cannot have active peptic ulcer disease; Patients with known active viral hepatitis or known HIV infection are excluded.

 

 
13-May-10
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look here  commented on  Monday, April 22, 2013  8:21 AM 
i am glad that I have land on this useful site. I never knew that Research has shown that vorinostat can be safely combined with platinum-based chemotherapy, and that it may sensitize head and neck cancer to this cytotoxic agent. I have book marked your page for further updates. Keep up the good works. Regards.


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