Rapamycin Therapy in Head and Neck Squamous Cell Carcinoma
Condition: Mouth Neoplasms; Head and Neck Neoplasms; Tongue Neoplasms; Carcinoma, Squamous Cell
MeSH terms: Carcinoma; Neoplasms; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck; Head and Neck Neoplasms; Mouth Neoplasms; Tongue Neoplasms
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Background:

      - Advanced-stage head and neck cancer (head and neck squamous cell carcinoma [HNSCC]) has
      moderately successful treatment outcomes, usually involving surgery as part of the standard
      treatment. Researchers are investigating the use of the drug rapamycin to prevent tumor
      growth in HNSCC, and are interested in using it to treat individuals with HNSCC that has not
      been treated previously with other drugs, radiation, or surgery.

      Objectives:

      - To evaluate the usefulness of rapamycin in decreasing tumor size prior to surgery for head
      and neck squamous cell carcinoma.

      Eligibility:

      - Individuals at least 18 years of age who have been diagnosed with advanced head and neck
      squamous cell carcinoma that has not yet been treated.

      Design:

        -  Participants will be screened with a physical examination, medical history, blood tests,
           and imaging studies.

        -  Approximately 1 month before scheduled surgery, participants will begin to receive
           rapamycin. Participants will take rapamycin once daily for 21 days, followed by a 7-day
           period without the drug.

        -  During the 21-day rapamycin treatment, participants will have weekly study visits to
           provide blood and urine samples and have possible tumor biopsies and imaging studies
           such as x-rays or tumor photographs. Participants will have additional study visits for
           tests 1 day and 1 week after the end of rapamycin treatment, followed by HNSCC surgery.

        -  Participants will have a final visit to provide blood samples 30 days after surgery.

        -  Participants medical records will be reviewed 1 year after surgery; however,
           participants will not need to have further study visits at this time.
    

Detailed description: 
      BACKGROUND:

        -  The five-year survival rate for head and neck squamous cell carcinoma (HNSCC) has
           remained at approximately 50% for more than three decades.

        -  In HNSCC, the AKT-mTOR-pS6 pathway is aberrantly activated and promotes tumorigenesis
           and metastasis.

        -  Rapamycin is the most extensively studied mTOR inhibitor for which therapeutic daily
           oral dose and schedule, pharmacologic levels in blood, and safety have been established.

        -  Inhibition of mTOR by rapamycin causes the rapid apoptotic death of HNSCC tumor
           xenografts and decreases the tumor burden and prolongs the survival of mice harboring
           early and advanced oral and skin SCC lesions in a variety of experimental cancer models.

        -  Preliminary evidence suggests that mTOR inhibitors cause tumor shrinkage and improved
           tumor margins in HNSCC patients.

      OBJECTIVES:

        -  The primary objectives are to evaluate the following for patients with HNSCC given
           rapamycin as neoadjuvant treatment prior to surgery or chemoradiation:

             -  Whether therapeutic activities of rapamycin lead to inhibition of mTOR complexes,
                mTORC1 and mTORC2, as assessed by the change in levels of pS6 and pAkt473 measured
                by immunohistochemistry (IHC) in tumor samples and by Western blotting in
                peripheral blood mononuclear cells (PBMCs) and reduce tumor cell proliferation, as
                judged by IHC for Ki-67 in tumor samples.

             -  Antitumor activity in terms of objective response.

        -  Secondary objectives include safety evaluation of rapamycin therapy, exploratory studies
           of possible effects of rapamycin on tumor size, dynamic CT perfusion, and FDG-PET; and
           evaluation of tumor proliferation, apoptosis, microvessel density, and molecular changes
           associated with these effects. Survival status, recurrence of disease, metastases, and
           adverse events/serious adverse events, including complications of wound healing, which
           are related to rapamycin therapy will also be assessed for 360 days after surgery or
           chemoradiation through medical record review.

      ELIGIBILITY:

        -  Males and females age 18 years and older

        -  Previously untreated HNSCC of the oral cavity or oropharynx

        -  Clinical stage II, III, or IVA disease without distant metastasis

        -  Definitive therapy to include surgical resection or chemoradiation for curative purposes

        -  Life expectancy greater than six months

      STUDY DESIGN:

        -  Pilot, single arm, open-label, interventional neoadjuvant clinical trial.

        -  Twenty one evaluable subjects will take rapamycin (sirolimus) orally once per day for 21
           days.

        -  Before and after dosing, the tumor will be photographed and biopsied, peripheral blood
           mononuclear cells (PBMCs) will be collected, and computed tomography and positron
           emission tomography scans will be performed.

        -  Surgical or chemoradiation treatment, which is being provided outside of this protocol,
           will be conducted after Day 28 and when rapamycin levels are less than or equal to 3
           nanograms per milliter.

        -  Subjects will be followed by medical record review for 360 days after surgery or
           chemoradiation to assess 1) survival, 2) recurrence of disease, 3) metastases, and 4)
           adverse events/serious adverse events that are related to rapamycin therapy, including
           complications of wound healing and infections due to immune compromise.

        -  Levels of pS6 and pAkt473 in tumor tissue and PBMCs and Ki-67 in tumor tissue before and
           after rapamycin therapy will be determined by immunohistochemistry and by Western
           blotting. Computed tomography (CT) and positron emission tomography (PET) scans of the
           head, neck, and chest region with and without contrast will be performed within 7 days
           prior to the first rapamycin administration. One day after the last administration of
           rapamycin the CT and PET scans (head and neck region only) with contrast will be
           repeated.

        -  A single stage design will be used based on response defined as > 25% tumor shrinkage. A
           Wilcoxon signed rank test will be used to compare levels of pS6, pAkt473, and Ki-67
           before and after rapamycin therapy. As part of secondary analysis, the number of
           subjects achieving a best response of complete response (CR), partial response (PR),
           stable disease (SD), or progressive disease (PD) according to Response Evaluation
           Criteria in Solid Tumors (RECIST) version 1.1 will also be summarized.
    

Intervention name(s): Sirolimus
Intervention type(s): Drug
Intervention description(s): 21 evaluable subjects will take rapamycin (sirolimus) orally once per day for 21 days. Before and after dosing tumor assessments to include: photographs, CT & amp; PET scans will be done for tumor measurement.
Other intervention name(s): Rapamycin
Intervention MeSH terms: Sirolimus
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Head and Neck Squamous Cell Carcinoma; Oral Cancer; mTOR Inhibitors; Targeted Therapies; Signal Transduction Inhibitors; Head and Neck Cancer; Squamous Cell Carcinoma; Tongue Cancer