Rapamycin Therapy in Head and Neck Squamous Cell Carcinoma

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Brief Title

Rapamycin Therapy in Head and Neck Squamous Cell Carcinoma

Official Title

A Pilot Trial Targeting mTOR as a Novel Mechanism-Based Neoadjuvant Therapy for Head and Neck Cancer

Brief Summary


      - 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.


      - To evaluate the usefulness of rapamycin in decreasing tumor size prior to surgery for head
      and neck squamous cell carcinoma.


      - 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.


        -  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


        -  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.


        -  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.


        -  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


        -  Pilot, single arm, open-label, interventional neoadjuvant clinical trial.

        -  Twenty one evaluable subjects will take rapamycin (sirolimus) orally once per day for 21

        -  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

        -  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.

Study Phase

Phase 1/Phase 2

Study Type


Primary Outcome

Percent (%) Change in Levels of pS6, pAKt473, and Ki-67


Mouth Neoplasms



Study Arms / Comparison Groups

Description:  Subjects will be treated with sirolimus 21 days


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status


Estimated Enrollment


Start Date

August 2010

Completion Date

December 2015

Primary Completion Date

June 2015

Eligibility Criteria


        Males and females and members of any race or ethnic group who meet the eligibility criteria
        may participate in this trial.


        Participants must meet all of the following inclusion criteria:

          1. Age 18 years and older

          2. Histologically confirmed previously untreated squamous cell carcinoma o f the oral
             cavity or oropharynx accessible for biopsy

          3. Clinical stage II, III, or IVA disease without distant metastasis, as defined by the
             American Joint Committee on Cancer Staging System, Seventh edition.

          4. Definitive therapy to include surgical resection or chemoradiation for curative

          5. Life expectancy o f greater than 6 months

          6. Eastern Cooperative Oncology Group ( ECOG) performance status of 0 or 1

          7. Willing and able to provide written informed consent


        Participants who meet any of the following criteria are not eligible for enrollment:

          1. Surgical resection or chemoradiation of the HNSCC is contraindicated

          2. Prior head or neck squamous cell carcinoma within 5 years, except for previously
             treated skin cancer

          3. Received chemotherapy targeted monoclonal antibody therapy or investigational therapy
             within 30 days prior to enrollment

          4. Previous radiation therapy to the head or neck

          5. No measurable tumor remaining after prior biopsy or negative margins from prior biopsy

          6. Inadequate hematologic, renal or liver function within l4 days prior to the first
             rapamycin dosing visit, as defined by:

               1. Absolute neutrophil count less than 1.5 times 10 (9)/L

               2. CD4 count < 400 (to account for natural fluctuations in CD4 levels, participants
                  with at least one CD4 count (Bullet) 400 within 14 days prior to dosing will not
                  be excluded)

               3. Platelet count less than 100 times 10(9)/L

               4. Hemoglobin less than l0 g/dL (eligibility level for hemoglobin may be reached by

               5. AST, ALT or bilirubin greater than 1.5 times the upper limit of local lab normal

               6. Total cholesterol level greater than 350 mg/dL

               7. Triglyceride level greater than 400 mg/dL

               8. International Normalized Ratio (INR) greater than 1.5

               9. Serum creatinine greater than 1.5mg/dL

          7. Active hepatitis or HBV or HCV infection

          8. Women who are pregnant or lactating (female of child-bearing age must be abstinent or
             use a barrier type birth control method throughout the study)

          9. Presence of any contraindications to rapamycin therapy, including HlV-protease
             inhibitors and drugs or agents that are modulators of cytochrome P-450 3A4 (CYP3A4)
             and p-glycoprotein(P-gp)

         10. Hypersensitivity to rapamycin

        11 .Has received live vaccine (such as influenza nasal vaccine measles mumps, rubella, oral
        polio, B CG, yellow fever, varicella, or TY2la typhoid) in the past 30 days or has plans to
        take a live vaccine in the next 3 months

        12. Any cognitive impairment that limits the subject s or the subject s legally authorized
        representative s ability to understand the protocol, provide informed consent or assent, or
        to comply with the protocol procedures

        13.Unable or unwilling to comply with the requirements of the protocol




18 Years - 80 Years

Accepts Healthy Volunteers



Janice S Lee, DDS, MD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations



Organization ID


Secondary IDs


Responsible Party


Study Sponsor

National Institute of Dental and Craniofacial Research (NIDCR)

Study Sponsor

Janice S Lee, DDS, MD, Principal Investigator, National Institute of Dental and Craniofacial Research (NIDCR)

Verification Date

October 2017