Phase II Study of Radiation Therapy and Vismodegib for Advanced Head/Neck Basal Cell Carcinoma
Condition: Locally Advanced Basal Cell Carcinoma; Skin Cancer; Cutaneous Malignancy
MeSH terms: Carcinoma; Neoplasms; Carcinoma, Basal Cell; Skin Neoplasms
Intervention: Vismodegib; Radiation therapy
Intervention description: Vismodegib will be taken daily for 12 weeks. It should be taken at approximately the same time each day. Patients will be given a supply of vismodegib on Week 1, Day 1 to last until their next study visit. They will be asked to keep a record of each dose of vismodegib you take. After 12 weeks, they will be evaluated again to make sure they are still eligible to participate in the study. If they are eligible to continue, they will continue taking vismodeib daily as before for another 7 weeks while they receive radiation therapy.; Radiation therapy will be started after the patient has finished taking vismodegib for 12 weeks. They will receive radiation once a day, Monday through Friday, for 7 weeks. Each radiation treatment may take up to 30 minutes.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 24.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Locally advanced basal cell carcinoma; Skin cancer; Radiation therapy; Vismodegib; Head and neck cancer; Cutaneous malignancy

Summary:

      Chemotherapy, radiation therapy, and surgery are standard treatments for basal cell carcinoma
      at most institutions. The purpose of this study is to determine whether adding vismodegib to
      radiation (chemoradiotherapy) is safe and tolerable. The purpose of this study is to assess
      the safety and tolerability of combined radiation therapy and vismodegib. This combination
      may increase the chances of the tumors being destroyed or unable to spread to other parts of
      the body in people with locally advanced basal cell carcinoma of the head and neck.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Patients with locally advanced BCC of the head and neck, consisting of at least one
             histologically or cytologically confirmed lesion greater than or equal to 20 mm in
             longest diameter that is considered to be inoperable or to have a medical
             contraindication to surgery, in the opinion of a Mohs dermatologic surgeon, head and
             neck surgeon, or plastic surgeon. Locally advanced disease is considered to include
             involved lymph nodes of the neck. A patient with regionally involved lymph nodes in
             the neck is considered eligible. The patient should be considered a candidate for
             radiotherapy and should not have medical contraindications to receipt of radiation
             therapy.

             If a patient has distant metastatic spread of BCC (e.g., spread to distant areas
             outside the regional lymph nodes, clearly non contiguous areas of bone involvement, or
             distant metastasis to lung, brain, or other visceral organs), the patient should be
             considered as having distant metastasis and is not eligible.

             Note: All lesions that the investigator proposes to follow as target lesions during
             the course of the study must have previously been histologically confirmed as BCC.

             Acceptable contraindications to surgery include:

               -  BCC that has recurred in the same location after two or more surgical procedures
                  and successful curative resection is deemed unlikely

               -  Complete surgical resection is not possible or is deemed excessively morbid (e.g.
                  invasion into cranial nerves or skull base, proximity to brain, spinal canal, or
                  orbit)

               -  Anticipated substantial morbidity and/or major deformity from surgery (e.g.
                  removal of a major facial structure, such as nose, ear, eyelid, eye, or jaw; or
                  requirement for upper limb amputation)

               -  Medical contraindication to surgery

               -  Patient refusal of surgery due to anticipated morbidity

               -  Other conditions considered to be contraindicating must be discussed with Data
                  Coordinator before enrolling the patient.

          2. Prior radiation therapy is acceptable but there cannot be major overlap of the
             previously irradiated tissues with the new radiation treatment volumes anticipated to
             be delivered for the purposes of this protocol, in such a way that curative intent
             with radiation cannot be met. Furthermore, the total dose from all radiation delivered
             and expected to be delivered should not exceed the suggested dose constraints given
             for normal structures.

          3. Zubrod Performance Status 0-2

          4. Age of greater than or equal to 18 years

          5. Adequate bone marrow and organ function defined as follows:

             Adequate bone marrow function:

             leukocytes:> 3,000/microliter (mcL) absolute neutrophil count: greater than or equal
             to 1000 cells/mm3 platelets: greater than or equal to 75,000 cells/mm3 hemoglobin:
             greater than or equal to 8.5 g/dl (recommended cutoff subject to judgment of medical
             oncologist), but cannot be transfusion dependent

             Adequate hepatic function:

             total bilirubin: less than or equal to 1.5x institutional upper limit of normal (ULN)
             or within 3x the ULN for patients with Gilbert disease aspartate aminotransferase
             (AST) / serum glutamic-oxaloacetic transaminase (SGOT) : < 3 X institutional upper
             limit of normal alanine aminotransferase (ALT) /serum glutamic-pyruvic transaminase
             (SGPT): < 3 X institutional upper limit of normal

             Adequate renal function:

             creatinine: within normal institutional limits OR creatinine clearance: > 60
             mL/min/1.73 m2 for patients with creatinine levels above institutional normal

          6. Agreement not to donate blood or blood products during the study and for 7 months
             after discontinuation of vismodegib; for male patients, agreement not to donate sperm
             during the study and for 7 months after discontinuation of vismodegib.

          7. For male patients, agreement not to donate sperm during the study and for 3 months
             after the final dose of vismodegib. Male patients must use condoms at all times, even
             after a vasectomy, during sexual intercourse with pregnant partners or female partners
             of reproductive potential during treatment with vismodegib. Vismodegib is present in
             semen. It is not known if the amount of vismodegib in semen can cause embryo-fetal
             harm.

          8. Verify the pregnancy status of females of reproductive potential within 7 days prior
             to initiating vismodegib. For women of childbearing potential, a negative pregnancy
             test within 7 days prior to commencement of dosing is required. Women of reproductive
             potential are required to use two forms of acceptable contraception (including one
             acceptable barrier method with spermicide) during therapy and for 7 months after
             completing therapy. Acceptable forms of primary contraception include the following:
             Combination hormonal contraceptives, subcutaneous hormonal implant, hormonal patch,
             hormonal contraceptives (levonorgestre-releasing intrauterine system,
             medroxyprogesterone acetate depot), tubal sterilization, vasectomy, and intrauterine
             device (IUD). Acceptable forms of barrier contraception include the following: any
             male condom (with spermicide) or diaphragm (with spermicide).

        Exclusion Criteria:

          1. Patients with distant metastasis (e.g. spread to distant areas outside the regional
             lymph nodes, clearly non contiguous areas of bone involvement, or distant metastasis
             to lung, brain, liver or other visceral organs) are ineligible.

          2. Patients with nevoid BCC syndrome (Gorlin syndrome) should not enroll in this study.

          3. A patient with a known other malignancy is eligible if there is a negligible risk for
             disease progression or death within one year, there is no active ongoing treatment for
             this malignancy, and the malignancy and/or any anticipated future treatments would not
             interfere with protocol-mandated evaluations at 1 year.

          4. Prior vismodegib or other antagonists of the Hh pathway;

          5. Concurrent non-protocol-specified anti-tumor therapy (e.g., chemotherapy, other
             targeted therapy, topical therapy such as 5-Fluorouracil or imiquimod, radiation
             therapy, surgery, or photodynamic therapy.

               -  For patients with multiple cutaneous BCCs at baseline that are not designated by
                  the investigator as target lesions, treatment of these non-target BCCs with
                  surgery may be permitted but must be discussed with Data Coordinator prior to any
                  surgical procedure.

          6. Recent (within 4 weeks of Registration), current, or planned participation in another
             experimental drug study.

          7. Prior radiotherapy to the region of the study cancer that would result in overlap of
             radiation therapy fields in such a way that curative intent with radiation cannot be
             met

          8. Inability or unwillingness to swallow capsules; Patients with any condition that may
             impair the ability to swallow or absorb oral medications/investigational product
             including:

               -  any lesion, whether induced by tumor, radiation or other conditions, which makes
                  it difficult to swallow capsules or pills;

               -  prior surgical procedures affecting absorption including, but not limited to
                  major resection of stomach or small bowel;

               -  active peptic ulcer disease;

               -  malabsorption syndrome

          9. Pregnant or lactating women. Patients who are unable or are unwilling to adhere to the
             required contraceptive methods are excluded from the study.

               -  Women of reproductive potential are required to use two forms of acceptable
                  contraception (including one acceptable barrier method with spermicide) during
                  therapy and for 7 months after completing therapy. Acceptable forms of primary
                  contraception include the following: Combination hormonal contraceptives,
                  subcutaneous hormonal implant, hormonal patch, hormonal contraceptives
                  (levonorgestre-releasing intrauterine system, medroxyprogesterone acetate depot),
                  tubal sterilisation, vasectomy and intrauterine device (IUD). Acceptable forms of
                  barrier contraception include the following: Any male condom (with spermicide) or
                  diaphragm (with spermicide).

               -  Male patients must use condoms at all times, even after a vasectomy, during
                  sexual intercourse with female partners of reproductive potential during
                  treatment with vismodegib and for 2 months after the last dose to avoid exposing
                  a pregnant partner and unborn fetus to vismodegib.

         10. Life expectancy of <1 year

         11. Patients with widespread superficial multifocal BCC who are considered unresectable
             due to breadth of involvement and do not have a single definable area of disease
             amenable to radiation therapy targeting.

             Note: If an area including one or more lesions is definable for radiation therapy
             targeting, the patient may be eligible for treatment on study using the designated
             target lesion(s) identified by the investigator.

         12. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection or psychiatric illness/social situations that would limit compliance with
             study requirements;

         13. History of other disease, metabolic dysfunction, physical examination finding, or
             clinical laboratory finding giving reasonable suspicion of a disease or condition that
             contraindicates use of an investigational drug or that might affect interpretation of
             the results of the study or renders the patient at high risk form treatment
             complications

         14. HIV-positive patients on combination antiretroviral therapy, because of the potential
             for pharmacokinetic interactions with vismodegib;