Study Evaluating the Efficacy of Oral Vismodegib in Various Histologic Subtypes

ML28485:Phase 2B Single-site,Open-label,Nonrandomized Study Evaluating Efficacy of Oral Vismodegib in Various Histologic Subtypes (Infiltrative/Morpheaform,Nodular and Superficial)of High Risk and/or Locally Advanced Basal Cell Carcinoma

The purpose of this study is to investigate the safety and effectiveness of oral vismodegib therapy in the treatment of different 'histologic subtypes' of basal cell skin cancer (BCC). The term 'histologic subtype' refers to how the cells and tumor tissue looks under the microscope. Three different 'histologic subtypes' of basal cell skin cancer (infiltrative/morpheaform, nodular and superficial) will be examined in this study.

The purpose of this study is to investigate the safety and effectiveness of oral vismodegib therapy in the treatment of different 'histologic subtypes' of basal cell skin cancer (BCC). The term 'histologic subtype' refers to how the cells and tumor tissue looks under the microscope. Three different 'histologic subtypes' of basal cell skin cancer (infiltrative/morpheaform, nodular and superficial) will be examined in this study. Each subtype has a characteristic look under the microscope, which is related to how the tumor will behave and grow.

ERIVEDGE (oral vismodegib capsule) has been approved for use in the United States for treatment of metastatic BCC tumors (mBCC), tumors that have spread further into the skin, bones or other tissues, or spread to other parts of the body and locally advanced basal cell skin cancer (laBCC), cancers that have come back after surgery or that the healthcare provider thinks cannot be treated with surgery or radiation. It works by blocking the signal, called Hedgehog, which basal cell skin cancer cells need to grow. It has been given to about 800 people during clinical trials.

Data from previous studies is mostly based on a subtype of BCC made up of little round collections of cancer cells, called "Nodular". There is almost no data on the use of vismodegib in other subtypes of BCC that that tend to extend deep into the skin ("Infiltrative" subtype), or spread widely near the surface of the skin ("Superficial" subtype).

A total of 36 subjects will be enrolled in the study. All study participants will receive oral vismodegib treatment.

At the Week 12 visit, skin biopsies will be performed to give the investigators more information on how the tumor is responding to vismodegib. If there is no evidence of tumor on the biopsy, the subject will be eligible to end treatment early and enter the Observation period. During this time the subject will be followed clinically every 3 months for up to 1 year.

For all other subjects, if any evidence of tumor is seen on biopsy at week 12, the subject will continue treatment for the full 24 weeks. At week 24 visit, skin biopsies will be performed again to see if there is any tumor left. If there is no evidence of tumor on the biopsy, the subject will be eligible to end treatment early and enter the Observation period. If there is tumor left, the subject will be referred for surgery or other standard of care treatment to remove the tumor.

Inclusion Criteria:

1. A signed and data informed consent

2. Willing to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures

3. 18 years of age or older at time of informed consent

4. Have one or more clinically suspicious lesions for BCC at Pre-Study screening Visit that has:

   1. a diameter ≥ 6 mm if located on the "mask areas" of face (central face, eyelids, eyebrows, periorbital,nose,lips,chin,mandible,preauricular and postauricular skin/sulci,temple,ear),genitalia,hands,or feet

   2. a diameter ≥ 10 mm if located on cheeks,forehead,scalp,or neck

   3. a diameter ≥ 20 mm if located on trunk and extremities

      or has a lesion suspicious for locally advanced BCC defined as a lesion that:

   4. is ≥ 10 mm,

   5. has recurred following surgery or surgical resection would result in substantial deformity, and

   6. has been deemed not appropriate for radiation.

5. Have a histologically-confirmed BCC prior to first dose of study drug

6. Have an Eastern Cooperative Oncology Group performance status of 2 or less at Baseline

7. Female of reproductive potential must use 2 effective methods to avoid pregnancy during therapy and for 7 months after completing therapy

8. Male patients must use effective measures to avoid pregnancy in their partner at all times during treatment and for 2 months after the last dose

9. Agree not to donate blood or blood products during the study and for 7 months after the last dose

10. Subjects with Basal Cell Nevus Syndrome are eligible for enrollment

Exclusion Criteria:

1. Women who are pregnant, lactating, or planning pregnancy while in the study
2. History of prior treatment with vismodegib or any Hh Pathway Inhibitor
3. Evidence of clinically significant and unstable diseases or conditions; Subjects with clinically stable chronic medical conditions will be allowed to enter the study
4. Any dermatological disease at treatment site that the investigator thinks may be exacerbated by treatment with vismodegib or cause difficulty with examination
5. The target lesion identified at Pre-study Screening visit has been determined to be mBCC by radiological assessment prior to first dose of study drug
6. Inability or unwillingness to swallow capsules
7. History of infection requiring hospitalization, IV antimicrobial therapy, or is otherwise judged to be clinically significant by the investigator within 4 wks prior to first dose of study drug
8. History of infection requiring antimicrobial therapy within 2 wks prior to first dose of study drug
9. History of alcohol or substance abuse, unless in full remission for greater than 6 months prior to first dose of study drug
10. Known to be infected with human immunodeficiency virus, hepatitis B or hepatitis C viruses
11. Participation in other study using an investigational or experimental therapy or procedure within 4 weeks or 5 half-lives (whichever is longer) before the study begins and/or during study participation
12. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results in the judgment of the investigator
13. Subjects who are study site staff members or who are Sponsor employees directly involved in the conduct of the trial
14. A subject who, in the opinion of the investigator or sponsor, will be uncooperative or unable to comply with study procedures