Study Evaluating the Efficacy of Oral Vismodegib in Various Histologic Subtypes

• Sponsor: Mayo Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT01700049
• Collaborator: Genentech, Inc. (Industry)
• Enrollment: 28
• Location: 1
• Arm: 1
• Actual Duration (Months): 65.6
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Basal Cell Carcinoma	Drug: vismodegib (150 mg PO daily)	Phase 2

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 28 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Jan 14, 2013
• Actual Primary Completion Date: Jul 3, 2017
• Actual Study Completion Date: Jul 3, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Open Label oral vismodegib This is a Phase 2B single-site, open-label, nonrandomized 24-week study of the efficacy and safety of vismodegib (150 mg PO daily) in subjects with high risk and/or locally advanced basal cell carcinoma (BCC). A total of 36 subjects with infiltrative/morpheaform, nodular, or superficial BCC will be enrolled in the study.	Drug: vismodegib (150 mg PO daily); Biopsies will be performed on all participants at baseline, week 12 and week 24.; Other Names: Brand name: Erivedge

Outcome Measures

Primary Outcome Measures

1. Efficacy of Vismodegib [Week 24]

   The efficacy of vismodegib was defined as the number of tumor biopsies with positive pathology after 24 weeks. Subjects had one target lesion and up to 3 additional non-target lesions. A cumulative total of 65 tumors was measured after 24 weeks of treatment. Histopathological subtypes were categorized primarily as infiltrative, nodular and superficial.

Secondary Outcome Measures

1. Safety of Vismodegib [Up to 18 months]

   The safety of Vismodegib was evaluated by monitoring adverse effects. All adverse events, expected and unexpected, were recorded and categorized using the Common Terminology Criteria for Adverse Events (CTCAE) guide. This is a set of criteria from the National Cancer Institute (NCI) used to standardize classification of adverse effects of drugs. Grade 1 events are defined as mild, grade 2 as moderate, grade 3 as severe; grade 4 as life-threatening and grade 5 as death.

2. Onset of Efficacy of Vismodegib [Up to week 24]

   Onset of efficacy was measured by tumor surface area reduction or increase. Subjects had one target lesion and up to 3 additional non-target lesions. Surface area of a cumulative total of 65 tumors (27 target lesions and 38 non-target lesions) was measured after 24 weeks of treatment. A complete response was defined as 100% reduction in tumor surface area. Partial response was defined as greater than 50% reduction in tumor surface area. Stable disease was defined as less than 50% reduction in tumor surface area and Progressive disease was defined as greater than 20% increase in tumor surface area.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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:

5. 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

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

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

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

1. is ≥ 10 mm,

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

3. has been deemed not appropriate for radiation.

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

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

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

7. 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

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

9. 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Saint Louis University Department of Dermatology	Saint Louis	Missouri	United States	63104

Sponsors and Collaborators

• Mayo Clinic
• Genentech, Inc.

Investigators

• Study Director: Scott Fosko, MD, [e-mail]

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jan 21, 2017

More Information

Additional Information:

• Mayo Clinic Clinical Trials

Publications

• Lorusso PM, Jimeno A, Dy G, Adjei A, Berlin J, Leichman L, Low JA, Colburn D, Chang I, Cheeti S, Jin JY, Graham RA. Pharmacokinetic dose-scheduling study of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with locally advanced or metastatic solid tumors. Clin Cancer Res. 2011 Sep 1;17(17):5774-82. doi: 10.1158/1078-0432.CCR-11-0972. Epub 2011 Jul 13.
• Sekulic A, Migden MR, Oro AE, Dirix L, Lewis KD, Hainsworth JD, Solomon JA, Yoo S, Arron ST, Friedlander PA, Marmur E, Rudin CM, Chang AL, Low JA, Mackey HM, Yauch RL, Graham RA, Reddy JC, Hauschild A. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med. 2012 Jun 7;366(23):2171-9. doi: 10.1056/NEJMoa1113713.
• Tang JY, Mackay-Wiggan JM, Aszterbaum M, Yauch RL, Lindgren J, Chang K, Coppola C, Chanana AM, Marji J, Bickers DR, Epstein EH Jr. Inhibiting the hedgehog pathway in patients with the basal-cell nevus syndrome. N Engl J Med. 2012 Jun 7;366(23):2180-8. doi: 10.1056/NEJMoa1113538.
• Von Hoff DD, LoRusso PM, Rudin CM, Reddy JC, Yauch RL, Tibes R, Weiss GJ, Borad MJ, Hann CL, Brahmer JR, Mackey HM, Lum BL, Darbonne WC, Marsters JC Jr, de Sauvage FJ, Low JA. Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. N Engl J Med. 2009 Sep 17;361(12):1164-72. doi: 10.1056/NEJMoa0905360. Epub 2009 Sep 2.
• Walling HW, Fosko SW, Geraminejad PA, Whitaker DC, Arpey CJ. Aggressive basal cell carcinoma: presentation, pathogenesis, and management. Cancer Metastasis Rev. 2004 Aug-Dec;23(3-4):389-402. Review.

• Responsible Party: Scott W. Fosko, Principal Investigator, Mayo Clinic
• ClinicalTrials.gov Identifier: NCT01700049
• Other Study ID Numbers: ML28485; 22355
• First Posted: Oct 4, 2012
• Last Update Posted: May 23, 2019
• Last Verified: May 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Scott W. Fosko, Principal Investigator, Mayo Clinic: advanced BCC; high risk; locally advanced
• Additional relevant MeSH terms: Carcinoma; Carcinoma, Basal Cell

Study Results

Participant Flow

Arm/Group Title	Open Label Oral Vismodegib
Arm/Group Description	This is a Phase 2B single-site, open-label, nonrandomized 24-week study of the efficacy and safety of vismodegib (150 mg PO daily) in subjects with high risk and/or locally advanced basal cell carcinoma (BCC). vismodegib (150 mg PO daily): Biopsies will be performed on all participants at baseline, week 12 and week 24.
Period Title: Overall Study
STARTED	28
COMPLETED	27
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Open Label Oral Vismodegib
Arm/Group Description	This is a Phase 2B single-site, open-label, nonrandomized 24-week study of the efficacy and safety of vismodegib (150 mg PO daily) in subjects with high risk and/or locally advanced basal cell carcinoma. vismodegib (150 mg PO daily): Biopsies will be performed on all participants at baseline, week 12 and week 24.
Overall Participants	28
Age (years) [Median (Standard Deviation) ]
Median (Standard Deviation) [years]	69.5 (13.0)
Sex: Female, Male (Count of Participants)
Female	12 42.9%
Male	16 57.1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 3.6%
White	27 96.4%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	28 100%

Outcome Measures

1. Primary Outcome

Title	Efficacy of Vismodegib
Description	The efficacy of vismodegib was defined as the number of tumor biopsies with positive pathology after 24 weeks. Subjects had one target lesion and up to 3 additional non-target lesions. A cumulative total of 65 tumors was measured after 24 weeks of treatment. Histopathological subtypes were categorized primarily as infiltrative, nodular and superficial.
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

A total of 65 tumors were categorized into histopathologic subtype where 24 of 65 were infiltrative, 29 of 65 were nodular, 10 of 65 were superficial and 2 out of 65 were keratotic.

Arm/Group Title	Open Label Oral Vismodegib
Arm/Group Description	This is a Phase 2B single-site, open-label, nonrandomized 24-week study of the efficacy and safety of vismodegib (150 mg PO daily) in subjects with high risk and/or locally advanced basal cell carcinoma. vismodegib (150 mg PO daily): Biopsies will be performed on all participants at baseline, week 12 and week 24.
Measure Participants	27
Measure tumors	65
Infiltrative	2
Nodular	5
Superficial	1
Keratotic	1

2. Secondary Outcome

Title	Safety of Vismodegib
Description	The safety of Vismodegib was evaluated by monitoring adverse effects. All adverse events, expected and unexpected, were recorded and categorized using the Common Terminology Criteria for Adverse Events (CTCAE) guide. This is a set of criteria from the National Cancer Institute (NCI) used to standardize classification of adverse effects of drugs. Grade 1 events are defined as mild, grade 2 as moderate, grade 3 as severe; grade 4 as life-threatening and grade 5 as death.
Time Frame	Up to 18 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Open Label Oral Vismodegib
Arm/Group Description	This is a Phase 2B single-site, open-label, nonrandomized 24-week study of the efficacy and safety of vismodegib (150 mg PO daily) in subjects with high risk and/or locally advanced basal cell carcinoma. vismodegib (150 mg PO daily): Biopsies will be performed on all participants at baseline, week 12 and week 24.
Measure Participants	28
Grade 1	133
Grade 2	48
Grade 3	8
Grade 4	1
Grade 5	2

3. Secondary Outcome

Title	Onset of Efficacy of Vismodegib
Description	Onset of efficacy was measured by tumor surface area reduction or increase. Subjects had one target lesion and up to 3 additional non-target lesions. Surface area of a cumulative total of 65 tumors (27 target lesions and 38 non-target lesions) was measured after 24 weeks of treatment. A complete response was defined as 100% reduction in tumor surface area. Partial response was defined as greater than 50% reduction in tumor surface area. Stable disease was defined as less than 50% reduction in tumor surface area and Progressive disease was defined as greater than 20% increase in tumor surface area.
Time Frame	Up to week 24

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Open Label Oral Vismodegib
Arm/Group Description	This is a Phase 2B single-site, open-label, nonrandomized 24-week study of the efficacy and safety of vismodegib (150 mg PO daily) in subjects with high risk and/or locally advanced basal cell carcinoma. vismodegib (150 mg PO daily): Biopsies will be performed on all participants at baseline, week 12 and week 24.
Measure Participants	27
Measure tumors	65
Complete response	13
Partial response	27
Stable Disease	24
Progressive Disease	1

Adverse Events

Time Frame	The study period during which all Adverse Events (AE) and Serious Adverse Events (SAE) must be reported begins after informed consent is obtained and initiation of study treatment and ends 30 days following the last administration of study treatment or study discontinuation/termination, whichever is earlier.
Arm/Group Title	Open Label Oral Vismodegib
Arm/Group Description	This is a Phase 2B single-site, open-label, nonrandomized 24-week study of the efficacy and safety of vismodegib (150 mg PO daily) in subjects with high risk and/or locally advanced basal cell carcinoma. vismodegib (150 mg PO daily): Biopsies will be performed on all participants at baseline, week 12 and week 24.
All Cause Mortality
	Open Label Oral Vismodegib
	Affected / at Risk (%)	# Events
Total	2/28 (7.1%)
Serious Adverse Events
	Open Label Oral Vismodegib
	Affected / at Risk (%)	# Events
Total	4/28 (14.3%)
Cardiac disorders
Myocardial infarction	1/28 (3.6%)	1
Congestive Heart Failure	1/28 (3.6%)	1
Gastrointestinal disorders
Duodenal ulcer	1/28 (3.6%)	1
Gastrointestinal bleed	1/28 (3.6%)	1
General disorders
Exacerbation of low back pain	1/28 (3.6%)	1
Nervous system disorders
Neurogenic claudication	1/28 (3.6%)	1
Other (Not Including Serious) Adverse Events
	Open Label Oral Vismodegib
	Affected / at Risk (%)	# Events
Total	28/28 (100%)
Blood and lymphatic system disorders
Hyperlipidemia	1/28 (3.6%)	1
Cardiac disorders
Elevated blood pressure	1/28 (3.6%)	1
Ear and labyrinth disorders
Vertigo	2/28 (7.1%)	2
Tinnitus	1/28 (3.6%)	1
Eye disorders
Blurry vision	2/28 (7.1%)	2
Gastrointestinal disorders
Diarrhea	7/28 (25%)	7
Constipation	2/28 (7.1%)	2
Dyspepsia	2/28 (7.1%)	2
Gastroenteritis	2/28 (7.1%)	2
Esophagitis	1/28 (3.6%)	1
General disorders
Dysgeusia/Loss of Taste	24/28 (85.7%)	24
Nausea	8/28 (28.6%)	8
Fatigue	7/28 (25%)	7
Swelling	4/28 (14.3%)	4
Abnormal hair growth	2/28 (7.1%)	2
Insomnia	2/28 (7.1%)	2
Scalp tenderness	2/28 (7.1%)	2
Headache	2/28 (7.1%)	2
Falls	2/28 (7.1%)	2
Vomiting	1/28 (3.6%)	1
Dehydration	1/28 (3.6%)	1
Decrease in eyelashes/eyebrows	1/28 (3.6%)	1
Stunted nail growth	1/28 (3.6%)	1
Bloating	1/28 (3.6%)	1
Dry mouth	1/28 (3.6%)	1
Tooth pain	1/28 (3.6%)	1
Numbness	1/28 (3.6%)	1
Rhinorrhea	1/28 (3.6%)	1
Visual hallucinations	1/28 (3.6%)	1
Burning sensation of tongue	1/28 (3.6%)	1
Halitosis	1/28 (3.6%)	1
Lower extremity edema/intermittent swelling	1/28 (3.6%)	1
Vitamin D deficiency	1/28 (3.6%)	1
Infections and infestations
Upper respiratory infection	5/28 (17.9%)	5
Wound infection	2/28 (7.1%)	2
Urinary Tract Infection	2/28 (7.1%)	2
Viral syndrome	1/28 (3.6%)	1
Bronchitis	1/28 (3.6%)	1
Sinus infection	1/28 (3.6%)	1
Salivary gland infection	1/28 (3.6%)	1
Metabolism and nutrition disorders
Decreased appetite/anorexia/weight loss	9/28 (32.1%)	9
Hypokalemia	1/28 (3.6%)	1
Musculoskeletal and connective tissue disorders
Muscle spasms	23/28 (82.1%)	23
Joint aches	5/28 (17.9%)	5
Muscle aches	2/28 (7.1%)	2
Maxillary fibrous cyst	1/28 (3.6%)	1
Fracture	1/28 (3.6%)	1
Dislocation	1/28 (3.6%)	1
Sprain	1/28 (3.6%)	1
Gout	1/28 (3.6%)	1
Orthostatic tremor	1/28 (3.6%)	1
Reproductive system and breast disorders
Vaginal bleeding	1/28 (3.6%)	1
Skin and subcutaneous tissue disorders
Alopecia	20/28 (71.4%)	20
Itching/pruritus	4/28 (14.3%)	4
Comedones	2/28 (7.1%)	2
Actinic keratosis	2/28 (7.1%)	2
Rash	1/28 (3.6%)	1
Biopsy site inflammation	1/28 (3.6%)	1
Acne	1/28 (3.6%)	1
Rosacea flare	1/28 (3.6%)	1
Squamous cell carcinoma	1/28 (3.6%)	1
Surgical and medical procedures
Eyelid reconstruction	1/28 (3.6%)	1
Vascular disorders
Peripheral arterial disease	1/28 (3.6%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.