Vismodegib in Treating Patients With Advanced Chondrosarcomas

Study Overview
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Brief Summary
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This phase II trial studies how well vismodegib works in treating patients with chondrosarcomas that have spread to other places in the body and usually cannot be cured or controlled with treatment. Drugs used in chemotherapy, such as vismodegib, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

Detailed Description
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PRIMARY OBJECTIVES: I. To evaluate the antitumor activity of GDC-0449 (vismodegib) in terms of 6-month clinical benefit rate (complete response, partial response, and stable disease, as per the revised Response Evaluation Criteria in Solid Tumors [RECIST] criteria 2009). SECONDARY OBJECTIVES: I. Best overall response (as per the revised RECIST criteria 2009). II. 1- and 2-year progression-free survival. III. 1- and 2-year overall survival. IV. GDC-0449 safety. V. Pharmacogenomics analysis of predictive markers of treatment outcome. OUTLINE: Patients receive vismodegib orally (PO) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study therapy, patients are followed up every 3 months.

Official Title
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A Phase 2 Study of GDC-0449 in Patients With Advanced Chondrosarcomas

Conditions
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Clear Cell Chondrosarcoma, Dedifferentiated Chondrosarcoma, Locally Advanced Chondrosarcoma, Mesenchymal Chondrosarcoma, Metastatic Chondrosarcoma, Primary Central Chondrosarcoma, Unresectable Primary Central Chondrosarcoma

Intervention / Treatment
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* Other: Laboratory Biomarker Analysis
* Other: Pharmacogenomic Study
* Drug: Vismodegib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically confirmed diagnosis of chondrosarcoma (conventional, mesenchymal, dedifferentiated or clear cell subtypes) Patients must have measurable disease (outside any previously irradiated field) defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 10 mm with spiral computed tomography (CT) scan No more than three prior lines of chemotherapy for advanced disease (including no more than 450 mg/m^2 doxorubicin); at least three weeks since last chemotherapy (six weeks in case of nitrosoureas and mitomycin C), immunotherapy or any other pharmacological treatment and/or radiotherapy Life expectancy of greater than 3 months Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) Leukocytes >= 3,000/mcL Absolute neutrophil count >= 1,500/mcL Platelets >= 100,000/mcL Total bilirubin within normal institutional limits Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional upper limit of normal Creatinine within normal institutional limits OR creatinine clearance > 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal Metastatic or unresectable locally advanced disease Documented disease progression (as per RECIST) before study entry Women of child-bearing potential and men must use two forms of contraception (i.e., barrier contraception and one other method of contraception) at least 4 weeks prior to study entry, for the duration of study participation, and for at least 24 months post-treatment for female patients and for 2 months for male patients; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately Women of childbearing potential are required to have a negative serum pregnancy test (with a sensitivity of at least 25 mIU/mL) within 7 days prior to initiation of GDC-0449 (serum or urine); a pregnancy test (serum or urine) will be administered every 4 weeks while on study within the 24-hour period prior to the administration of GDC-0449; a positive urine test must be confirmed by a serum pregnancy test; prior to dispensing GDC-0449, the investigator must confirm and document the patient's use of two contraceptive methods, dates of negative pregnancy test, and confirm the patient's understanding of the teratogenic potential of GDC-0449 Women of childbearing potential are defined as follows: Patients with regular menses Patients with amenorrhea, irregular cycles, or using a contraceptive method that precludes withdrawal bleeding Women who have had a tubal ligation Women are considered not to be of childbearing potential for the following reasons: The patient has undergone hysterectomy and/or bilateral oophorectomy The patient is post-menopausal defined by amenorrhea for at least 1 year in a woman > 50 years old The patient has permanent premature ovarian failure confirmed by specialist gynecologist Ability to understand and the willingness to sign a written informed consent document In accordance with French Regulatory Authorities: Patients with French Social Security in compliance with the French law relating to biomedical research (Huriet Law 88-1138 and related decrees) Exclusion Criteria: Patients who have had chemotherapy or radiotherapy within 3 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 3 weeks earlier Patients may not be receiving any other investigational agents Patients with known brain metastases should be excluded from this clinical trial History of allergic reactions attributed to compounds of similar chemical or biologic composition to GDC-0449 or other agents used in the study Patients with malabsorption syndrome or other condition that would interfere with intestinal absorption; patients must be able to swallow capsules Patients with clinically important history of liver disease, including viral or other hepatitis, or cirrhosis are ineligible Patients with uncontrolled hypocalcemia, hypomagnesemia, hyponatremia, or hypokalemia defined as less than the lower limit of normal for the institution, despite adequate electrolyte supplementation, are excluded from this study Tumor tissue sample not available for pathological review and/or correlative studies Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with GDC-0449; these potential risks may also apply to other agents used in this study Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (vismodegib)<br>Patients receive vismodegib PO on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacogenomic Study<br>* Correlative studies<br>* Other names: PHARMACOGENOMIC;Drug: Vismodegib<br>* Given PO<br>* Other names: Hedgehog Antagonist GDC-0449;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Benefit Rate (CBR) Based on Centralized Imaging Review as Per RECIST 1.1 | CBR was defined as the percentage of participants with complete or partial responses (CR, PR) or stable disease (SD) per RECIST 1.1. CR was defined as disappearance of all non-nodal target lesions. PR was defined as at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. Analysis of response was performed based on radiological centralized review. A 2-stage optimal Simon's design with 37 participants (first stage: 17 participants) was used. If 3 or less non-progressions (CR + PR + SD) at 6 months were observed during stage 1 (out of 17 participants), the trial would stopped early. Otherwise, 20 additional patients would be accrued for stage 2. If 11 or more non-progressions (out of 37 participants) were observed at the end of recruitment, further investigation of this therapy would be warranted. | At 6 months after inclusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | Will be analyzed using the Kaplan-Meier method. The median survival rates will be reported with a 95% confidence interval. Median follow-up will be calculated using the reverse Kaplan-Meier method. | Time from start of treatment to time of progression or death, whichever occurs first, assessed up to 3 years | 
| Overall Survival Per Response Evaluation Criteria in Solid Tumors Criteria 2009 | Overall survival will be analyzed using the Kaplan-Meier method. The median survival rates will be reported with a 95% confidence interval. Median follow-up will be calculated using the reverse Kaplan-Meier method. | Time from start of treatment to the time of death, assessed up to 3 years | 
| Duration of Response | Will be described in responding subjects using descriptive statistics (median, extreme values, etc.). | From the time measurement criteria are met for complete response or partial response (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, assessed up to 3 years | 
| Mutational Status of Patched 1 and Smoothened | The 6-months clinical benefit rate will be correlated with the mutational status of patched and smoothened in order to identify predictive factors of clinical benefit from vismodegib. | Baseline | 
| Expression Pattern of Hedgehog Signaling Molecules by Using Quantitative Reverse Transcription-polymerase Chain Reaction and Immunohistochemistry | The 6-months clinical benefit rate will be correlated with the expression score of hedgehog signaling molecules in order to identify predictive factors of clinical benefit from vismodegib. | Baseline |