A phase II study of GDC-0449 in patients with advanced chondrosarcomas. - CHONDROG

• Conditions: Adult patients with unresectable locally advanced or metastatic chondrosarcomas.; MedDRA version: 12.1Level: LLTClassification code 10008736Term: Chondrosarcoma metastatic

• Registration Number: EUCTR2010-019817-20-FR
• Lead Sponsor: Institut Bergonié

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2010-10-07
• Last Update Posted: 19 March 2012

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: Not specified

Inclusion Criteria

1. Patients must have histologically confirmed diagnosis of chondrosarcoma (conventional, mesenchymal, dedifferentiated or clear cell subtypes) ;
2. 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 >20 mm with conventional techniques or as >10 mm with spiral CT scan. See Section 12 for the evaluation of measurable disease.
3. No more than two prior lines of therapy for advanced disease (including no more than 450 mg/m² 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.
4. Age >18 years.
5. Life expectancy of greater than 3 months
6. ECOG performance status <2 (Karnofsky >60%; see Appendix A).
7. Patients must have normal organ and marrow function as defined below:
i. leukocytes > 3,000/mcL
ii. absolute neutrophil count > 1,500/mcL
iii. platelets > 100,000/mcL
iv. total bilirubin within normal institutional limits
v. AST(SGOT)/ALT(SGPT) < 2.5 X institutional upper limit of normal
vi.Creatinine within normal institutional limits or
creatinine clearance > 60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal
8. Metastatic or unresectable locally advanced disease.
9. Documented disease progression (as per RECIST; Appendix 7) before study entry.
10.The effects of GDC-0449 on the developing human fetus at the recommended
therapeutic dose are unknown. For this reason and because Hh signal pathway inhibitors are known to be teratogenic, 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 12 months post-treatment. For appropriate methods of contraception considered acceptable see Appendix C. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
11.Pregnancy Testing. Women of childbearing potential are required to have a negative serum pregnancy test (with a sensitivity of at least 25 mIU/mL) within 10-14 days and within 24 hours prior to the first dose 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.
i.Women of childbearing potential are defined as follows:
ii.Patients with regular menses
iii.Patients with amenorrhea, irregular cycles, or using a contraceptive method that precludes withdrawal bleeding
iv.Women who have had a tubal ligation
v.Women are considered not to be of childbearing potential for the following reasons:
vi.The patient has undergone hysterectomy and/or bilateral oophorectomy.
vii.The patient is post-menopausal defined by amenorrhea for at least 1 year in a woman > 45 years old.
12.Ability to understand and the willingness to sign a written informed consent document.
13.In accordance with French Regulatory A

Exclusion Criteria

1. Tumor tissue sample not available for pathological review and/or correlative studies.
2. 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.
3. Patients may not be receiving any other investigational agents.
4. Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
5. History of allergic reactions attributed to compounds of similar chemical or biologic composition to GDC-0449 or other agents used in the study.
6. Patients with malabsorption syndrome or other condition that would interfere with intestinal absorption. Patients must be able to swallow capsules.
7. Patients with clinically important history of liver disease, including viral or other hepatitis or cirrhosis are ineligible.
8. 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.
9. 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.
10. Pregnant women are excluded from this study because GDC-0449 is a Hh pathway inhibiting agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with GDC-0449, breastfeeding should be discontinued if the mother is treated with GDC-0449.
11.HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with GDC-0449. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To evaluate the antitumor activity of GDC-0449 in terms of 6-month clinical benefit (Complete response, partial response and stable disease, as per the Response Evaluation Criteria in Solid Tumors, Revised RECIST criteria 2009, Appendix 7).;Secondary Objective: * Best overall response (as per the revised RECIST criteria 2009 Appendix 7);<br>* 1- and 2-year progression-free survival;<br>* 1- and 2-year overall survival;<br>* GDC-0449 safety;<br>* Pharmacogenomic analysis of predictive markers of treatment outcome;Primary end point(s): The 6-months clinical benefit (CR + PR + SD) rate is the primary endpoint. At six months, patients will be classified as success (Alive at 6 months AND CR/PR/ SD) or failure (dead OR alive with progression).