Efficacy of XL184 (Cabozantinib) in Advanced Medullary Thyroid Cancer

An International, Randomized, Double-Blinded, Phase 3 Efficacy Study of XL184 Versus Placebo in Subjects With Unresectable, Locally Advanced, or Metastatic Medullary Thyroid Cancer

The purpose of this research study is to evaluate the progression-free survival (PFS) with XL184 as compared with placebo (an inactive substance) in subjects with unresectable, locally advanced, or metastatic medullary thyroid cancer (MTC). Subjects will be randomized to receive XL184 or placebo in a 2:1 ratio. XL184 is an investigational drug that inhibits VEGFR2, MET and RET, kinases implicated in tumor formation, growth and migration.

The Clinical Steering Committee for this study, comprised of study doctors who specialize in medullary thyroid cancer, has provided guidance regarding the design of the study. The committee includes: Douglas Ball, MD, Barry Nelkin, PhD, Martin Schlumberger, MD and Steven Sherman, MD.

Inclusion Criteria:

• The subject has a histologically confirmed diagnosis of MTC that cannot be removed by surgery, is locally advanced, or has spread in the body.
• The subject is at least 18 years old.
• The subject has an ECOG (Eastern Cooperative Oncology Group) performance status ≤ 2.
• The subject has documented worsening of disease (progressive disease) at screening compared with a previous CT scan or MRI image done within 14 months of screening.
• The subject has recovered from clinically significant adverse events (side effects) due to any other medications that were administered prior to randomization.
• The subject has adequate organ and bone marrow function.
• Subjects who are sexually active (male and female) must agree to use medically accepted methods of contraception during the course of the study and for 3 months following discontinuation of study treatments.
• The subject has no other diagnosis of cancer (unless non-melanoma skin cancer, an early form of cervical cancer, or another cancer diagnosed ≥ 2 years previously) and currently has no evidence of malignancy (unless non-melanoma skin cancer or an early form of cervical cancer).
• Female subjects of childbearing potential must have a negative pregnancy test at screening.

Exclusion Criteria:

• The subject has received prior treatment for their cancer within 4 weeks of randomization (6 weeks for nitrosoureas or mitomycin C).
• The subject has received radiation to ≥ 25 % of bone marrow.
• The subject has received treatment with other investigational agents (unapproved therapies) within 4 weeks of randomization.
• The subject has received treatment with XL184.
• The subject has brain metastases or spinal cord compression, unless completed radiation therapy ≥ 4 weeks prior to randomization and stable without steroid and without anti-convulsant treatment for ≥ 10 days.
• The subject has a history of clinically significant episodes of vomiting blood or a recent history of vomiting > 2.5 mL (about 1/2 teaspoon) of red blood.
• The subject has serious illness other than cancer.
• The subject is pregnant or breastfeeding.
• The subject has an active infection requiring ongoing treatment.
• The subject is incapable of understanding and complying with the protocol or unable to provide informed consent.