Study of Cabozantinib (XL184) in Adults With Advanced Malignancies

• Safety and tolerability of XL184 in subjects with advanced solid tumors [ Time Frame: Assessed approximately every 3 weeks, during study visits ] [ Designated as safety issue: Yes ]
• To correlate the pathway dysfunction of disease-related genes or proteins such as MET and downstream signaling molecules with clinical outcome [ Time Frame: Assessed approximately every 6 weeks through blood samples and tumor biopsies ] [ Designated as safety issue: No ]
• To further characterize the pharmacokinetic (PK) and pharmacodynamic parameters of XL184 [ Time Frame: Assessed approximately every 6 weeks through blood samples ] [ Designated as safety issue: No ]

The purpose of this study is to determine whether or not XL184 demonstrates anti-tumor activity in selected tumor types under a randomized discontinuation trial (RDT) design. Subjects who have responded to study drug after 12 weeks of open-label XL184 administration will continue to take XL184. Subjects who are clearly progressing will discontinue study treatment and subjects who demonstrate stable disease will be randomized to either XL184 or placebo. For individual patients, once disease progression is observed, the blind will be broken and subjects who were randomized to placebo will be offered the option to receive open-label XL184. Subjects who progressed while taking XL184 will discontinue study treatment.

Emerging data may support enrollment in an open-label, non-randomized expansion cohort (NRE). There will be NRE cohorts for prostate and ovarian cancers.

• Solid Tumors
• Cancer

• Drug: XL184
  All subjects receive 100 mg XL184 (supplied at 19.7-, 50-, and 60-mg strength capsules) daily for 12 weeks. Subjects with a partial or complete response will continue daily XL184 administration until disease progression. Subjects with stable disease will be randomized to Arm 2 or 3.
• Drug: Placebo
  After 12 weeks of open-label daily XL184, subjects with stable disease randomized to Arm 3 will receive capsules of placebo that are size- and color-matched to XL184 administered daily until disease progression. Subjects will be unblinded at disease progression and, if found to be receiving placebo, given the option to receive XL184.
• Drug: XL184
  After 12 weeks of open-label daily XL184, subjects with stable disease randomized to Arm 2 will continue to receive XL184 (blinded) administered daily until disease progression.
• Drug: XL184
  All subjects receive open-label, 100 mg XL184 (supplied at 19.7-, 50-, and 60 mg strength capsules) daily until disease progression.

• Experimental: Arm 1
  RDT Open-Label
  Intervention: Drug: XL184
• Experimental: Arm 2
  RDT Randomized Blinded-XL184
  Intervention: Drug: XL184
• Placebo Comparator: Arm 3
  RDT Randomized Blinded
  Intervention: Drug: Placebo
• Experimental: Non-Randomized Expansion (NRE) Cohorts
  Drug: XL184
  Intervention: Drug: XL184

Inclusion Criteria:

• The subject has a cytologically or histologically and radiologically confirmed, advanced, recurrent, or metastatic solid tumor of the nine types listed below:

  • Pancreatic Cancer
  • Castration-Resistant Prostate Cancer (CRPC)
  • Hepatocellular Carcinoma (HCC)
  • Gastric or Gastroesophageal Junction Cancer
  • Melanoma
  • Small Cell Lung Cancer (SCLC)
  • Ovarian cancer, primary peritoneal or fallopian tube carcinoma
  • Breast cancer that is one of the following subtypes: estrogen receptor positive breast cancer, estrogen receptor/progesterone receptor/HER2-negative (triple-negative), or inflammatory (regardless of receptor status) disease histology
  • Non-Small Cell Lung Cancer (NSCLC)
• Certain requirements for prior therapies may apply
• The subject has documented progressive disease at screening
• Subjects having any tumor type of other than CRPC must have at least one lesion that is not within a previously irradiated field and is measurable on CT or MRI scan
• The subject has recovered to baseline or CTCAE ≤ Grade 1 from toxicities related to prior treatment (some exceptions apply)
• The subject is ≥ 18 years old on the day of consent
• Tissue samples from archival or fresh tissue, or a tissue block of the subject's tumor
• The subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• The subject has adequate organ function
• The subject is capable of understanding and complying with the protocol requirements and has signed the informed consent document
• Sexually active fertile subjects (male and female), and their partners, must agree to use medically accepted methods of contraception during the course of the study and for 3 months after the last dose of the study drug(s)
• Female subjects of childbearing potential must have a negative pregnancy test at screening

Exclusion Criteria:

• The subject has experienced clinically-significant hematemesis or hemoptysis of >0.5 teaspoon of red blood, or other signs indicative of pulmonary hemorrhage within 3 months before the first dose of study treatment
• The subject has a cavitating pulmonary lesion(s) or a pulmonary lesion abutting or encasing a major blood vessel
• Certain restrictions on prior treatments apply
• The subject has received drugs used to control loss of bone mass within 4 weeks prior to the first dose of study treatment
• The subject has known symptomatic or uncontrolled brain metastases or epidural disease
• The subject has prothrombin time/International Normalized Ratio (PT/INR) or partial thromboplastin time (PTT) test results that are above (1.3x)the laboratory upper limit of normal
• The subject has a corrected QT interval(QTcF)>500 ms at screening
• The subject requires concomitant treatment, in therapeutic doses, with anticoagulants such as warfarin or Coumadin-related agents, heparin, thrombin or FXa inhibitors, and antiplatelet agents (low-dose aspirin (≤81 mg/day), low-dose warfarin (≤1mg/day, and prophylactic low molecular weight heparin (LMWH) are permitted)
• The subject has uncontrolled, significant intercurrent illness
• The subject is unable to swallow capsules
• The subject is pregnant or breastfeeding
• The subject has a previously-identified allergy or hypersensitivity to components of the study treatment formulation
• The subject is unable or unwilling to abide by the study protocol or cooperate fully with the investigator or designee
• The subject has had another diagnosis of malignancy requiring systemic treatment within the last two years, unless non-melanoma skin cancer, in-situ carcinoma of the cervix, or superficial bladder cancer