Cabozantinib in Treating Patients With Locally Advanced or Metastatic Unresectable Adrenocortical Carcinoma
Cabozantinib in Treating Patients With Locally Advanced or Metastatic Unresectable Adrenocortical Carcinoma
This phase II trial studies how well cabozantinib works in treating patients with adrenal
 cortex cancer that has spread to nearby tissue, lymph nodes, or other places in the body, and
 cannot be removed by surgery. Cabozantinib may stop the growth of tumor cells by blocking
 some of the enzymes needed for cell growth.
PRIMARY OBJECTIVES:

 I. To estimate progression free survival at 4 months.

 SECONDARY OBJECTIVES:

 I. Best overall response rate. II. Overall survival (OS). III. Toxicity assessment by the
 Common Terminology Criteria for Adverse Events (CTCAE) version (V)4.0.

 EXPLORATORY OBJECTIVES:

 I. Pharmacokinetics and cabozantinib serum levels to assess correlation with response to
 therapy.

 II. Steroid hormone biomarkers as markers of disease response. III. Study the effect of
 cabozantinib on immune markers by obtaining optional biopsy and blood samples collections at
 baseline, during therapy and at time of progression.

 IV. Pharmacogenomics of drug disposition gene variants that potentially influence
 cabozantinib pharmacokinetics (PK).

 OUTLINE:

 Patients receive cabozantinib orally (PO) once daily (QD) in the absence of disease
 progression or unacceptable toxicity.

 After completion of study treatment, patients are followed up at 30-37 days.
Inclusion Criteria:

 -  Histological confirmation of adrenocortical carcinoma (ACC) based on either: i). Weiss
 Score of >= 3 in patients who had earlier surgical resection OR ii). biopsy results
 compatible with ACC in the context of clinical setting highly suggestive of ACC
 (adrenal mass > 4 cm invading surrounding organs or associated with distant
 metastases).

 -  Locally advanced or metastatic disease not amenable to surgery with curative intent
 with measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
 as determined by the investigator based on an assessment of all known disease sites by
 computerized tomography (CT) scan or magnetic resonance imaging (MRI) of
 chest/abdomen/pelvis within 28 days before the first dose of cabozantinib. In patients
 with intravenous (IV) contrast allergy or borderline renal function, CT without IV
 contrast or 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) CT may
 be used as clinically indicated.

 -  Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.

 -  Recovery to baseline or =< grade 1 CTCAE v.4.0 from toxicities related to any prior
 treatments, unless adverse events (AEs) are clinically nonsignificant and/or stable on
 supportive therapy.

 -  Life expectancy of at least 3 months.

 -  Absolute neutrophil count (ANC) >= 1500/mm^3 without colony stimulating factor support
 (obtained within 28 days prior to the first dose of cabozantinib).

 -  Platelets >= 100,000/mm^3 (obtained within 28 days prior to the first dose of
 cabozantinib).

 -  Hemoglobin >= 9 g/dL (obtained within 28 days prior to the first dose of
 cabozantinib).

 -  Bilirubin =< 1.5 x the upper limit of normal (ULN). For subjects with known Gilbert's
 disease, bilirubin =< 3.0 mg/dL (obtained within 28 days prior to the first dose of
 cabozantinib).

 -  Serum albumin >= 2.8 g/dl (obtained within 28 days prior to the first dose of
 cabozantinib).

 -  Serum creatinine =< 1.5 x ULN or creatinine clearance (CrCl) >= 50 mL/min. For
 creatinine clearance estimation, the Cockcroft and Gault equation should be used
 (obtained within 28 days prior to the first dose of cabozantinib).

 -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3.0 x ULN
 (obtained within 28 days prior to the first dose of cabozantinib).

 -  Lipase =< 2.0 x the upper limit of normal and no radiologic or clinical evidence of
 pancreatitis (obtained within 28 days prior to the first dose of cabozantinib).

 -  Urine protein/creatinine ratio (UPCR) =< 1 (obtained within 28 days prior to the first
 dose of cabozantinib).

 -  Serum phosphorus >= 2.5 mg/dl (obtained within 28 days prior to the first dose of
 cabozantinib).

 -  Calcium >= 8 mg/dL (obtained within 28 days prior to the first dose of cabozantinib).

 -  Magnesium >= 1.2 mg/dL (obtained within 28 days prior to the first dose of
 cabozantinib).

 -  Potassium >= 3.0 meq/L (obtained within 28 days prior to the first dose of
 cabozantinib).

 -  Capable of understanding and complying with the protocol requirements and has signed
 the informed consent document.

 -  Sexually active patients (men and women) must agree to use medically accepted barrier
 methods of contraception (e.g. male or female condom) during the course of the study
 and for 4 months after the last dose of study drug(s), even if oral contraceptives are
 also used. All sexually active subjects of reproductive potential must agree to use
 both a barrier method and a second method of birth control during the course of the
 study and for 4 months after the last dose of study drug(s).

 -  Women of childbearing potential must have a negative pregnancy test at screening.
 Women of childbearing potential include women who have experienced menarche and who
 have not undergone successful surgical sterilization (hysterectomy, bilateral tubal
 ligation, or bilateral oophorectomy) or are not postmenopausal. Postmenopause is
 defined as amenorrhea >= 12 consecutive months. Note: women who have been amenorrheic
 for 12 or more months are still considered to be of childbearing potential if the
 amenorrhea is possibly due to prior chemotherapy, anti-estrogens, ovarian suppression
 or any other reversible reason.

 Exclusion Criteria:

 -  Received cytotoxic chemotherapy, radiation therapy, or targeted therapy (including
 investigational cytotoxic chemotherapy) or biologic agents (e.g., cytokines or
 antibodies) within 28 days of study enrollment.

 -  For patients who received mitotane within 6 months of consenting, mitotane should have
 been stopped at least 28 days prior to study enrollment AND to have mitotane serum
 level of < 2 mg/L.

 -  Prior treatment with cabozantinib or other cMET inhibitors.

 -  Known brain metastases or cranial epidural disease unless adequately treated with
 radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks
 before the first dose of study treatment. Eligible subjects must be neurologically
 asymptomatic and without corticosteroid treatment at the time of the start of study
 treatment.

 -  The subject has not recovered to baseline or CTCAE =< grade 1 from toxicity due to all
 prior therapies except alopecia and other non-clinically significant AEs.

 -  Prothrombin time (PT)/ international normalized ratio (INR) or partial thromboplastin
 time (PTT) test >= 1.3 x the laboratory ULN within 28 days before the first dose of
 study treatment.

 -  Concomitant anticoagulation with oral anticoagulants (e.g., warfarin, direct thrombin
 and Factor Xa inhibitors), platelet inhibitors (e.g., clopidogrel) or therapeutic
 doses of low molecular weight heparins (LMWH). Low dose aspirin for cardioprotection
 (per local applicable guidelines) and low-dose LMWH are permitted. Anticoagulation
 with therapeutic doses of LMWH is allowed in subjects who are on a stable dose of LMWH
 for at least 6 weeks before the first dose of study treatment, and who have had no
 clinically significant hemorrhagic complications from the anticoagulation regimen or
 the tumor.

 -  Severe and uncontrolled Cushing syndrome despite medical management (e.g., systolic
 blood pressure > 160 mmHg or hyperglycemia with fasting glucose above 300 mg/dL).

 -  The use of strong CYP3A4 inhibitor (with the exception of ketoconazole).

 -  The subject has experienced any of the following: a. clinically-significant
 gastrointestinal bleeding within 6 months before the first dose of study treatment; b.
 hemoptysis >= 0.5 teaspoon (2.5 mL) of red blood within 3 months before the first dose
 of study treatment; c. any other signs indicative of pulmonary hemorrhage within 3
 months before the first dose of study treatment. Tumor invading any major blood vessel
 at the time of study enrollment.

 -  Evidence of tumor invading the gastrointestinal (GI) tract (esophagus, stomach, small
 or large bowel, rectum or anus), or any evidence of endotracheal or endobronchial
 tumor within 28 days before the first dose of cabozantinib, or the subject with
 radiographic evidence of cavitating pulmonary lesion(s); or subjects with tumor
 invading or encasing any major blood vessels.

 -  Uncontrolled, significant concurrent or recent illness including, but not limited to,
 the following conditions: a. Cardiovascular disorders including i. congestive heart
 failure (CHF): New York Heart Association (NYHA) class III (moderate) or class IV
 (severe) at the time of screening ii. concurrent uncontrolled hypertension defined as
 sustained blood pressure (BP) > 150 mm Hg systolic, or > 90 mm Hg diastolic despite
 optimal antihypertensive treatment within 7 days of the first dose of study treatment
 iii. any history of congenital long QT syndrome or iv. any of the following within 6
 months before the first dose of study treatment: unstable angina pectoris,
 clinically-significant cardiac arrhythmias, stroke (including transient ischemic
 attack [TIA], or other ischemic event) within 90 days of the first dose of study
 treatment, myocardial infarction, clinically significant thromboembolic event within
 42 days of randomization requiring therapeutic anticoagulation.

 -  (Note: subjects with a venous filter (e.g. vena cava filter) are not eligible for this
 study) b. gastrointestinal disorders particularly those associated with a high risk of
 perforation or fistula formation including: i. any of the following within 28 days
 before the first dose of study treatment: intra-abdominal tumor/metastases invading GI
 mucosa, active peptic ulcer disease; patients must be completely recovered,
 inflammatory bowel disease (including ulcerative colitis and Crohn's disease), acute
 pancreatitis, pancreatic duct or common bile duct obstruction, acute diverticulitis,
 acute cholecystitis, symptomatic cholangitis or recent appendicitis within 1 month of
 first dose of cabozantinib; patients must be completely recovered from these
 conditions, clinically significant malabsorption syndrome, c. endocrine disorders,
 uncontrolled Cushing syndrome despite of adequate medical therapy.

 -  Any of the following within 6 months before the first dose of study treatment:
 abdominal fistula, gastrointestinal perforation, bowel obstruction or gastric outlet
 obstruction, intra-abdominal abscess. Note: complete resolution of an intra-abdominal
 abscess must be confirmed prior to initiating treatment with cabozantinib even if the
 abscess occurred more than 6 months before the first dose of study treatment. Other
 disorders associated with a high risk of fistula formation including percutaneous
 endoscopic gastrostomy (PEG) tube placement within 90 days before the first dose of
 study therapy.

 -  Other clinically significant disorders such as: i. active infection requiring systemic
 antibiotic treatment within 14 days before the first dose of study treatment ii.
 serious non-healing wound/ulcer/bone fracture within 28 days before the first dose of
 study treatment iii. history of organ transplant iv. concurrent uncompensated
 hypothyroidism or thyroid dysfunction (thyroid-stimulating hormone [TSH] above 10)
 within 28 days before the first dose of study treatment v. major surgery within 12
 weeks before the first dose of study treatment. Complete wound healing from major
 surgery must have occurred 1 month before the first dose of study treatment. Minor
 surgery within 28 days before the first dose of study treatment with complete wound
 healing at least 10 days before the first dose of study treatment. Subjects with
 clinically relevant ongoing complications from prior surgery are not eligible.

 -  Unable to swallow tablets.

 -  A corrected QT interval calculated by the Fridericia formula (QTcF) > 500 milliseconds
 within 28 days before first dose of study treatment. Three electrocardiograms (ECGs)
 must be performed for eligibility determination. If the average of these three
 consecutive results for QTcF is =< 500 milliseconds, the subject will be eligible.

 -  Pregnant or breastfeeding.

 -  A previously identified allergy or hypersensitivity to components of the study
 treatment formulation.

 -  Unable or unwilling to abide by the study protocol or cooperate fully with the
 investigator or designee.

 -  Evidence within 2 years of the start of study treatment of another malignancy which
 required systemic treatment except for breast ductal carcinoma-in situ, cured
 non-melanoma skin cancer, or cured in situ cervical carcinoma.

 -  Any other severe acute or chronic medical or psychiatric condition or laboratory
 abnormality which, in the judgment of the investigator, would have made the patient
 inappropriate for entry into this study.