Cabozantinib (XL-184) Monotherapy for Advanced Cholangiocarcinoma
Condition: Bile Duct Cancer; Intrahepatic Cholangiocarcinoma; Cholangiocarcinoma of the Extrahepatic Bile Duct
MeSH terms: Cholangiocarcinoma; Bile Duct Neoplasms
Intervention: Cabozantinib
Intervention description: Cabozantinib 60 mg (free base weight) per day will be administered daily and continuously for a cycle length of 28 days. Subjects will be provided with a sufficient supply of study treatment and instructions for taking the study treatment on days without scheduled clinic visits. After fasting (with exception of water) for 2 hours, subjects will take study treatment daily with a full glass of water (minimum of 8 oz/ 240 mL) and continue to fast for 1 hour after each dose of study treatment.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 19.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Bile Duct Cancer; intrahepatic cholangiocarcinoma; extrahepatic cholangiocarcinoma; Cabozantinib

Summary:

      This research study is evaluating a drug called cabozantinib as a possible treatment cancer
      of the bile duct. Cabozantinib is a drug that targets specific pathways inside the cells of
      the body. By blocking the c-MET and VEGFR2 pathways from sending signals, cabozantinib may
      prevent cells from multiplying. This drug has been used in other research studies and
      information from those other research studies suggests that this drug may help to stop the
      growth of bile duct cancer.

      In this research study, the investigators are looking to see how well cabozantinib works in
      slowing the growth of bile duct cancer. The investigators are also assessing the safety and
      tolerability of cabozantinib in participants with this type of cancer.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Participants must have unresectable or metastatic histologically or cytologically
             confirmed intrahepatic cholangiocarcinoma or extrahepatic cholangiocarcinoma (i.e.
             hilar and distal cholangiocarcinoma).

          -  Participants must have measurable disease, 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 10
             for the evaluation of measureable disease.

          -  Participants must have failed at least 1 but no more than 2 lines of systemic regimens
             for advanced cholangiocarcinoma due to disease progression or toxicity.

          -  Age ≥ 18 years.

          -  Life expectancy of ≥ 3 months.

          -  ECOG performance status < 1 (see Appendix A).

          -  Participants must have adequate organ and marrow function as defined below:

          -  Absolute neutrophil count > 1,500/mcL

          -  Platelets > 100,000/mcL

          -  Hemoglobin ≥ 9 g/dL

          -  Total bilirubin ≤ 2.0 x the upper limit of normal

          -  AST (SGOT)/ALT (SGPT) ≤ 5 X institutional upper limit of normal

          -  PT/PTT ≤ 1.5 x ULN

          -  Creatinine ≤ 1.5 or GFR ≥ 60 mL/min/1.73m2

          -  Lipase < 2.0 x the upper limit of normal and no radiologic or clinical evidence of
             pancreatitis

          -  Serum phosphorus, calcium, magnesium and potassium ≥ LLN

          -  Urine protein: creatinine ratio ≤ 1

          -  Serum Albumin ≥ 2.8 g/dl

          -  Prior chemoembolization, radiofrequency ablation, or radiation to the liver is allowed
             as long as the patient has measurable disease outside of the treated area or
             measurable progression at the site of the treated area

          -  Ability to understand and the willingness to sign a written informed consent document.

          -  Sexually active subjects (men and women) must agree to use medically accepted barrier
             methods of contraception (eg, 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 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, antiestrogens, ovarian suppression
             or any other reversible reason.

        Exclusion Criteria:

          -  Participants who exhibit any of the following conditions at screening will not be
             eligible for admission into the study.

          -  Prior treatment with cabozantinib or other VEGF-R directed therapies

          -  Gallbladder carcinoma or periampullary tumors

          -  Chemotherapy within 4 weeks prior to entering the study (6 weeks for nitrosoureas or
             mitomycin) or those who have not recovered from adverse events due to agents
             administered more than 4 weeks earlier.

          -  The subject has received radiation therapy:

          -  to the thoracic cavity, abdomen or pelvis within 3 months of the first dose of study
             treatment or has with ongoing complications or is without complete recovery and
             healing from prior radiation therapy

          -  to bone or brain metastasis within 14 days of the first dose of study treatment

          -  to any other site(s) within 28 days of the first dose of study treatment

          -  The subject has a primary brain tumor.

          -  The subject has active brain metastases or epidural disease (Note: Subjects with brain
             metastases previously treated with whole brain radiation or radiosurgery or subjects
             with epidural disease previously treated with radiation or surgery who are
             asymptomatic and do not require steroid treatment for at least 2 weeks before starting
             study treatment are eligible. Neurosurgical resection of brain metastases or brain
             biopsy is permitted if completed at least 3 months before starting study treatment.
             (Baseline brain imaging with contrast-enhanced CT or MRI scans for subjects with known
             brain metastases is required to confirm eligibility.)

          -  The subject has uncontrolled, significant intercurrent or recent illness including,
             but not limited to, the following conditions:

          -  Cardiovascular disorders including

          -  Congestive heart failure (CHF): New York Heart Association (NYHA) Class III (moderate)
             or Class IV (severe) at the time of screening

          -  Concurrent uncontrolled hypertension defined as sustained BP > 140 mm Hg systolic, or
             > 90 mm Hg diastolic despite optimal antihypertensive treatment within 7 days of the
             first dose of study treatment

          -  Any history of congenital long QT syndrome

          -  Any of the following within 6 months before the first dose of study treatment:

          -  unstable angina pectoris

          -  clinically-significant cardiac arrhythmias

          -  stroke (including TIA, or other ischemic event)

          -  myocardial infarction

          -  thromboembolic event requiring therapeutic anticoagulation (Note: subjects with a
             venous filter (e.g. vena cava filter) are not eligible for this study)

          -  Gastrointestinal disorders particularly those associated with a high risk of
             perforation or fistula formation including:

          -  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,

          -  inflammatory bowel disease (including ulcerative colitis and Crohn's disease),
             diverticulitis, cholecystitis, symptomatic cholangitis, or appendicitis

          -  malabsorption syndrome

          -  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 that 6 months before the first dose of study treatment.

          -  Other disorders associated with a high risk of fistula formation including PEG tube
             placement within 3 months before the first dose of study therapy

          -  Other clinically significant disorders such as:

          -  active infection requiring systemic treatment within 28 days before the first dose of
             study treatment

          -  serious non-healing wound/ulcer/bone fracture within 28 days before the first dose of
             study treatment

          -  history of organ transplant

          -  concurrent uncompensated hypothyroidism or thyroid dysfunction within 7 days before
             the first dose of study treatment

          -  history of major surgery as follows:

          -  Major surgery within 3 months of the first dose of cabozantinib if there were no wound
             healing complications or within 6 months of the first dose of cabozantinib if there
             were wound complications

          -  Minor surgery within 1 months of the first dose of cabozantinib if there were no wound
             healing complications or within 3 months of the first dose of cabozantinib if there
             were wound complications

          -  Clinically significant gastrointestinal bleeding within six months of the first dose
             of study treatment

          -  Previous history of pulmonary embolism or deep venous thrombosis

          -  Severely impaired lung function or history of interstitial lung disease

          -  Concurrent malignancy (other than adequately treated non-melanoma skin cancer,
             superficial transitional cell carcinoma of the bladder, and cervical carcinoma in
             situ) diagnosed within the past 3 years or any currently active malignancy

          -  Psychiatric illness/social situations that would limit compliance with study
             requirements.

          -  The subject has a history of clinically significant hematemesis, hemoptysis of > 2.5
             mL of red blood, radiation (including brachytherapy) to pulmonary lesions, or signs
             indicative of significant pulmonary hemorrhage within 3 months before the first dose
             of study treatment.

          -  The subject has radiographic evidence of cavitating pulmonary lesion(s)

          -  The subject has a lesion abutting, invading, or encasing a major blood vessel.

          -  The subject has evidence of tumor invading the 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.

          -  The subject has received any other type of investigational agent within 28 days before
             the first dose of study treatment.

          -  The subject has a corrected QT interval calculated by the Fridericia formula (QTcF)
             >500 ms within 28 days before randomization. . Note: if initial QTcF is found to be >
             500 ms, two additional EKGs separated by at least 3 minutes should be performed. If
             the average of these three consecutive results for QTcF is ≤ 500 ms, the subject meets
             eligibility in this regard

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to cabozantinib.

          -  The subject requires concomitant treatment, in therapeutic doses, with anticoagulants
             such as warfarin, warafarin-related agents, heparin, thrombin inhibitors, Factor Xa
             inhibitors, or antiplatelet agents (eg, clopidogrel). Low dose aspirin (≤ 81 mg/day),
             low-dose warfarin (≤ 1 mg/day), and prophylactic Low Molecular Weight Heparin (LMWH)
             are permitted.

          -  The subject requires concomitant use of strong CYP3A4 inducers (eg, dexamethasone,
             phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, and St.
             John's Wort) or strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole,
             clarithromycin, indinavir, nefazodone, nelfinavir, and ritonavir).

          -  The subject has received prior treatment with a small molecule kinase inhibitor or a
             hormonal therapy (including investigational kinase inhibitors or hormones) within 14
             days or five half-lives of the compound or active metabolites, whichever is longer,
             before the first dose of study treatment. Note: Subjects with prostate cancer
             currently receiving LHRH or GnRH agonists may be maintained on these agents.

          -  The subject is unable to swallow tablets

          -  Individuals who are known to be HIV-positive are excluded from this study. HIV
             positive individuals are at increased risk of lethal infection when treated with
             marrow-suppressive agents, and cabozantinib has not adequately been tested in this
             population. Also, antiretroviral therapy may have pharmacokinetic interactions with
             cabozantinib that have not been fully characterized yet.

          -  Pregnant women are excluded from this study due to the potential for teratogenic or
             abortifacient effects. Because there is an unknown but potential risk of adverse
             events in nursing infants secondary to treatment of the mother with cabozatinib,
             breastfeeding should be discontinued if the mother is treated with cabozantnib. These
             potential risks may also apply to other agents used in this study.

          -  Subjects may not be receiving any other study agents concurrently while on this study