Cabozantinib for Advanced Urothelial Cancer

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier:
NCT01688999
First received: September 14, 2012
Last updated: June 18, 2014
Last verified: June 2014
  Purpose

Background:

- Cabozantinib is a drug that slows the growth of blood vessels that feed tumors. It has not been approved for cancer treatment. However, studies have shown that prostate and ovarian tumors respond to it. Researchers want see if cabozantinib can be a safe and effective treatment for urothelial cancer.

Objectives:

- To test the safety and effectiveness of cabozantinib for advanced urothelial cancer.

Eligibility:

- Individuals at least 18 years of age who have advanced urothelial cancer that has not responded to standard treatments.

Design:

  • Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected. Tumor tissue samples will also be collected. Imaging studies will also be performed.
  • Participants will take cabozantinib by mouth once per day on each day of a 28-day cycle.
  • Treatment will be monitored with frequent blood tests and imaging studies.
  • Participants will continue to take the study drug for as long as their cancer does not worsen and side effects are not too severe.

Condition Intervention Phase
Urethral Neoplasms
Ureteral Neoplasms
Urinary Bladder Neoplasms
Kidney Neoplasms
Drug: Cabozantinib
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Study of Cabozantinib (XL184) in Patients With Advanced/Metastatic Urothelial Carcinoma

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • overall response rate [ Time Frame: At end of treatment ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Overall survival [ Time Frame: At death ] [ Designated as safety issue: No ]
  • progression free survival [ Time Frame: At disease progression ] [ Designated as safety issue: No ]
  • Tabulation of worst grade toxicity per patient [ Time Frame: At treatment discontinuation ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 55
Study Start Date: September 2012
Estimated Study Completion Date: August 2016
Estimated Primary Completion Date: August 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1
60 mg cabozantinib - single arm
Drug: Cabozantinib
60 mg PO daily each 28 day cycle. Treatment continues until toxicity or disease progression.

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

Cohort 1 only (urothelial progressive disease)

  • Patients must have a histologically confirmed diagnosis of urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis. Confirmation may be obtained from any CLIA certified lab.
  • Patients must have progressive metastatic disease. Progressive disease will be defined as new or progressive lesions on cross-sectional imaging.
  • Patients must have at least one measurable site of disease

Cohort 2 only (Bone-only)

  • Patients must have a histologically confirmed diagnosis of urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis. Confirmation may be obtained from any CLIA certified lab.
  • Patients must not have measurable progressive disease
  • Patient must have appearance of at least one new bone lesion.

Cohort 3 (Rare histologies)

  • Patient must have a histologically confirmed diagnosis of non-transitional cell carcinoma of the bladder, urethra, ureter, or renal pelvis including but not limited to squamous cell, neuroendocrine, adenocarcinoma including urachal and sarcomatoid. Confirmation may be obtained from any CLIA certified lab.
  • Patients must have progressive metastatic disease. Progressive disease will be defined as new or progressive lesions on cross-sectional imaging.
  • Patients must have at least one measurable site of disease

All cohorts

  • Patients must have been previously treated, as defined by treatment with at least one prior cytotoxic regimen or agent.
  • Age greater than or equal to 18 years. Because no dosing or adverse event data are currently available on the use of cabozantinib in patients < 18 years of age, children are excluded from this study, but may be eligible for future pediatric trials.
  • ECOG performance status less than or equal to 2 (Karnofsky greater than or equal to 60%
  • Adequate organ function as defined by the following criteria:
  • Hemoglobin greater than or equal to 9 g/dL
  • Absolute neutrophil count (ANC) greater than or equal to 1500/microL
  • Platelets greater than or equal to 75,000/ L
  • Serum aspartate transaminase (AST; serum glutamic oxaloacetic transaminase [SGOT]) and serum alanine transaminase (ALT; serum glutamic pyruvic transaminase [SGPT]) less than or equal to 3.0 times upper limit of normal (ULN); less than or equal to 5.0 times ULN in cases of liver metastases
  • Total serum bilirubin less than or equal to 1.5 times the upper limit of normal (ULN). For subjects with known Gilbert s disease or similar syndrome with slow conjugation of bilirubin, total bilirubin less than or equal to 3.0 mg/dL
  • Serum creatinine less than or equal to 1.5 X institutional upper limits of normal or for patients with creatinine levels above 1.5 x institutional normal: creatinine clearance greater than or equal to 50 mL/min/1.73 m2 by 24 hour urine collection or estimated creatinine clearance of greater than or equal to 50 mL/min. For creatinine clearance estimation , the Cockcroft and Gault equation should be used:
  • Male: CrCl (mL/min) = (140 - age) times wt (kg) / (serum creatinine times 72)
  • Female: Multiply above result by 0.85
  • Urine protein/creatinine ratio (UPCR) less than or equal to 2
  • Patient must be able to provide either archival tumor samples (H& E slides and one paraffin block or 10 unstained slides) or undergo tumor biopsy.
  • Patient must be capable of understanding and complying with protocol requirements and is willing to give informed consent
  • The effects of XL184 on the developing human fetus are unknown. For this reason and because tyrosine kinase inhibitors agents are known to be teratogenic, women of childbearing potential and men must agree to use adequate contraception prior to study entry and for the duration of study participation. Should a woman become

pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the

duration of study participation, and 4 months after completion of XL184 administration.

Sexually active subjects (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 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 greater than or equal to 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:

  • The subject has received cytotoxic chemotherapy (including investigational cytotoxic chemotherapy) or biologic agents (eg, cytokines or antibodies) within 3 weeks, or nitrosoureas or mitomycin within 6 weeks before the first dose of study treatment.
  • Prior treatment with cabozantinib
  • Prior treatment with other small molecule inhibitors of VEGFR within less than or equal to 2 years of study enrollment.
  • The subject has received radiation therapy:
  • to the thoracic cavity or gastrointestinal tract within 3 months before the first dose of study treatment
  • to bone or brain metastasis within 14 days before the first dose of study treatment
  • to any other site(s) within 28 days before the first dose of study treatment
  • The subject has received radionuclide treatment within 6 weeks before the first dose of study treatment
  • 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.
  • The subject has received any other type of investigational agent within 28 days before the first dose 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.
  • The subject has a primary brain tumor
  • The subject has active brain metastases, leptomeningeal 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 scans are not required to confirm eligibility.)
  • The subject has prothrombin time (PT)/ International Normalized Ratio (INR) or partial thromboplastin time (PTT) test greater than or equal to 1.3 times the laboratory ULN within 7 days before the first

dose of study treatment.

  • The subject requires treatment, in therapeutic doses, with oral anticoagulants such as warfarin prior to initiation of protocol therapy. Low dose aspirin (less than or equal to 81 mg/day), lowdose warfarin (less than or equal to 1 mg/day), and low molecular weight heparin (LMWH) are permitted. Subjects will be permitted to use anticoagulation as described if treatment is required while they are enrolled on the protocol.
  • The subject requires chronic concomitant treatment of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, and St. John's Wort).

Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/; medical reference texts such as the Physicians Desk Reference may also provide this

information. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-thecounter medicine or herbal product.

  • The subject has experienced any of the following within 3 months before the first dose of study treatment:
  • clinically-significant hematemesis or gastrointestinal bleeding
  • hemoptysis of greater than or equal to 0.5 teaspoon (greater than or equal to 2.5 mL) of red blood
  • any other signs indicative of pulmonary hemorrhage
  • The subject has tumor invading (or concern for invasion) major blood vessels
  • Other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the Investigator would make the patient inappropriate for entry into this

study.

  • The subject has evidence of tumor invading the GI trac (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 uncontrolled, significant intercurrent 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 BP > 150 mm Hg systolic, or > 90 mm Hg diastolic despite optimal antihypertensive treatment (BP must be controlled at screening)

iii. Any history of congenital long QT syndrome

iv. 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)

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 cabozantinib

  • active peptic ulcer disease,
  • active inflammatory bowel disease (including ulcerative colitis and

Crohn s disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis

  • active malabsorption syndrome

ii. Any of the following within 6 months before the first dose of study treatment:

  1. abdominal fistula
  2. gastrointestinal perforation
  3. bowel obstruction or gastric outlet obstruction
  4. 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 ago.

    c. Other disorders associated with a high risk of fistula formation including PEG tube placement within 3 months before the first dose of study therapy.

    d. Other clinically significant disorders such as:

    i. no active infection requiring parenteral antibiotics

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 within 7 days before the first dose of study treatment

v. history of major surgery as follows:

  1. 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.
  2. 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

In addition, complete wound healing from prior surgery must be confirmed at least 28 days before the first dose of cabozantinib irrespective of the time from surgery

  • The subject is unable to swallow tablets
  • The subject has a corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms within 28 days before treatment initiation.
  • 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 within 2 years before the start of study treatment evidence of another malignancy which required systemic treatment
  • HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with the study agents. 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01688999

Contacts
Contact: Kattie Khadar, R.N. (301) 435-4341 khadark@mail.nih.gov
Contact: Andrea B Apolo, M.D. (301) 451-1984 apoloab@mail.nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
Sponsors and Collaborators
Investigators
Principal Investigator: Andrea B Apolo, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier: NCT01688999     History of Changes
Other Study ID Numbers: 120205, 12-C-0205
Study First Received: September 14, 2012
Last Updated: June 18, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Kidney Cancer
Tyrosine Kinase Inhibitor
Bladder Cancer

Additional relevant MeSH terms:
Urinary Bladder Neoplasms
Neoplasms
Kidney Neoplasms
Ureteral Neoplasms
Urethral Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Urinary Bladder Diseases
Urologic Diseases
Kidney Diseases
Ureteral Diseases
Urethral Diseases

ClinicalTrials.gov processed this record on August 20, 2014