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Protocol Details

A Phase II Study of Cabozantinib (XL184) in Patients With Advanced/Metastatic Urothelial Carcinoma

This study is NOT currently recruiting participants.

Summary | Eligibility | Citations | Contacts

Summary

Number

12-C-0205

Sponsoring Institute

National Cancer Institute (NCI)

Recruitment Detail

Type: Completed Study; data analyses ongoing
Gender: Male & Female
Min Age: 18 Years
Max Age: N/A

Referral Letter Required

No

Population Exclusion(s)

Children;
Pregnant Women;
Fetuses

Keywords

Kidney Cancer;
Tyrosine Kinase Inhibitor;
Bladder Cancer

Recruitment Keyword(s)

None

Condition(s)

Ureteral Neoplasms;
Urothelial Carcinoma;
Urethral Neoplasms;
Urinary Bladder Neoplasms;
Kidney Neoplasms

Investigational Drug(s)

Cabozantinib

Investigational Device(s)

None

Intervention(s)

Drug: Cabozantinib

Supporting Site

National Cancer Institute

Background:

- Cabozantinib is a drug that slows the growth of blood vessels that feed tumors. It is approved for medullary thyroid cancer. 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.

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Eligibility

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 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 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

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:

--No active systemic infection requiring parenteral antibiotics

--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:

(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.


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Citations:

Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin. 2009 Jul-Aug;59(4):225-49. Epub 2009 May 27.

McCaffrey JA, Hilton S, Mazumdar M, Sadan S, Kelly WK, Scher HI, Bajorin DF. Phase II trial of docetaxel in patients with advanced or metastatic transitional-cell carcinoma. J Clin Oncol. 1997 May;15(5):1853-7.

Vaughn DJ, Broome CM, Hussain M, Gutheil JC, Markowitz AB. Phase II trial of weekly paclitaxel in patients with previously treated advanced urothelial cancer. J Clin Oncol. 2002 Feb 15;20(4):937-40.

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Contacts:

Principal Investigator

Referral Contact

For more information:

Andrea B. Apolo, M.D.
National Cancer Institute (NCI)
NIHBC 10 - CLINICAL CENTER BG RM 13N240
10 CENTER DR
BETHESDA MD 20892
(301) 480-0536
apoloab@mail.nih.gov

Corrine M. Keen, R.N.
National Cancer Institute (NCI)
National Institutes of Health
Building 10
Room 8D44B
10 Center Drive
Bethesda, Maryland 20892
(240) 760-6097
ck232s@nih.gov

NCI Referral Office
National Institute of Health Clinical Center (CC), 9000 Rockville Pike, Bethesda, Maryland 20892, United States: NCI Clinical Trials Referral Office
1-888-NCI-1937

Clinical Trials Number:

NCT01688999

Additional Linkshttp://medicine.iupui.edu/clinpharm/ddis/

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