AzTrials
AzTrials

Urothelial CarcinomaPhase 2NCT01688999

Cabozantinib for Advanced Urothelial Cancer

A Phase 2 study testing Cabozantinib in people with Urothelial Carcinoma and Urethral Neoplasms, run by National Cancer Institute (NCI) at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

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. Read more about this study

Who is it for?
Ages 18 to 99 years
What is being tested?
Cabozantinib
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
69 participants
Where
1 siteUnited States
Study dates
11 Sep 2012to 14 Sep 2020
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 99 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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 Clinical Laboratory Improvement Amendments (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.
Show all 31Show fewer
  • 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.
  • Eastern Cooperative Oncology Group (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 Gilberts 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 m^2 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: Creatinine Clearance (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 (haematoxylin and eosin (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.

Who cannot join

  • 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 Vascular Endothelial Growth Factor Receptors (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
Show all 30Show fewer
  • 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 Common Terminology Criteria in Adverse Events (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 upper limit of normal (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 Cytochrome P450 3A4 (CYP3A4) inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, 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-the counter 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 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.
  • The subject is unable to swallow tablets
  • The subject has a corrected Q wave, T wave (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
  • Human immunodeficiency virus (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.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • National Institutes of Health Clinical Center, 9000 Rockville Pike

    Bethesda, Maryland, 20892

Other trials in United States

About this study

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

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.
Read more

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.
Read the detailed description

Background:

  • In the United States, urothelial carcinoma (UC) of the bladder is the fourth most common malignancy in men and the ninth most common in women with an estimated 69,250 new cases and 14,990 deaths in the year 2011
  • There is no Food and Drug Administration (FDA)-approved second line drug for patients with metastatic Urothelial Cancer (UC)
  • Multiple lines of evidence support targeting angiogenesis in UC
  • In human bladder cancer, overexpression of tyrosine-protein kinase (c-Met)/Axl/platelet derived growth factor receptor- (PDGFR)-alpha or c-Met alone showed significant correlation with poor survival
  • Cabozantinib is a new chemical entity that inhibits multiple receptor tyrosine kinases with growth-promoting and angiogenic properties.
  • The primary targets of cabozantinib are mesenchymal epithelial transition factor (MET), vascular endothelial factor receptor 2 (VEGFR2), and rearranged during transfection (RET)

Objectives:

  • To determine the response rate of cabozantinib in patients with progressive urothelial cancer who have received prior cytotoxic chemotherapy

Eligibility:

  • Patients in cohort 1 must have a histologically confirmed diagnosis of metastatic, progressive urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis.
  • Patients in cohort 2 must have a histologically confirmed diagnosis of bone only metastatic, urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis.
  • Patients in cohort 3 must have a histologically confirmed diagnosis of non-transitional cell carcinoma cancer (including but not limited to squamous cell, neuroendocrine, adenocarcinoma including urachal and sarcomatoid) of the bladder, urethra, ureter, or renal pelvis.
  • Patients must have been previously treated, as defined by treatment with at least one prior cytotoxic chemotherapy regimen or agent. Patients may have received any number of prior cytotoxic agents.
  • 18 years of age or older.

Design:

  • A maximum of 71subjects will be enrolled in this open label, non-randomized, phase II trial of 60 mg each day of cabozantinib. Up to 50 patients will be accrued to cohort 1 (metastatic, progressive urothelial cancer. The remainder will be enrolled on exploratory cohorts 2 \& 3, bone only metastatic urothelial disease and non transitional cell carcinoma (TCC) bladder cancer respectively, during the time the study is accruing patients for cohort 1. Note: Patients who tolerate cabozantinib at 60 mg daily during the first 2 cycles (first restaging time period) without (Bullet) grade 2 toxicity may undergo dose escalation to 80 mg daily at the discretion of the Principal Investigator.
  • A Simon 2 stage design with alpha=0.05 and beta = 0.10 as acceptable error probabilities. Initially 21 subjects will be enrolled and followed for progression. If 2 or more of cohort 1 subjects experiences a response, enrollment will continue until a total of 41 evaluable subjects with progressive urothelial cancer have been entered. 2-3 patients per month may enroll on this trial; thus, 2 to 3 years is anticipated as the accrual period.
  • Each patient will undergo response evaluation assessments with chest abdomen pelvis computed tomography (CAP CT) (or magnetic resonance imaging (MRI)) with or without 18F-Sodium Fluoride (Na18F) positron emission tomography (PET CT) every 8 weeks while on active protocol therapy starting at baseline. Patients will undergo investigational Fludeoxyglucose, (FDG) PET/CT and PET/MRI (optional) at baseline, week 4 and week 8.
Being tested
Cabozantinib
Keywords
Kidney Cancer, Tyrosine Kinase Inhibitor, Bladder Cancer
Medical subject headings
Carcinoma, Transitional Cell, Urethral Neoplasms, Urinary Bladder Neoplasms, Kidney Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • CabozantinibDrug

    Also called Cometriq

    60 mg by mouth (PO) daily each 28 day cycle. Treatment continues until toxicity or disease progression.

Study groups in NCT01688999
Study groupRoleWhat they receive
CabozantinibExperimentalAdministered orally at a dose of 60 mg once daily on each day of a 28-day cycle.
Receives: Drug: Cabozantinib

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Percentage of Participants With Overall Response

    Complete Response (CR) or Partial Response (PR) to Cabozantinib (XL184) assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.0. Complete Response is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

    Measured: Median follow-up was 61.2 months

Secondary outcomes (4)

  1. Overall Survival

    Measure the timing from the study start until death.

    Measured: Median follow-up was 61.2 months

  2. Progression Free Survival

    Measure the timing of maintaining stable disease or partial response until disease progression assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.0. Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Progressive disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions. Stable disease is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest um diameters while on study.

    Measured: Median follow-up was 61.2 months

  3. Number of Participants With Grade 4 Toxicity Hypomagnesium Related to Cabozantinib

    Grade 4 toxicity hypomagnesium experienced by participants related to Cabozantinib. Grade 4 toxicity is life-threatening consequences; urgent intervention indicated.

    Measured: Median follow-up was 61.2 months

  4. Number of Participants With Serious and Non-serious Adverse Events Regardless of Attribution

    Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

    Measured: Median follow-up was 61.2 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted20 Sep 2012 (estimated)
  2. Study start11 Sep 2012
  3. Primary completion11 Dec 2017
  4. Study completion14 Sep 2020

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
69 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01688999
Sponsor's protocol ID
120205
Other IDs
12-C-0205
Status last verified
Sep 2022
First submitted
14 Sep 2012
Last updated
18 Oct 2022
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • 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. doi: 10.3322/caac.20006. Epub 2009 May 27.

    PubMed 19474385

  • 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. doi: 10.1200/JCO.1997.15.5.1853.

    PubMed 9164195

  • 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. doi: 10.1200/JCO.2002.20.4.937.

    PubMed 11844814

  • Apolo AB, Nadal R, Tomita Y, Davarpanah NN, Cordes LM, Steinberg SM, Cao L, Parnes HL, Costello R, Merino MJ, Folio LR, Lindenberg L, Raffeld M, Lin J, Lee MJ, Lee S, Alarcon SV, Yuno A, Dawson NA, Allette K, Roy A, De Silva D, Lee MM, Sissung TM, Figg WD, Agarwal PK, Wright JJ, Ning YM, Gulley JL, Dahut WL, Bottaro DP, Trepel JB. Cabozantinib in patients with platinum-refractory metastatic urothelial carcinoma: an open-label, single-centre, phase 2 trial. Lancet Oncol. 2020 Aug;21(8):1099-1109. doi: 10.1016/S1470-2045(20)30202-3. Epub 2020 Jul 6.

    PubMed 32645282

  • Folio LR, Turkbey EB, Steinberg SM, Apolo AB. Viable tumor volume: Volume of interest within segmented metastatic lesions, a pilot study of proposed computed tomography response criteria for urothelial cancer. Eur J Radiol. 2015 Sep;84(9):1708-14. doi: 10.1016/j.ejrad.2015.05.026. Epub 2015 Jun 10.

    PubMed 26149529

  • Zuo RC, Apolo AB, DiGiovanna JJ, Parnes HL, Keen CM, Nanda S, Dahut WL, Cowen EW. Cutaneous adverse effects associated with the tyrosine-kinase inhibitor cabozantinib. JAMA Dermatol. 2015 Feb;151(2):170-7. doi: 10.1001/jamadermatol.2014.2734.

    PubMed 25427282

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Cabozantinib in people with Urothelial Carcinoma and Urethral Neoplasms, run by National Cancer Institute (NCI) at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 31 inclusion and 30 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 18 Oct 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 6 Oct 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Percentage of Participants With Overall Response (time frame: Median follow-up was 61.2 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01688999, which also lists 6 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Oct 2022.

AzTrials uses cookies for analytics and advertising. You can accept or reject them; the site works either way. Privacy Policy.

Free account

Log in to keep searching

You’ve used your 3 free searches. AzTrials is free: log in or create a free account to keep searching clinical trials and save the ones you want to follow.

Create a free accountLog in