Clinical trial NCT01688999: Cabozantinib for Advanced Urothelial Cancer
Official title: A Phase II Study of Cabozantinib (XL184) in Patients With Advanced/Metastatic Urothelial Carcinoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Urothelial Carcinoma
Urethral Neoplasms
Urinary Bladder Neoplasms
Kidney Neoplasms
Keywords: Kidney Cancer
Tyrosine Kinase Inhibitor
Bladder Cancer
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2012-09-20
Enrollment: 69
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

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.

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.

Eligibility 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 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.
* 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.

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 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
* 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.

Primary outcomes:
measure: Percentage of Participants With Overall Response
timeFrame: Median follow-up was 61.2 months
Secondary outcomes:
measure: Overall Survival
timeFrame: Median follow-up was 61.2 months
measure: Progression Free Survival
timeFrame: Median follow-up was 61.2 months
measure: Number of Participants With Grade 4 Toxicity Hypomagnesium Related to Cabozantinib
timeFrame: Median follow-up was 61.2 months
measure: Number of Participants With Serious and Non-serious Adverse Events Regardless of Attribution
timeFrame: Median follow-up was 61.2 months
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
affiliation: National Cancer Institute (NCI)
name: Andrea B Apolo, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.