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LCI-GU-URO-CRI-001: Crizotinib in Patients With c-MET or RON-Positive Metastatic Urothelial Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT02612194
Recruitment Status : Recruiting
First Posted : November 23, 2015
Last Update Posted : February 8, 2018
Information provided by (Responsible Party):
Earle Burgess, Carolinas Healthcare System

Brief Summary:
Following informed consent and registration, subjects will undergo tissue pre-screen eligibility screening. Tumor specimens from potential subjects will then undergo c-MET and RON expression characterization. Eligible subjects will then undergo treatment eligibility screening and then be enrolled into available open molecularly defined cohorts. If at least one response is observed within a cohort, it will be considered for expansion with additional subjects enrolled. The cohort showing the highest response rate will be given highest consideration, as determined by the Sponsor-Investigator. Trial accrual is anticipated to occur over two years with 21 subjects enrolled during the first stage (7 in each cohort) with the opportunity for an additional 25 to be enrolled if a cohort is expanded. Subjects enrolled will follow the same procedure and treatment schedule, regardless of cohort assignment.

Condition or disease Intervention/treatment Phase
Urinary Bladder Neoplasms Ureteral Neoplasms Urethral Neoplasms Drug: Crizotinib Phase 2

Detailed Description:

This is a single arm two-stage phase II study designed to evaluate the overall response rate in patients with metastatic urothelial cancer demonstrating c-MET or RON overexpression who have failed prior therapy with a cisplatin or carboplatin containing regimen. Immunohistochemistry will be utilized to define tumor sample c-MET and RON protein expression patterns for assignment into molecular cohorts. In the first stage of this study, seven patients will be enrolled in parallel to three molecularly defined cohorts as follows:

  1. c-MET high (>50%), RON null (0-9%)
  2. c-MET-positive (10-100%), RON-positive (10-100%)
  3. c-MET null (0-9%), RON-positive (10-100%)

All enrolled subjects will continue with study treatment until radiographic progression based on RECIST version 1.1, unacceptable toxicity, investigator discretion, or consent withdrawal.

If a response is observed in a cohort in Stage 1, the cohort may be considered for expansion, and an additional 25 patients may then be enrolled into that cohort in Stage 2. An expansion cohort will be defined by the Sponsor- Investigators following review of all available trial data by the sponsor and LCI Data and Safety Monitoring Committee (DSMC) which will be conducted after the first Stage 1 cohort has completed accrual and at least every six months thereafter until all Stage 1 cohorts have completed accrual.

If more than one cohort has at least one Stage 1 responder, then the cohort showing the highest response rate will be given highest consideration for expansion. It is possible that the cohort with the highest response rate can be determined prior to completion of Stage 1 enrollment in all cohorts. If there is a lag in enrollment in Stage 1 cohorts, an expansion decision may be made without regard to the lagging cohorts.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 46 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: LCI-GU-URO-CRI-001: A Phase II Study of Crizotinib in Patients With c-MET or RON-Positive Metastatic Urothelial Cancer
Study Start Date : February 2016
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : December 2019

Resource links provided by the National Library of Medicine

Drug Information available for: Crizotinib

Arm Intervention/treatment
Experimental: Cohort 1
c-MET high (> 50%), RON null (0-9%)
Drug: Crizotinib
All arms will receive crizotinib.
Other Name: Xalkori

Experimental: Cohort 2
c-MET + (10-100%), RON + (10-100%)
Drug: Crizotinib
All arms will receive crizotinib.
Other Name: Xalkori

Experimental: Cohort 3
c-MET null (0-9%), RON + (10-100%)
Drug: Crizotinib
All arms will receive crizotinib.
Other Name: Xalkori

Primary Outcome Measures :
  1. Overall response rate [ Time Frame: Through study completion, an average of 1 year. ]

Secondary Outcome Measures :
  1. Overall survival [ Time Frame: Through study completion, an average of 1 year. ]
  2. Progression free survival [ Time Frame: Through study completion, an average of 1 year. ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Histologically confirmed stage IV urothelial carcinoma of the bladder, upper urinary tract or urethra.
  • One or more prior treatments (not to exceed three) for metastatic disease with a cisplatin or carboplatin-based multi-agent chemotherapeutic regimen.
  • Chemotherapy received peri-operatively for non-metastatic bladder cancer will be considered a prior regimen if less than 6 months have elapsed since treatment.
  • Measurable disease per RECIST 1.1.
  • Biopsy accessible disease if inadequate archival tissue does not exist for molecular characterization.
  • Archived tissue must have been obtained within 60 months of subject signing tissue pre-screen consent.
  • Age greater than or equal to 18 years.
  • ECOG performance status less than or equal to 2.
  • Adequate liver function: AST and ALT less than or equal to 2.5x upper limit of normal, bilirubin less than or equal to 1.5x upper limit of normal.
  • Adequate bone marrow function: Platelets greater than 100,000 cells/mm3, Hemoglobin greater than 8.0g/dL and ANC greater than or equal to 1,500 cells/mm3.
  • Adequate renal function with a creatinine clearance (based on modified Cockcroft-Gault formula) greater than or equal to 45 mL/min.
  • Ability to understand and the willingness to sign a written informed consent document.
  • Able to swallow and retain oral medication.

Exclusion Criteria:

  • Any prior chemotherapy regimens that did not include at least one cisplatin or carboplatin containing regimen.
  • Currently receiving any other investigational agents, a prior cMET inhibitor, or crizotinib.
  • Pregnant or breast feeding
  • Uncontrolled and current illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
  • Presence of any of the following within previous 3 months: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, congestive heart failure, or cerebrovascular accident including transient ischemic attack.
  • History of active malignancy other than urothelial carcinoma within the prior 12 months of the date of consent (except non-melanoma skin cancer or localized, treated prostate cancer).
  • Prolonged QT interval (QTc greater than 480 msec), symptomatic bradycardia, ongoing cardiac dysrhythmias of CTCAE version 4.0 grade greater than or equal to 2 or uncontrolled atrial fibrillation of any grade.
  • Pulmonary disorder requiring supplemental oxygen or history of pulmonary fibrosis.
  • Patients receiving any medications or substances that are strong inhibitors or inducers of CYP3A are ineligible.
  • Medical condition requiring the use of strong CYP3A inhibitors, including but not limited to atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, suboxone, telithromycin, troleandomycin, and voriconazole.
  • Use of grapefruit or grapefruit juice, which are considered strong CYP3A inhibitors.
  • Medical condition requiring the use of strong CYP3A inducers, including but not limited to carbamazepine, efavirenz, modafinil, nevirapine, oxcarbazepine, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, St. Johns Wort, and troglitazone.
  • Receiving any medications that are CYP3A substrates with a narrow therapeutic range (alfentanil, cyclosporine, dihydroergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus).
  • Patients may be screened for study participation though may not begin study medication within 4 weeks of major surgery, 4 weeks of prior chemotherapy, 2 weeks of prior non-palliative radiotherapy, 48 hours of completion of palliative radiotherapy (less than or equal to 10 fractions) or until recovery of serious adverse events due to prior therapies to less than or equal to grade 1 (except alopecia).
  • Presence of untreated brain metastases or less than or equal to 6 months from prior treatment, active neurologic symptoms or the use of prohibited medications in patients with a history of brain metastases.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02612194

Contact: Gretchen Nobis, RN 980-442-2305

United States, North Carolina
Carolinas Healthcare System Recruiting
Charlotte, North Carolina, United States, 28203
Sponsors and Collaborators
Earle Burgess
Principal Investigator: Earle Burgess, MD Carolinas Healthcare System

Responsible Party: Earle Burgess, Earle Burgess MD, Carolinas Healthcare System Identifier: NCT02612194     History of Changes
Other Study ID Numbers: LCI-GU-URO-CRI-001
First Posted: November 23, 2015    Key Record Dates
Last Update Posted: February 8, 2018
Last Verified: February 2018

Additional relevant MeSH terms:
Urethral Neoplasms
Urinary Bladder Neoplasms
Ureteral Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Urinary Bladder Diseases
Urologic Diseases
Ureteral Diseases
Urethral Diseases
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action