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

NCT02612194

Last updated date
Study Location
Levine Cancer Institute
Charlotte, North Carolina, , United States
Contact
1-800-718-1021

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Eligibility Criteria
condition
The disease, disorder, syndrome, illness, or injury that is being studied.
Urinary Bladder Neoplasms, Ureteral Neoplasms, Urethral Neoplasms
Sex
Females and Males
Age
Pediatric Trials: 0-17 Years
Adult Trials: 18+ Years
18 + years
Inclusion Criteria
The factors, or reasons, that allow a person to participate in a clinical study.
Show details

Subjects must meet all of the following criteria:

1. Histologically confirmed stage IV urothelial carcinoma of the bladder, upper urinary tract or urethra.

2. Prior treatment for metastatic disease with at least one cisplatin or carboplatin-based multi-agent chemotherapeutic regimen. Prior immunotherapy with anti-PD-L1 or anti-PD1 agents is allowed.

o Chemotherapy received peri-operatively for non-metastatic bladder cancer will be considered a prior regimen if less than 24 months have elapsed since treatment.

3. Measurable disease per RECIST 1.1. See Section 10 for the evaluation of measurable disease.

4. Tissue Pre-screen: Archived tissue must have been obtained within 60 months of subject signing tissue pre-screen consent. Biopsy accessible disease if adequate archival tissue does not exist for molecular characterization.

Treatment: Available tumor specimen C-MET/RON expression results that meet the criteria for one of the three molecularly defined cohorts per Section 4.2

5. Age ≥ 18 years

6. ECOG performance status ≤ 2

7. Adequate liver function: AST and ALT ≤ 2x upper limit of normal, bilirubin ≤ 1.5x upper limit of normal

8. Adequate bone marrow function: Platelets ≥ 100,000 cells/mm3, hemoglobin > 8.0 g/dL and ANC ≥ 1,500 cells/mm3

9. Adequate renal function with a creatinine clearance (based on Cockgroft-Gault formula) ≥ 45 mL/min

10. Ability to understand and the willingness to sign a written informed consent document

11. Able to swallow oral medication

Exclusion Criteria
The factors, or reasons, that prevent a person from participating in a clinical study.
Show details


Subjects must not meet any of the following criteria


1. Currently receiving any other investigational agents, a prior c-MET inhibitor, or
crizotinib


2. Pregnant or breast feeding, because crizotinib can cause fetal harm


3. Uncontrolled and current illness including, but no 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


4. Presence of any of the following within the previous 3 months of treatment consent:


- Myocardial infarction


- Severe/unstable angina


- Coronary/peripheral artery bypass graft


- Congestive heart failure, or


- Cerebrovascular accident including transient ischemia attack


5. History of active malignancy other than urothelial carcinoma within the prior 12
months of the date of treatment consent (except non-melanoma skin cancer or localized,
treated prostate cancer)


6. Prolonged QT interval (QTc > 480 msec), symptomatic bradycardia, ongoing cardiac
dysrhythmias of CTCAE version 4.0 grade 2 ≥ or uncontrolled atrial fibrillation of any
grade


7. Pulmonary disorder requiring supplemental oxygen or history of pulmonary fibrosis.
Sleep apnea considered to be a sleep disorder (and not a pulmonary disorder) by the
investigator will be allowed.


8. Subjects receiving any medications or substances that are strong inhibitors or
inducers of CYP3A are ineligible. 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/table/aspx; medical reference texts such as
the Physicians' Desk Reference may also provide this information. As part of the
enrollment/informed consent procedures, the subject 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 subject is considering a new over-the-counter medicine or herbal
product.


- Medical condition requiring the use of strong CPY3A 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. John's Wort, and
troglitazone.


9. Receiving any medications that are CYP3A substrates with a narrow therapeutic range
(alfentanil, cyclosporine, dihydroergotamine, fentanyl, pimozide, quinidine, sirolimus
and tacrolimus)


10. Subjects may be screened for study participation though may not begin study treatment:


- Within 4 weeks of major surgery


- Within 2 weeks of prior systemic therapy


- Within 2 weeks of prior non-palliative radiotherapy


- Within 48 hours of completion of palliative radiotherapy (≤ 10 fractions)


- Until recovery of adverse events due to prior therapies to ≤ 1 (except alopecia)


11. Presence of untreated brain metastases or ≤ 6 months from prior treatment (from the
time of enrollment), active neurologic symptoms or the use of prohibited medications
in subjects with a history of brain metastases

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Urinary Bladder Neoplasms, Ureteral Neoplasms, Urethral NeoplasmsLCI-GU-URO-CRI-001: Crizotinib in Patients With c-MET or RON-Positive Metastatic Urothelial Cancer
NCT02612194
  1. Charlotte, North Carolina
ALL GENDERS
18 Years+
years
MULTIPLE SITES
Advanced Information
Descriptive Information
Brief Title  ICMJE LCI-GU-URO-CRI-001: Crizotinib in Patients With c-MET or RON-Positive Metastatic Urothelial Cancer
Official Title  ICMJE LCI-GU-URO-CRI-001: A Phase II Study of Crizotinib in Patients With c-MET or RON-Positive Metastatic Urothelial Cancer
Brief Summary

This is a single arm two-stage phase II study with crizotinib (Xalkori®) in the treatment of subjects with metastatic urothelial cancer of the bladder, upper (ureter or renal pelvis) or lower (urethra) urinary tracts. The purpose of this study is to see if this experimental drug has a potential benefit in subjects with stage 4 urothelial cancer.

This study tests crizotinib used alone in subjects with urothelial cancer, previously treated with chemotherapy, and whose tumors have certain proteins. Proteins are complex natural substances essential to the structure and function of all living cells. These proteins, c-MET or RON, may trigger molecular pathways that are involved in the growth and spread of bladder or upper urinary tract cancer. Crizotinib is a drug taken by mouth that blocks these pathways. Early laboratory research suggests that crizotinib may benefit patients with urothelial and other cancers with these molecular pathways.

Detailed Description

This is a single arm two-stage phase II study designed to evaluate the objective response rate in subjects with metastatic urothelial cancer demonstrating c-MET or RON overexpression who have received prior therapy with a cisplatin or carboplatin containing regimen.

Subjects will be recruited at Levine Cancer Institute (LCI) and other participating sites.

Immunohistochemistry will be utilized to define tumor sample c-MET and RON protein expression patterns for assignment into molecular cohorts as described in section 12.1.

In the first stage of this study, subjects will be enrolled in parallel to three molecularly defined cohorts as follows:

  1. c-MET high (>50%), RON null (0-9%) (n = 14 subjects)
  2. c-MET-positive (10-100%), RON-positive (10-100%) (n = 7 subjects)
  3. c-MET null (0-9%), RON-positive (10-100%) (n = 7 subjects)

All enrolled subjects will continue with study treatment until criteria for treatment discontinuation has been met.

If Stage 1 response criteria are met in a cohort, the cohort may be considered for expansion, and additional subjects (16 in Cohort 1 or 25 in Cohorts 2 or 3) may then be enrolled into that cohort in Stage 2. An expansion cohort will be defined by the Sponsor- Investigator following review of all available trial data 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 meets Stage 1 response criteria (2 responses out of 14 subjects for Cohort 1 or 1 response out of 7 subjects for each of Cohorts 2 and 3), then the cohort showing the highest response rate will be given highest consideration for expansion.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Urinary Bladder Neoplasms
  • Ureteral Neoplasms
  • Urethral Neoplasms
Intervention  ICMJE Drug: Crizotinib
All arms will receive crizotinib.
Other Name: Xalkori
Study Arms  ICMJE
  • Experimental: Cohort 1
    c-MET high (> 50%), RON null (0-9%)
    Intervention: Drug: Crizotinib
  • Experimental: Cohort 2
    c-MET + (10-100%), RON + (10-100%)
    Intervention: Drug: Crizotinib
  • Experimental: Cohort 3
    c-MET null (0-9%), RON + (10-100%)
    Intervention: Drug: Crizotinib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Estimated Enrollment  ICMJE
 (submitted: November 20, 2015)
46
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE November 21, 2019
Actual Primary Completion Date September 17, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria

Subjects must meet all of the following criteria:

  1. Histologically confirmed stage IV urothelial carcinoma of the bladder, upper urinary tract or urethra.
  2. Prior treatment for metastatic disease with at least one cisplatin or carboplatin-based multi-agent chemotherapeutic regimen. Prior immunotherapy with anti-PD-L1 or anti-PD1 agents is allowed.

    o Chemotherapy received peri-operatively for non-metastatic bladder cancer will be considered a prior regimen if less than 24 months have elapsed since treatment.

  3. Measurable disease per RECIST 1.1. See Section 10 for the evaluation of measurable disease.
  4. Tissue Pre-screen: Archived tissue must have been obtained within 60 months of subject signing tissue pre-screen consent. Biopsy accessible disease if adequate archival tissue does not exist for molecular characterization.

    Treatment: Available tumor specimen C-MET/RON expression results that meet the criteria for one of the three molecularly defined cohorts per Section 4.2

  5. Age ? 18 years
  6. ECOG performance status ? 2
  7. Adequate liver function: AST and ALT ? 2x upper limit of normal, bilirubin ? 1.5x upper limit of normal
  8. Adequate bone marrow function: Platelets ? 100,000 cells/mm3, hemoglobin > 8.0 g/dL and ANC ? 1,500 cells/mm3
  9. Adequate renal function with a creatinine clearance (based on Cockgroft-Gault formula) ? 45 mL/min
  10. Ability to understand and the willingness to sign a written informed consent document
  11. Able to swallow oral medication

Exclusion Criteria

Subjects must not meet any of the following criteria

  1. Currently receiving any other investigational agents, a prior c-MET inhibitor, or crizotinib
  2. Pregnant or breast feeding, because crizotinib can cause fetal harm
  3. Uncontrolled and current illness including, but no 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
  4. Presence of any of the following within the previous 3 months of treatment consent:

    • Myocardial infarction
    • Severe/unstable angina
    • Coronary/peripheral artery bypass graft
    • Congestive heart failure, or
    • Cerebrovascular accident including transient ischemia attack
  5. History of active malignancy other than urothelial carcinoma within the prior 12 months of the date of treatment consent (except non-melanoma skin cancer or localized, treated prostate cancer)
  6. Prolonged QT interval (QTc > 480 msec), symptomatic bradycardia, ongoing cardiac dysrhythmias of CTCAE version 4.0 grade 2 ? or uncontrolled atrial fibrillation of any grade
  7. Pulmonary disorder requiring supplemental oxygen or history of pulmonary fibrosis. Sleep apnea considered to be a sleep disorder (and not a pulmonary disorder) by the investigator will be allowed.
  8. Subjects receiving any medications or substances that are strong inhibitors or inducers of CYP3A are ineligible. 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/table/aspx; medical reference texts such as the Physicians' Desk Reference may also provide this information. As part of the enrollment/informed consent procedures, the subject 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 subject is considering a new over-the-counter medicine or herbal product.

    • Medical condition requiring the use of strong CPY3A 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. John's Wort, and troglitazone.
  9. Receiving any medications that are CYP3A substrates with a narrow therapeutic range (alfentanil, cyclosporine, dihydroergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus)
  10. Subjects may be screened for study participation though may not begin study treatment:

    • Within 4 weeks of major surgery
    • Within 2 weeks of prior systemic therapy
    • Within 2 weeks of prior non-palliative radiotherapy
    • Within 48 hours of completion of palliative radiotherapy (? 10 fractions)
    • Until recovery of adverse events due to prior therapies to ? 1 (except alopecia)
  11. Presence of untreated brain metastases or ? 6 months from prior treatment (from the time of enrollment), active neurologic symptoms or the use of prohibited medications in subjects with a history of brain metastases
Sex/Gender  ICMJE
Sexes Eligible for Study:All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02612194
Other Study ID Numbers  ICMJE LCI-GU-URO-CRI-001
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Earle Burgess, MD, Atrium Health
Study Sponsor  ICMJE Earle Burgess, MD
Collaborators  ICMJE Pfizer
Investigators  ICMJE
Principal Investigator:Earle Burgess, MDAtrium Health (formerly Carolinas HealthCare System)
PRS Account Atrium Health
Verification Date August 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP