Urinary Bladder NeoplasmsPhase 2NCT02612194
LCI-GU-URO-CRI-001: Crizotinib in Patients With c-MET or RON-Positive Metastatic Urothelial Cancer
A Phase 2 study testing Crizotinib in people with Urinary Bladder Neoplasms and Ureteral Neoplasms, run by Wake Forest University Health Sciences at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Urinary Bladder Neoplasms, Ureteral Neoplasms, Urethral Neoplasms
- What is being tested?
- Crizotinib
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 8 participants
- Where
- 1 siteUnited States
- Study dates
- 27 Sep 2016to 21 Nov 2019
- 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 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Subjects must meet all of the following criteria:
- Histologically confirmed stage IV urothelial carcinoma of the bladder, upper urinary tract or urethra.
- 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.
- Measurable disease per RECIST 1.1. See Section 10 for the evaluation of measurable disease.
- 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.
Show all 14Show fewer
- 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
- Age ≥ 18 years
- ECOG performance status ≤ 2
- Adequate liver function: AST and ALT ≤ 2x upper limit of normal, bilirubin ≤ 1.5x upper limit of normal
- Adequate bone marrow function: Platelets ≥ 100,000 cells/mm3, hemoglobin > 8.0 g/dL and ANC ≥ 1,500 cells/mm3
- Adequate renal function with a creatinine clearance (based on Cockgroft-Gault formula) ≥ 45 mL/min
- Ability to understand and the willingness to sign a written informed consent document
- Able to swallow oral medication
Who cannot join
- Subjects must not meet any of the following criteria
- Currently receiving any other investigational agents, a prior c-MET inhibitor, or crizotinib
- Pregnant or breast feeding, because crizotinib can cause fetal harm
- Uncontrolled and current illness including, but no limited to:
- Ongoing or active infection
- Symptomatic congestive heart failure
Show all 30Show fewer
- Unstable angina pectoris
- Cardiac arrhythmia, or
- Psychiatric illness/social situations that would limit compliance with study requirements
- 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
- 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)
- 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
- 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.
- 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.
- Receiving any medications that are CYP3A substrates with a narrow therapeutic range (alfentanil, cyclosporine, dihydroergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus)
- 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)
- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
Levine Cancer Institute
Charlotte, North Carolina, 28204
About this study
Official title: LCI-GU-URO-CRI-001: A Phase II Study of Crizotinib in Patients With c-MET or RON-Positive Metastatic Urothelial Cancer
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.
Read the 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:
- c-MET high (>50%), RON null (0-9%) (n = 14 subjects)
- c-MET-positive (10-100%), RON-positive (10-100%) (n = 7 subjects)
- 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.
- Being tested
- Crizotinib
- Medical subject headings
- Urinary Bladder Neoplasms, Ureteral Neoplasms, Urethral Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
CrizotinibDrug
Also called Xalkori
Crizotinib was administered orally at 250mg twice daily
| Study group | Role | What they receive |
|---|---|---|
| Cohort 1 | Experimental | c-MET high (> 50%), RON null (0-9%) Receives: Drug: Crizotinib |
| Cohort 2 | Experimental | c-MET + (10-100%), RON + (10-100%) Receives: Drug: Crizotinib |
| Cohort 3 | Experimental | c-MET null (0-9%), RON + (10-100%) Receives: Drug: Crizotinib |
What is being measured
The primary outcome is the main question the study is designed to answer.
Overall Response
Overall response will be determined as the best treatment response for each patient as a binary variable indicating whether or not the patient achieved a Complete Response (CR) or Partial Response (PR) as determined by RECIST v1.1 criteria. Per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1):Complete Response (CR) is the disappearance of all lesions (target and non target); Partial Response (PR) is at least 30% decrease in the sum of the diameters of target lesions from baseline and no new lesions or unequivocal progression in non target lesions from baseline; Stable Disease (SD) is neither sufficient shrinkage in target lesions to qualify for PR (less than 30% decrease) nor sufficient increase in target lesions (versus smallest sum of diameters) to qualify for PD (less than 20% increase), with no new lesions or unequivocal progression in non target lesions from baseline. For the purposes of response determination, confirmatory scan for CR and PR is required.
Measured: From enrollment to best response while on crizotinib; Subjects remained on treatment until disease progression or death or unacceptable toxicity (subjects were on treatment for an average of 6 weeks)
Secondary outcomes (2)
Overall Survival
Overall survival was defined as the duration from enrollment date to the date of death from any cause. Subjects who were alive or lost to follow-up at the time of the analysis were censored at the last known date they were alive.
Measured: From date of treatment start to date of death, or censored as described above; assessed for approximately 2 years.
Progression Free Survival
PFS was defined as duration of time from enrollment to the study to time of progression or death. Disease progression (PD) can be objectively determined as per RECIST v1.1 (Response Evaluation Criteria in Solid Tumors, where PD is defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in non-target lesion, or the appearance of new lesions) or progression can be subjective as determined by the investigator. Evidence for subjective progressions must be documented in medical records. For surviving subjects who do not have documented PD, PFS will be censored at last radiologic assessment. For subjects who receive subsequent anti-cancer therapy prior to documented PD, PFS will be censored at last radiologic assessment prior to commencement of subsequent therapy. Subjects who experience a PFS event following an interval equal to two or more scheduled assessments will be censored at date of last assessment prior to first missed assessment.
Measured: From date of treatment start to date of progression or death, or censored as described above; assessed for approximately 2 years.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Nov 2015 (estimated)
- Study start27 Sep 2016
- Primary completion17 Sep 2019
- Study completion21 Nov 2019
Why it stopped: Study closed to accrual due to low accrual numbers.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Urinary Bladder NeoplasmsStudies of the same condition, open and under way.
- More trials run by Wake Forest University Health SciencesThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
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
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 8 participants (actual)
Sponsor and investigators
- Lead sponsor
- Wake Forest University Health Sciences
- Sponsor type
- University, hospital or other
- Collaborators
- Pfizer
- Responsible party
- Sponsor
- Investigators
- Earle Burgess, MD, Principal investigator, Atrium Health (formerly Carolinas HealthCare System)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02612194
- Sponsor's protocol ID
- LCI-GU-URO-CRI-001
- Status last verified
- May 2021
- First submitted
- 19 Nov 2015
- Last updated
- 3 Nov 2022
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 3 Nov 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- LCI-GU-URO-CRI-001: A Phase II Study of Crizotinib in Patients With c-MET or RON-Positive Metastatic Urothelial Cancer
- ClinicalTrials.gov ID
- NCT02612194
- Acronym / sponsor ID
- LCI-GU-URO-CRI-001
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Study closed to accrual due to low accrual numbers.
- Enrolment
- 8 participants (actual)
- Lead sponsor
- Wake Forest University Health SciencesUniversity, hospital or other
- Collaborators
- Pfizer
- Study start
- 27 Sep 2016 (actual)
- Primary completion
- 17 Sep 2019 (actual)
- Study completion
- 21 Nov 2019 (actual)
- First posted
- 23 Nov 2015 (estimated)
- Results
- Posted 9 Jun 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- c-MET high (>50%), RON null (0-9%) (n = 14 subjects)
- c-MET-positive (10-100%), RON-positive (10-100%) (n = 7 subjects)
- 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 design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Cohort 1 | Experimental | Drug: Crizotinibc-MET high (> 50%), RON null (0-9%) |
| Cohort 2 | Experimental | Drug: Crizotinibc-MET + (10-100%), RON + (10-100%) |
| Cohort 3 | Experimental | Drug: Crizotinibc-MET null (0-9%), RON + (10-100%) |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (14 listed)
- Histologically confirmed stage IV urothelial carcinoma of the bladder, upper urinary tract or urethra.
- 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.
- Measurable disease per RECIST 1.1. See Section 10 for the evaluation of measurable disease.
- 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.
Key exclusion criteria (30 listed)
- Subjects must not meet any of the following criteria
- Currently receiving any other investigational agents, a prior c-MET inhibitor, or crizotinib
- Pregnant or breast feeding, because crizotinib can cause fetal harm
- Uncontrolled and current illness including, but no limited to:
- Presence of any of the following within the previous 3 months of treatment consent:
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| CrizotinibAlso: XalkoriCrizotinib was administered orally at 250mg twice daily | Drug | Cohort 1, Cohort 2, Cohort 3 |
Primary outcome
Overall Response
Time frame: From enrollment to best response while on crizotinib; Subjects remained on treatment until disease progression or death or unacceptable toxicity (subjects were on treatment for an average of 6 weeks)
Overall response will be determined as the best treatment response for each patient as a binary variable indicating whether or not the patient achieved a Complete Response (CR) or Partial Response (PR) as determined by RECIST v1.1 criteria. Per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1):Complete Response (CR) is the disappearance of all lesions (target and non target); Partial Response (PR) is at least 30% decrease in the sum of the diameters of target lesions from baseline and no new lesions or unequivocal progression in non target lesions from baseline; Stable Disease (SD) is neither sufficient shrinkage in target lesions to qualify for PR (less than 30% decrease) nor sufficient increase in target lesions (versus smallest sum of diameters) to qualify for PD (less than 20% increase), with no new lesions or unequivocal progression in non target lesions from baseline. For the purposes of response determination, confirmatory scan for CR and PR is required.
2 secondary outcomes
Overall Survival
Time frame: From date of treatment start to date of death, or censored as described above; assessed for approximately 2 years.
Progression Free Survival
Time frame: From date of treatment start to date of progression or death, or censored as described above; assessed for approximately 2 years.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 Nov 2022.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Earle Burgess, MD principal investigator
Atrium Health (formerly Carolinas HealthCare System)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Crizotinib in people with Urinary Bladder Neoplasms and Ureteral Neoplasms, run by Wake Forest University Health Sciences 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 14 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: stopped early, as of the sponsor's last update on 3 Nov 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 9 Jun 2021). 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?
Overall Response (time frame: From enrollment to best response while on crizotinib; Subjects remained on treatment until disease progression or death or unacceptable toxicity (subjects were on treatment for an average of 6 weeks)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 3 Nov 2022.