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.
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.
|Overal Status||Start Date||Phase||Study Type|
|Recruiting||Start Date: February 2016||Phase 2||Interventional|
Primary Outcome 1 - Measure: Overall response rate
Primary Outcome 1 - Time Frame: Through study completion, an average of 1 year.
- 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
- Archived tissue must have been obtained within 60 months of subject signing tissue
- 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.
- 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
- 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
- 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
- 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
- Receiving any medications that are CYP3A substrates with a narrow therapeutic range
(alfentanil, cyclosporine, dihydroergotamine, fentanyl, pimozide, quinidine, sirolimus
- 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.
Minimum Age: 18 Years
Maximum Age: N/A
Healthy Volunteers: No
Name: Earle Burgess, MD
Role: Principal Investigator
Affiliation: Carolinas Healthcare System
Name: Gretchen Nobis, RN
|Carolinas Healthcare System
Charlotte, North Carolina 28203