LCI-GU-URO-CRI-001: Crizotinib in Patients With c-MET or RON-Positive Metastatic Urothelial Cancer
Condition: Urinary Bladder Neoplasms; Ureteral Neoplasms; Urethral Neoplasms
MeSH terms: Neoplasms; Urinary Bladder Neoplasms; Ureteral Neoplasms; Urethral Neoplasms
Intervention: Crizotinib
Intervention description: Crizotinib was administered orally at 250mg twice daily
Intervention MeSH terms: Crizotinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 8.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

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.
    

Eligibility criteria:

        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