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

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.

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