Safety, Dose Tolerance, Pharmacokinetics, Pharmacodynamics of CPX-POM in Patients With Newly Diagnosed or Recurrent Bladder Tumors

This is a phase II, single center open label to determine safety, dose tolerance, PK and PD of the recommended Phase 2 dose (RP2D) of CPX-POM administered in patients with any newly diagnosed or recurrent bladder tumors.

This will be an open-label study to determine the safety, dose tolerance, pharmacokinetics, and pharmacodynamics of CPX-POM in patients with newly diagnosed or recurrent, untreated or intravesical treatment completed \>6 months before the current diagnosis, resectable tumors. Approximately 12 patients will be enrolled and treated with 900 mg/m2 CPX-POM administered IV over 20 minutes once per day for 5 days followed by TURBT on Day 5 after the fifth dose. TURBT will be performed 2 to 6 hours following drug administration on Day 5.

Pretreatment bladder tumor tissues will be obtained at the time of in-office cystoscopy by cold cup biopsy within 4 weeks of TURBT. Posttreatment bladder tumor tissues will be obtained at TURBT. Bladder tumor tissues will undergo pathological evaluation at each site.

Prior to administration of the first CPX-POM dose on Day 1, pre-dose blood (plasma) and urine (clean catch) samples will be collected. At the time of TURBT on Day 5, one 3-mL blood (plasma) sample and a urine specimen will be collected for measurement of CPX-POM concentrations.

Patients will be followed for at least 30 days after the last dose of CPX-POM for safety

Eligibility Criteria:
Inclusion Criteria:

1. Patient is male or female aged ≥18 years.
2. Patient provided signed and dated informed consent prior to initiation of any study procedures.
3. Patient is likely to have a new bladder tumor based on clinical presentation or is at high risk for tumor recurrence based on previous history.
4. Patient has a cystoscopically confirmed bladder tumor and will be scheduled to undergo TURBT.
5. Patient has not received prior treatment for bladder cancer or completed their last intravesical therapy \>6 months before screening.
6. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 (fully active, able to carry out all pre-disease activities without restriction) or 1 (unable to perform physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature).
7. Patient has a predicted life expectancy of ≥3 months.
8. Patient has adequate renal function (creatinine ≤1.5 × the upper limit of the normal range (ULN) or an estimated glomerular filtration rate (eGFR) of \>30 mL/min/1.73 m2).
9. Patient has adequate hepatic function, as evidenced by a total bilirubin ≤1.5 × ULN, aspartate aminotransferase (AST) ≤3 × ULN and /or alanine aminotransferase (ALT) ≤3 × ULN.
10. Patient has adequate bone marrow function, as evidenced by hemoglobin ≥9.0 g/dL in the absence of transfusion within the previous 72 hours, platelet count ≥100×10\^9cells/L, and absolute neutrophil count (ANC) ≥1.5×10\^9 cells/L.
11. Patient has no significant ischemic heart disease or myocardial infarction within 6 months before the first dose of CPX-POM and currently has adequate cardiac function, as evidenced by a left ventricular ejection fraction of \>50% as assessed by multi-gated acquisition (MUGA) or ultrasound/echocardiography (ECHO); and corrected QT interval by Fridericia's correction formula (QTcF) \<450 msec for males and \<470 msec for females. The eligibility of patients with ventricular pacemakers for whom the QT interval may not be accurately measurable will be determined on a case-by-case basis by the Sponsor in consultation with the Medical Monitor.
12. Patient and his/her partner agree to use adequate contraception after providing written informed consent through 3 months after the last dose of CPX-POM, as follows:

    1. For women: Negative pregnancy test during Screening and at Day 1 of each treatment cycle and compliant with a medically-approved contraceptive regimen during and for 3 months after the treatment period or documented to be surgically sterile or postmenopausal.
    2. For men: Compliant with a medically-approved contraceptive regimen during and for 3 months after the treatment period or documented to be surgically sterile. Men whose sexual partners are of child-bearing potential must agree to use 2 methods of contraception prior to study entry, during the study, and for 3 months after the treatment period.
13. Patient is willing and able to participate in the study and comply with all study requirements.

Exclusion Criteria:

Patients who meet any of the following exclusion criteria are not to be enrolled in this study.

1. Patients received prior intravesical therapy for bladder cancer within ≤6 months of the current diagnosis.
2. Patients must not have had any of the following within 6 months before study drug administration:

   1. Myocardial infarction
   2. Severe/unstable angina
   3. Symptomatic congestive heart failure
   4. Cerebrovascular accident or transient ischemic attack, or
   5. Pulmonary embolism
3. Ongoing cardiac dysrhythmias of National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 grade 2.
4. Evidence of New York Heart Association (NYHA) functional class III or IV heart disease.
5. Uncontrolled hypertension (\>150/100 mmHg despite optimal medical therapy).
6. Patient has an uncontrolled or severe intercurrent medical condition. The decision to exclude a patient from the study for an uncontrolled or severe intercurrent medical condition will be made by the Principal Investigator. Examples could include epilepsy, resistant infection, or any other neurological disease that would make clinical assessment difficult.
7. Patient underwent major surgery or radiation therapy within 4 weeks before the first dose of CPX-POM or received an investigational drug or device within 4 weeks or 5 half-lives of that agent (whichever is shorter) before the first dose of CPX-POM. A minimum of 10 days between termination of the investigational drug and administration of CPX-POM is required.
8. If female, patient is pregnant or breast-feeding.
9. Patient has evidence of a serious active infection (e.g., infection requiring treatment with IV antibiotics).
10. Patient has a known, active Hepatitis A infection.
11. Patient has known human immunodeficiency virus (HIV) or Hepatitis B, or C infection, as such patients may be at increased risk for toxicity due to concomitant treatment and disease-related symptoms may preclude accurate assessment of the safety of CPX POM.
12. Patient has an important medical illness or abnormal laboratory finding that, in the Investigator's opinion, would increase the risk of participating in this study.
13. Patient is taking warfarin.
14. Patients may not have another malignancy that could interfere with the evaluation of safety or efficacy of the study drug. Patients with a prior malignancy will be allowed without approval in the following circumstances:

    1. Not currently active and diagnosed at least 3 years prior to the date of registration.
    2. Non-invasive diseases such as low risk cervical cancer or any cancer in situ.
    3. Localized (early stage) cancer treated with curative intent (without evidence of recurrence and intent for further therapy), and in which no chemotherapy was indicated.(e.g., low/intermediate risk prostate cancer, etc.).
    4. Non-muscle invasive bladder cancer (NMIBC) for which treatment was completed \>6 months before the current diagnosis.
15. Patient has known allergy or hypersensitivity to any component of CPX-POM.
16. Patient is taking any iron replacement therapy administered IV, intramuscularly, or orally due to the potential for loss of anticancer activity due to drug and/or metabolites chelating iron.