A Phase I Intravesical PPM Therapy for NMIBC

Inclusion Criteria:

Patients must meet all of the following criteria to be eligible for study entry.

• Histologically confirmed bladder carcinoma in situ (CIS) urothelial or urothelialcarcinoma, with or without T1 cancer. Patients are eligible if the biopsy was donewithin 3 months of enrollment and a cystoscopy demonstrates no gross diseaseinvasion into muscularis propria within 4 weeks of enrollment.

• Patient must have BCG-unresponsive non-muscle-invasive bladder cancer (NMIBC) orintolerance of treatment with BCG. Treatment of pembrolizumab is not an inclusion orexclusion criteria as intravesical taxane probably has comparable efficacy asintravenous pembrolizumab. BCG-unresponsive disease is defined as being at least oneof the following:

• Persistent or recurrent CIS alone or with recurrent Ta/T1 (noninvasivepapillary disease/tumor invades the subepithelial connective tissue) diseasewithin 12 months of completion of adequate BCG therapy

• Recurrent high-grade Ta/T1 disease within 6 months of completion of adequateBCG therapy

• T1 high-grade disease at the first evaluation following an induction BCG course

In this context, adequate BCG therapy is defined as at least one of the following:

• At least five of six doses of an initial induction course plus at least two of threedoses of maintenance therapy

• At least five of six doses of an initial induction course plus at least two of sixdoses of a second induction course

• Refuse or intolerant of a radical cystectomy recommended by the treatingurologist as the standard next therapy per urologic guidelines.

• Age 18 years.

• Performance status: ECOG performance status of 0, 1, or 2 (Appendix A) orKarnofsky performance status of 50 or higher (Appendix B).

• Patient with life expectancy greater than 24 months.

• No concurrent radiotherapy, chemotherapy, or other immunotherapy

• No scheduled radiotherapy, chemotherapy, other immunotherapy, or surgery beforethe scheduled response evaluation.

• Recovery from prior treatment side effects that might interfere with the studytreatment, in the judgment of the participating urologist.

• Laboratory tests performed within 14 days of study enrollment:

• Absolute neutrophil count (AGC/ANC) 1,500/uL

• Platelets 100,000/uL [Patients may be transfused to meet this requirement]

• Hemoglobin 8 g/dL [Patients may be transfused to meet this requirement]

• Calculated glomerular filtration rate (GFR) 50 mL/min/1.73m2

• Total bilirubin 2.0 X ULN (< 3 x ULN for patients with Gilbert's syndrome)

• AST, ALT, ALP 3.0 X ULN

• Adequate pulmonary function with no clinical signs of severe pulmonarydysfunction.

• Negative serum pregnancy test if the study participant is a female and ofchildbearing potential (non-childbearing is defined as greater than one yearpostmenopausal or surgically sterilized).

• Female participants of childbearing potential must adhere to using a medicallyaccepted method of birth control, i.e. a tubal ligation, an approved hormonalcontraceptive or an intrauterine device, prior to screening and agree tocontinue its use during the study and up to 3 months after finishing this studyor be surgically sterilized (e.g., hysterectomy or tubal ligation). Males mustagree to use barrier methods of birth control while on study.

• Provide signed informed consent and HIPAA authorization and agree to complywith all protocol-specified procedures and follow-up evaluations.

Exclusion Criteria:

Patients who meet any of the following criteria will be excluded from study entry.

• Existence of cancer at the upper urinary tract

• Concurrent use of other investigational agents.

• Evidence of regional and/or distant metastasis.

• NYHA (New York Heart Association) Class III or IV heart failure (Appendix C),uncontrollable supraventricular arrhythmias, any history of a ventriculararrhythmia, or other clinical signs of severe cardiac dysfunction.

• Symptomatic congestive heart failure (CHF), severe/unstable angina pectoris, ormyocardial infarction within 6 months prior to study entry.

• Patient has an intractable bleeding disorder (e.g., coagulation factorsdeficiencies, Von Willebrand Disease).

• Patient taking medications that affect coagulation, such as aspirin (aspirin 81 mgoral once daily is allowed), Coumadin/Warfarin, heparin, low molecular weightheparin, direct thrombin inhibitors, and direct factor Xa inhibitors. Othernonsteroidal anti-inflammatory drugs (NSAIDs) are allowed as long as they arediscontinued the day before therapy.

• History or evidence of uncontrollable central nervous system (CNS) disease.

• Active systemic infection requiring parenteral antibiotic therapy.

• Women who are pregnant or nursing.

• Psychiatric illness/social situations that would limit compliance with studyrequirements

• Other illness that in the opinion of the investigator would exclude the patient fromparticipating in this study.

• Any other malignancy diagnosed within 3 years of trial entry with the exception of:

• Basal or squamous cell skin cancers, or

• Noninvasive cancer of the cervix, or

• Any other cancer deemed to be of low-risk for progression or patient morbidityduring trial period, such as localized prostate cancer after definitivetreatment and prostate-specific antigen (PSA) less than 0.2 ng/ml.

• Patients unwilling to or unable to comply with the protocol.

• Patients with impaired decision-making capacity.