Intravesical Romidepsin in Combination with Durvalumab for the Treatment of Localized Muscle Invasive Bladder Cancer

Inclusion Criteria

• Patients must have histologically confirmed MIBC (T2-T4a, N0, M0 per American Joint Commission on Cancer [AJCC]) pure or mixed histology urothelial carcinoma
• Patients planning to be treated with radical cystectomy (RC) must be ineligible for cisplatin‐based chemotherapy due to any of the following: * Creatinine clearance (CrCl) < 60 mL/min by the Cockcroft-Gault formula * Hearing impaired ≥ grade 2 by CTCAE criteria * Neuropathy ≥ grade 2 by CTCAE criteria * Heart failure New York Heart Association (NYHA) ≥ III * Eastern Cooperative Oncology Group (ECOG) ≥ 2
• Refusal of enfortumab vedotin due to pre-existing diabetes or peripheral neuropathy is allowed with any of the following: * Neuropathy ≥ grade 2 by CTCAE criteria * hemoglobin (Hb) A1c > 8%
• Patients undergoing consolidative surgery must be medically fit for both TURBT and RC
• Patients unable to tolerate RC or refusing RC will be eligible if planning for disease consolidation with bladder chemoradiation
• Bladder sparing patients must be medically fit for maximal TURBT prior to chemoradiation
• Age ≥ 18 years
• Body weight > 30 kg
• Ability to understand and willingness to sign institutional review board (IRB)-approved informed consent
• Willing to provide tumor tissue, blood, and urine samples for research
• ECOG performance status 0 or 1 (Karnofsky ≥ 80%)
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
• Hemoglobin ≥ 9.0 g/dL
• Absolute neutrophil count (ANC) ≥ 1500/mcL
• Platelet count ≥ 100,000/mcL
• Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN); total bilirubin must be < 3 x ULN for patients with Gilbert's syndrome
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) ≤ 2.5 x institutional upper limit of normal
• Measured creatinine clearance (CL) > 40 mL/min or calculated creatinine CL> 40 mL/min by the Cockcroft-Gault formula or by 24-hour urine collection for determination of creatinine clearance
• Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause * The following age-specific requirements apply: ** Women < 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy) ** Women ≥ 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses > 1 year ago, had chemotherapy-induced menopause with last menses > 1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy) ** Females of childbearing potential must be willing to use a highly effective method of birth control for the duration of the study, and for ≥ 120 days after the last dose of durvalumab and have a negative urine or serum pregnancy test ≤ 7 days before first dose of study drug
• Non-sterile males must be willing to use a highly effective method of birth control for the duration of the study and for ≥ 120 days after the last dose of durvalumab * A sterile male is defined as one for whom azoospermia has been previously demonstrated in a semen sample examination as definitive evidence of infertility * Males with known "low sperm counts" (consistent with "sub-fertility") are not to be considered sterile for purposes of this study
• Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up
• Patient must have a life expectancy of at least 12 weeks

Exclusion Criteria

• Patients with active or prior documented autoimmune disease within the past 2 years prior to Screening or other immunosuppressive agent within 14 days of study treatment. NOTE: Patients with well controlled type 1 diabetes mellitus, vitiligo, Graves’ disease, Hashimoto’s disease, eczema, lichen simplex chronicus, or psoriasis not requiring systemic treatment (within the past 2 years prior to screening) are not excluded. The following exceptions also apply: * Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection) * Systemic corticosteroids at physiologic doses not to exceed <<10 mg/day>> of prednisone or its equivalent * Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
• Patients who have concurrent upper urinary tract (i.e. ureter, renal pelvis) invasive urothelial carcinoma. Patients with history of non-invasive (Ta, T1, Tis) upper tract urothelial carcinoma that has been definitively treated with at least one post-treatment disease assessment (i.e. cytology, biopsy, imaging) that demonstrates no evidence of residual disease are eligible
• Patients who have another malignancy that could interfere with the evaluation of safety or efficacy of the study drugs. Patients with a prior malignancy will be allowed without Principal Investigator approval in the following circumstances: * Not currently active and diagnosed at least 5 years prior to the date of registration * Non-invasive diseases such as low risk cervical cancer or any cancer in situ * 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.). Patients with other malignancies not meeting these criteria must be discussed prior to registration
• Patients who have received any prior immune checkpoint inhibitor (i.e. anti-killer immunoglobulin G-like receptor [KIR], anti-programmed cell death [PD]-1, anti-programmed cell death 1 ligand 1 [PD-L1], [including durvalumab] anti-cytotoxic T-lymphocyte-associated protein 4 [CTLA4] or other)
• Patients who have undergone major surgery (e.g. intra-thoracic, intra-abdominal or intra-pelvic), open biopsy or significant traumatic injury or specific anti-cancer treatment ≤ 4 weeks prior to starting study drug, or patients who have had placement of vascular access device ≤ 1 week prior to starting study drug, or who have not recovered from side effects of such procedure or injury
• Patients who have clinically significant cardiac diseases deemed not fit for radical cystectomy, including any of the following: * History or presence of serious uncontrolled ventricular arrhythmias * Clinically significant resting bradycardia * Any of the following within 3 months prior to starting study drug: severe/unstable angina, congestive heart failure (CHF), cerebrovascular accident (CVA), transient ischemic attack (TIA) * Uncontrolled hypertension defined by a systolic blood pressure (SBP) ≥ 180 mm Hg and/or diastolic blood pressure (DBP) ≥ 100 mm Hg, with or without anti-hypertensive medication(s)
• Patients who have history of chronic active liver disease or evidence of acute or chronic hepatitis B virus (HBV) or hepatitis C (hepatitis C virus [HCV])
• Patients who have known diagnosis of human immunodeficiency virus (HIV) infection. Testing is not required in absence of clinical suspicion
• Patients who have known diagnosis of any condition (e.g. post-hematopoietic or solid organ transplant, pneumonitis, inflammatory bowel disease, etc.) that requires chronic immunosuppressive therapy which cannot be stopped for the duration of the clinical trial. Usage of non-steroidal anti-inflammatory medications (NSAIDS) for the treatment of osteoarthritis and uric acid synthesis inhibitors for the treatment of gout are permitted
• Patients with any serious and/or uncontrolled concurrent medical conditions (e.g. active or uncontrolled infection, uncontrolled diabetes) or psychiatric illness that could, in the investigator’s opinion, cause unacceptable safety risks or potentially interfere with the completion of the treatment according to the protocol
• Patients who have used any live viral vaccine for prevention of infectious diseases within 4 weeks prior to study drug(s). Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, BCG, and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed. COVID vaccination is allowed
• Patients unwilling or unable to comply with the protocol
• Patients with a known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent
• Patients who participate in any other therapeutic clinical trials, including those with other investigational agents not included in this trial throughout the duration of this study
• Patients 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 medical reference
• Patients with local symptoms from bladder cancer, (e.g. gross hematuria, dysuria, etc.) who are deemed to be unable to complete the treatment protocol per principal investigator (PI)
• Any concurrent chemotherapy, intraperitoneal (IP), biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable