Clinical Trial 22623

• Overview

  Study Title:

  HERO Trial: Phase I Study Investigating Intravesical HDAC Inhibition to Improve Response to Immuno-Oncology Agents in localized bladder cancer

  Summary:

  In this study, we aim to evaluate the safety and efficacy of neoadjuvant combination using intravesical romidepsin and durvalumab in cisplatin-ineligible patients with muscle invasive bladder cancer (MIBC).

  Objective:

  Primary Objective: To evaluate the safety of combination therapy using intravesical romidepsin and durvalumab according to Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0). To determine the maximally tolerated dose (MTD) and recommended phase 2 dose (RP2D) of intravesical romidepsin when combined with durvalumab Secondary Objectives To assess the antitumor efficacy of combination therapy.

• Treatments

  Therapies:

  Chemotherapy (NOS); Immunotherapy

  Medications:

  AMP-514 (Durvalumab); Durvalumab (); FK228 (Romidepsin); MEDI4736 (Durvalumab); Romidepsin ()

• Inclusion Criteria

  Key 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) > 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, HbA1c >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 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.
  • Participants must have adequate organ and marrow function as defined below: 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 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.
  • 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.
  • 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 24 weeks.
  • Additional criteria may apply.

• Exclusion Criteria

  Key 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.
  • 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-KIR, anti-PD-1, anti- PD-L1, (including durvalumab) anti-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 SBP ≥ 180 mm Hg and/or 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 (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.
  • Additional criteria may apply.

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