Clinical Trial 23405

• Overview

  Study Title:

  ENHANCE (Elevated NKG2A and HLA-E Amplify NK/CD8 Checkpoint Engagers): A Phase 2 Trial of Durvalumab (MEDI4736) plus Monalizumab in Non-Muscle-Invasive Bladder Cancer

  Summary:

  This is a phase 2 open-label two cohort study of durvalumab plus monalizumab in patients with BCG-unresponsive or BCG-exposed CIS NMIBC. Arm A will enroll 43 participants who have cancer in situ (CIS) with or without high grade papillary urothelial cancer. Arm B will enroll 17 participants who do not have cancer in situ (CIS) but do have high grade papillary urothelial cancer. Eligible patients will be enrolled to receive up to 13 cycles of monthly combination of monalizumab and durvalumab. Both monalizumab and durvalumab will be administered intravenously (IV) every 28 days.

  Objective:

  Primary Objective -To estimate the 6-month complete response rate of treatment with durvalumab plus monalizumab in patients with BCG-unresponsive or BCG-exposed CIS +/- papillary high-grade Ta or T1 urothelial cancer (Cohort A). Secondary Objectives -To characterize the safety profile of the combination of durvalumab plus monalizumab in patients with BCG-unresponsive or BCG-exposed Ta/CIS NMIBC (Cohorts A and B). -To estimate progression-free survival of patients with BCG unresponsive or BCG-exposed Ta/CIS NMIBC treated with durvalumab plus monalizumab (Cohorts A). -To estimate overall survival of patients with BCG-unresponsive or BCG-exposed Ta/CIS NMIBC treated with durvalumab plus monalizumab (Cohorts A). -To estimate 12-month event free survival in patients with BCG-unresponsive or BCG-exposed Ta/CIS NMIBC treated with durvalumab plus monalizumab (Cohort A). -To estimate cystectomy-free survival of patients with BCG-unresponsive or BCG-exposed Ta/CIS NMIBC treated with durvalumab plus monalizumab (Cohort A). -To estimate duration of response of patients in the CIS population who achieve a complete response (Cohort A). -To estimate the 12-month recurrence-free survival rate of treatment with durvalumab plus monalizumab in patients with high grade Ta or T1 urothelial cancer (Cohort B)

• Treatments

  Therapies:

  Immunotherapy

  Medications:

  AMP-514 (Durvalumab); Durvalumab (); IPH2201 (Monalizumab); MEDI4736 (Durvalumab); Monalizumab ()

• Inclusion Criteria

  Key Inclusion Criteria:
  • Age ≥18 years at the time of consent.
  • 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. Able and willing to provide written informed consent.
  • Eastern Cooperative Oncology Group scores ≤ 1 within 28 days prior to registration.
  • Non-muscle-invasive bladder cancer.
  • Mixed variant histology (adenocarcinoma, squamous cell carcinoma) is eligible, but pure variant histology is ineligible. NOTE: Pathology report required for documentation purposes.
  • Patients can have BCG-unresponsive or BCG-exposed NMIBC11. Adequate BCG therapy is defined as completing at least induction BCG (≥ 5 doses) and the first round of maintenance or second induction course BCG (≥ 2 doses). The subsequent round of BCG, either maintenance or repeat induction, must be given within 6 months of initial induction BCG.
  • Patients may have received up to 2 lines of prior therapy (including chemotherapy or other approved agents) for NMIBC (NOTE: prior PD-1/PD-L1 blockade is prohibited).
  • Patients must be deemed unfit for radical cystectomy by the treating physician or refuse radical cystectomy. NOTE: Reason for being deemed unfit or refusal should be documented in the medical record.
  • All visible tumor must be completely resected within 60 days prior to registration (residual pure CIS is permitted).
  • All patients with T1 tumors must undergo restaging TURBT within 60 days prior to registration.
  • Patients must have baseline tumor tissue from either initial or repeat TURBTs for submission of a minimum of 2 and up to 10 unstained slides for translational study objectives. If archival tissue is not available, the subject is not eligible.
  • Adequate organ function as defined by the protocol.
  • Females of childbearing potential (FOCBP) must have a negative urine or serum pregnancy test within 7 days of registration. If a urine test is done and it is positive or cannot be confirmed as negative, a serum pregnancy test will be required. FOCBP must agree to use contraception during the study.
  • Men capable of fathering a child must agree to use contraception during the study.
  • Must have a life expectancy of at least 12 weeks.
  • Other criteria may apply.

• Exclusion Criteria

  Key Exclusion Criteria:
  • Prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137).
  • Prior CIS of the ureters or prostatic urethra within 24 months prior to registration.
  • Evidence of metastatic disease on imaging (CT or MRI) of the abdomen and pelvis within 90 days of registration.
  • Body weight ≤ 30 kg.
  • History of allogeneic organ transplantation.
  • History of another primary malignancy other than muscle-invasive bladder cancer less than 5 years prior to Day 1 of this trial, with the exception of a malignancy treated with curative intent and with no known active disease ≥ 5 years before the first dose of study drug and of low potential risk for recurrence. Other exceptions include those with a negligible risk of metastasis or death and with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer (non-melanoma skin cancer) or lentigo maligna without evidence of disease, localized prostate cancer treated surgically with curative intent, or ductal carcinoma in situ without evidence of disease treated surgically with curative intent) or undergoing active surveillance per standard-of-care management (e.g., chronic lymphocytic leukemia Rai Stage 0, prostate cancer with Gleason score ≤ 6, and prostate specific antigen [PSA] ≤ 10 mg/mL, etc.)
  • Currently participating in or has participated in a trial of an investigational agent within 4 weeks prior to the first dose of study treatment or 5 half-lives, whichever is longer without recovery of clinically significant toxicities from that therapy.
  • Active or prior autoimmune or inflammatory disorders requiring systemic treatment within 24 months prior to registration. Autoimmune or inflammatory disorders include, but not limited to, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease(colitis or Crohn's disease), diverticulitis (with the exception of diverticulosis),antiphospholipid syndrome, Sarcoidosis syndrome, or Wegener's syndrome (granulomatosis with polyangiitis, Graves' disease, hypophysitis, uveitis, etc), Sjogren's syndrome, Bell's palsy, Guillain-Barre syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis. NOTE: The following are exceptions to this criterion: Patients with vitiligo or alopecia, hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement. Any chronic skin condition that does not require systemic therapy. Patients without active disease in the last 5 years may be included but only after consultation with the study physician. Patients with celiac disease controlled by diet alone.
  • A diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to registration. NOTE: Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
  • Known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study.
  • Active known tuberculosis.
  • Symptomatic herpes zoster within the past 30 days.
  • Active infection requiring systemic therapy. NOTE: Prophylactic antibiotics are permitted. Treatment for a UTI is allowed but must be deemed adequately treated by the treating physician prior the start of C1D1.
  • History of idiopathic pulmonary fibrosis or organizing pneumonia.
  • History of (non-infectious) pneumonitis that required steroids or have current pneumonitis.
  • Additional criteria may apply.

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