A Trial of Durvalumab (MEDI4736) Plus Monalizumab in Non-Muscle-Invasive Bladder Cancer

Inclusion Criteria:

1. Age ≥18 years at the time of consent.

2. Patient is willing and able to comply with the protocol for the duration of thestudy including undergoing treatment and scheduled visits and examinations includingfollow up. Able and willing to provide written informed consent.

3. Eastern Cooperative Oncology Group scores ≤ 1 within 28 days prior to registration.

4. Non-muscle-invasive bladder cancer

• Cohort A: CIS +/- high grade papillary urothelial cancer (Ta or T1) after 3-moevaluation after induction BCG.

• Cohort B: High grade papillary urothelial cancer (Ta or T1) after 3-moevaluation after induction BCG.

5. Mixed variant histology (adenocarcinoma, squamous cell carcinoma) is eligible, butpure variant histology is ineligible. NOTE: Pathology report required fordocumentation purposes.

6. Persistent disease (defined as not achieving disease free status) after completingtherapy with at least induction BCG (≥ 5 doses) and the first round of maintenanceor second induction course (≥ 2 doses). The subsequent round of BCG, eithermaintenance or repeat induction, must be given within 6 months of initial inductionBCG.

• Persistent high risk NMIBC (T1, high grade papillary urothelial cancer Taand/or CIS) must be within 9 months of the last BCG instillation despite havingreceived adequate BCG as defined above.

7. High grade T1 after completing therapy with at least induction BCG (≥ 5 doses) orafter completing therapy with at least induction BCG (≥ 5 doses) and first round ofmaintenance or second induction course (≥ 2 doses). The subsequent round of BCG,either maintenance or repeat induction, must be given within 6 months of initialinduction BCG.

• Disease recurrence (T1) must be within 9 months of the last BCG instillationdespite having received adequate BCG as defined above.

8. Patients who are disease free at 6 months after starting BCG but have high graderecurrence (T1, Ta, CIS) while on maintenance therapy would be eligible.

• The recurrence must be within 6 months of the last BCG dose.

9. NMIBC patients, with high grade recurrence, having received adequate BCG within 24months of last BCG exposure, are eligible.

10. Patients may have received up to 1 line of prior therapy (6 cycles of inductionchemotherapy) for NMIBC after BCG (NOTE: prior PD-1/PD-L1 blockade is prohibited).

11. Patients must be deemed unfit for radical cystectomy by the treating physician orrefuse radical cystectomy. NOTE: Reason for being deemed unfit or refusal should bedocumented in the medical record.

12. All visible tumor must be completely resected within 60 days prior to registration (residual pure CIS is permitted).

• All patients must have had a cystoscopy (or TURBT with complete resection)without papillary tumor and negative urine cytology within 28 days prior toregistration (positive cytology is allowed in patients with CIS).

13. All patients with T1 tumors must undergo restaging TURBT within 60 days prior toregistration.

• There must be uninvolved muscularis propria in the restaging TURBT specimen.

• The initial TURBT prior to the restaging TURBT may be > 60 days prior toregistration.

14. Patients must have baseline tumor tissue from either initial or repeat TURBTs forsubmission of a minimum of 2 and up to 10 unstained slides for translational studyobjectives. If archival tissue is not available, the subject is not eligible.

15. Adequate organ function as defined by ALL of the following within 28 days prior toregistration:

• Absolute neutrophil count ≥ 1500/µL

• Platelets ≥ 100,000/µL

• Hemoglobin ≥ 9 g/dL

• Aspartate aminotransferase/alanine aminotransferase ≤ 1.5× upper limit ofnormal (ULN)

• Total serum bilirubin ≤ 1.5×ULN*; *Patients with Gilbert's disease: ≤ 3×ULN

• International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5×ULN unless the patient is on therapeutic anticoagulation.

• Creatinine clearance ≥ 40 mL/min by Cockcroft-Gault estimation. The patient'sestimated CrCl will be calculated by the local laboratory (for eligibilitypurposes) using screening/baseline height (m), actual weight (kg), and serumcreatinine: Males: CrCl = ((140 - age in years) × weight (kg)) / (72× serum creatinine (mg/dL))Females: CrCl = ((140 - age in years) × weight (kg) ×0.85) / (72× serum creatinine (mg/dL))

16. Females of childbearing potential (FOCBP) must have a negative urine or serumpregnancy test within 7 days of registration. If a urine test is done and it ispositive or cannot be confirmed as negative, a serum pregnancy test will berequired. FOCBP must agree to use contraception during the study.

17. Men capable of fathering a child must agree to use contraception during the study.

18. Must have a life expectancy of at least 12 weeks.

Exclusion Criteria:

1. Prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agentdirected to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137).

2. Prior CIS of the ureters or prostatic urethra within 24 months prior toregistration.

3. Evidence of metastatic disease on imaging (CT or MRI) of the abdomen and pelviswithin 90 days of registration.

4. Body weight ≤ 30 kg.

5. History of allogeneic organ transplantation.

6. History of another primary malignancy other than muscle-invasive bladder cancer lessthan 5 years prior to Day 1 of this trial, with the exception of a malignancytreated with curative intent and with no known active disease ≥ 5 years before thefirst dose of study drug and of low potential risk for recurrence. Other exceptionsinclude those with a negligible risk of metastasis or death and with expectedcurative outcome (such as adequately treated carcinoma in situ of the cervix, basalor squamous cell skin cancer (non-melanoma skin cancer) or lentigo maligna withoutevidence of disease, localized prostate cancer treated surgically with curativeintent, or ductal carcinoma in situ without evidence of disease treated surgicallywith curative intent) or undergoing active surveillance per standard-of-caremanagement (e.g., chronic lymphocytic leukemia Rai Stage 0, prostate cancer withGleason score ≤ 6, and prostate specific antigen [PSA] ≤ 10 mg/mL, etc.)

7. Currently participating in or has participated in a trial of an investigationalagent 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 thattherapy.

8. Active or prior autoimmune or inflammatory disorders requiring systemic treatmentwithin 24 months prior to registration. Autoimmune or inflammatory disordersinclude, but not limited to, systemic lupus erythematosus, rheumatoid arthritis,inflammatory bowel disease(colitis or Crohn's disease), diverticulitis (with theexception of diverticulosis),antiphospholipid syndrome, Sarcoidosis syndrome, orWegener's syndrome (granulomatosis with polyangiitis, Graves' disease, hypophysitis,uveitis, etc), Sjogren's syndrome, Bell's palsy, Guillain-Barre syndrome, multiplesclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis. NOTE: Thefollowing 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 withoutactive disease in the last 5 years may be included but only after consultation withthe study physician. Patients with celiac disease controlled by diet alone.

9. A diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (indosing exceeding 10 mg daily of prednisone equivalent) or any other form ofimmunosuppressive therapy within 7 days prior to registration. NOTE: Replacementtherapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapyfor adrenal or pituitary insufficiency) is not considered a form of systemictreatment and is allowed.

10. Known psychiatric or substance abuse disorder that would interfere with theparticipant's ability to cooperate with the requirements of the study.

11. Active tuberculosis.

12. Symptomatic herpes zoster within the past 30 days.

13. Active infection requiring systemic therapy. NOTE: Prophylactic antibiotics arepermitted. Treatment for a UTI is allowed but must be deemed adequately treated bythe treating physician prior the start of C1D1.

14. History of idiopathic pulmonary fibrosis or organizing pneumonia.

15. History of (non-infectious) pneumonitis that required steroids or have currentpneumonitis.

16. Patients known to have tested positive for human immunodeficiency virus (HIV) (positive HIV 1/2 antibodies) are eligible with the following:

• On effective anti-retroviral therapy with undetectable viral load within 6months of registration.

• HIV-infected participants must not have a history of Kaposi sarcoma and/orMulticentric Castleman Disease.

17. Known active hepatitis infection, positive hepatitis C virus (HCV) antibody,hepatitis B virus (HBV) surface antigen (HBsAg) or HBV core antibody (anti-HBc), atscreening. Participants with a past or resolved HBV infection (defined as thepresence of anti HBc and absence of HBsAg) are eligible. Participants positive forHCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA.NOTE: No testing for Hepatitis B and Hepatitis C is required unless mandated by alocal health authority.

18. Participants with a known co-infection with HBV and HCV, or co-infection with HBVand HDV, namely: HBV positive (presence of HBsAg and/or anti HBcAb with detectableHBV DNA); AND HCV positive (presence of anti-HCV antibodies); OR HDV positive (presence of anti-HDV antibodies).

19. Known allergy or hypersensitivity to any of the study drugs or any of the study drugexcipients.

20. Received live vaccines within 30 days of study treatment. Examples of live vaccinesinclude, but are not limited to, the following: measles, mumps, rubella,varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generallykilled virus vaccines and are allowed; however, intranasal influenza vaccines (e.g.,FluMist®) are live attenuated vaccines and are not allowed. COVID-19 vaccinationsare permitted.

21. Major surgical procedure (as defined by the Investigator) within 28 days prior tothe first dose of study drug. Note: Local surgery of isolated lesions for palliativeintent is acceptable.

22. Uncontrolled intercurrent illness, including but not limited to, symptomaticcongestive heart failure, uncontrolled hypertension, unstable angina pectoris,cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinalconditions associated with diarrhea, or psychiatric illness/social situations thatwould limit compliance with study requirement, substantially increase risk ofincurring AEs or compromise the ability of the patient to give written informedconsent.

23. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 mscalculated from 3 ECGs (within 15 minutes at 5 minutes apart).

24. Female patients who are pregnant or breastfeeding or male or female patients ofreproductive potential who are not willing to employ effective birth control.

25. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with theexception of alopecia, vitiligo, and the laboratory values defined in the inclusioncriteria

• Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basisafter consultation with the Study Physician.

• Patients with irreversible toxicity not reasonably expected to be exacerbatedby treatment with durvalumab may be included only after consultation with theStudy Physician.

26. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment.Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormonereplacement therapy) is acceptable.

27. History of leptomeningeal carcinomatosis

28. Prior randomization or treatment in a previous durvalumab clinical study regardlessof treatment arm assignment.

29. Current or prior use of immunosuppressive medication within 14 days before the firstdose of durvalumab. The following are exceptions to this criterion:

• Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intraarticular injection)

• Systemic corticosteroids at physiologic doses not to exceed <<10 mg/day>> ofprednisone or its equivalent

• Steroids as premedication for hypersensitivity reactions (e.g., CT scanpremedication