CV301 Combined With PD-1/L1 Blockade in Patients With Locally Advanced or Metastatic Urothelial Bladder Cancer

This is a Phase 2, single-arm, multi-institutional clinical trial designed to study the combination of CV301 with atezolizumab in the first-line treatment of UC not eligible for cisplatin-containing chemotherapy (Cohort 1) and in the second-line treatment of UC previously treated with standard first-line cisplatin-based chemotherapy (Cohort 2).

This is a Phase 2, single-arm, multi-institutional clinical trial designed to study the combination of CV301 with atezolizumab in the first-line treatment of UC not eligible for cisplatin-containing chemotherapy (Cohort 1) and in the second-line treatment of UC previously treated with standard first-line cisplatin-based chemotherapy (Cohort 2). The trial will be performed using an optimal two-stage design within each cohort.

Stage 1, Cohort 1: Enroll 14 subjects. If objective response is not achieved in at least four patients, the cohort will be stopped for futility. If objective response is achieved in at least four subjects, the cohort will proceed to stage 2. If any patient is not evaluable for the primary endpoint, the patient may be replaced.

Stage 1, Cohort 2: Enroll 13 subjects. If objective response is not achieved in at least three patients, the cohort will be stopped for futility. If objective response is achieved in at least three subjects, the cohort will proceed to stage 2. If any patient is not evaluable for the primary endpoint, the patient may be replaced.

Stage 2, Cohort 1: Enroll an additional 19 subjects. If any patient is not evaluable for the primary endpoint, the patient may be replaced until a total of 33 patients are evaluable for the primary endpoint.

Stage 2, Cohort 2: Enroll an additional 22 subjects. If any patient is not evaluable for the primary endpoint, the patient may be replaced until a total of 35 patients are evaluable for the primary endpoint.

Eligibility Criteria:
Inclusion Criteria:

1. Age ≥ 18 years at date of ICF signature having the ability to comply with protocol.
2. Histologically or cytologically documented locally advanced (T4b, any N; or any T, N 2-3) or metastatic (M1, Stage IV; or metastatic recurrence after locoregional treatment) UC (including renal pelvis, ureters, urinary bladder, urethra)

   1. Patients with mixed histologies were required to have a dominant transitional cell pattern.
   2. Locally advanced bladder cancer that was inoperable on the basis of involvement of the pelvic sidewall or adjacent viscera (clinical stage T4b) or bulky nodal metastasis (N2-N3).
3. Life expectancy ≥ 12 weeks.
4. Measurable disease, as defined by RECIST v1.1. Previously irradiated lesions cannot be counted as target lesions unless there has been demonstrated progression in the lesion since radiotherapy and no other lesions are available for selection as target lesions.
5. Demonstrate adequate organ function.
6. For female patients of childbearing potential and male patients with partners of childbearing potential, agreement (by patient and/or partner) to use a highly effective form(s) of contraception (i.e., one that results in a low failure rate \[\< 1% per year\] when used consistently and correctly) and to continue its use for 5 months after the last dose of atezolizumab.
7. Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin blocks (blocks preferred) or 10-15 unstained slides, with an associated pathology report.

   For Cohort 1:
8. Untreated with chemotherapy
9. Have at least one of the following:

   1. ECOG (Eastern Cooperative Oncology Group) performance status of 2.
   2. Glomerular filtration rate calculated as creatinine clearance (Cockroft-Gault formula) of ≥20 mL/min and less than 60 mL/min
   3. Hearing loss or neuropathy of any cause Common Terminology Criteria for Adverse Events (CTCAE) Grade ≥2

   For Cohort 2:
10. Disease progression during or following treatment with at least one platinum-containing regimen (e.g., GC, MVAC, CarboGem, carboplatin-paclitaxel) for inoperable locally advanced or metastatic urothelial carcinoma or disease recurrence, as defined by:

    1. Regimen is defined as patients receiving at least one cycle of a platinum-containing regimen with response assessment. Patients who received one cycle of a platinum-containing regimen but discontinued due to toxicity are also eligible.
    2. Patients who received prior adjuvant/neoadjuvant chemotherapy and progressed within 12 months of treatment with a platinum-containing adjuvant/neoadjuvant regimen are considered as second-line patients.
11. ECOG (Eastern Cooperative Oncology Group) performance status of \< 2
12. Calculated creatinine clearance (Cockroft-Gault formula) of ≥20 mL/min

Exclusion Criteria:

1. Any approved anti-cancer therapy, including chemotherapy, within 3 weeks prior to initiation of trial treatment; the following exceptions are allowed:

   1. Palliative radiotherapy for bone metastases or non-target soft tissue lesions completed \>7 days prior to baseline imaging.
   2. Hormone-replacement therapy or oral contraceptives.
2. Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 28 days prior to screening given that all AEs related to prior treatment have resolved to baseline or Grade 1.
3. Active central nervous system (CNS) metastases as determined by computed tomography (CT) or magnetic resonance imaging (MRI) evaluation during screening and prior radiographic assessments or Leptomeningeal disease.
4. Uncontrolled tumor-related pain:

   1. Patients requiring pain medication must be on a stable regimen at trial entry.
   2. Symptomatic lesions amenable to palliative radiotherapy (e.g., bone metastases or metastases causing nerve impingement) should be treated prior to trial entry.
   3. Asymptomatic metastatic lesions whose further growth would likely cause functional deficits or intractable pain (e.g., epidural metastasis that is not currently associated with spinal cord compression) could be considered for loco-regional therapy if appropriate prior to enrollment.
5. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently)

   a. Patients with indwelling catheters (e.g., PleurX) are allowed.
6. Uncontrolled hypercalcemia (\>1.5 mmol/L ionized calcium or Ca \>12 mg/dL or corrected serum calcium \>ULN) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab:

   1. Patients who are receiving bisphosphonate therapy or denosumab specifically to prevent skeletal events and who did not have a history of clinically significant hypercalcemia are eligible.
   2. Patients who are receiving denosumab prior to enrollment have to be willing and eligible to receive a bisphosphonate instead while in the trial.
7. Malignancies other than urothelial carcinoma within 3 years prior to Day 1, with the exception of those with a negligible risk of metastasis or death treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, or ductal carcinoma in situ treated surgically with curative intent) or localized prostate cancer treated with curative intent and no intent for further treatment or incidental prostate cancer (T1/T2b, Gleason score ≤7 undergoing active surveillance and treatment naive).
8. Pregnant and lactating women.
9. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins, or aminoglycoside antibiotics or egg products, poxvirus-based vaccinations, or beef or bovine meat.
10. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation.
11. History of autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with anti-phospholipid syndrome, granulomatosis with polyangiitis, Sjogren's syndrome, Guillain-Barre syndrome, multiple sclerosis, vasculitis, or glomerulonephritis.

    1. Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone are eligible for this trial.
    2. Patients with controlled Type I diabetes mellitus on a stable dose of insulin regimen are eligible for this trial.
    3. Patients with history of vitiligo and controlled psoriasis are eligible for the trial.
12. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan

    a. History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
13. Positive test for Human Immunodeficiency Virus (HIV).
14. Patients with active hepatitis B virus (HBV; chronic or acute, defined as having a positive hepatitis B surface antigen \[HBsAg\] test at screening) or hepatitis C virus (HCV)

    1. Patients with past HBV infection or resolved HBV infection (defined as the presence of hepatitis B core antibody \[HBcAb\] and absence of HbsAg, negative polymerase chain reaction (PCR) for HBV) are eligible. HBV Deoxyribonucleic Acid (DNA) PCR must be obtained in these patients prior to Day 1.
    2. Patients positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV Ribonucleic Acid (RNA) prior to enrollment.
15. Active tuberculosis.
16. Signs or symptoms clinically significant of infection within 2 weeks prior to Day 1.
17. Received therapeutic oral or intravenous (IV) antibiotics within 1 week prior to Day 1

    a. Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or to prevent chronic obstructive pulmonary disease exacerbation) are eligible.
18. Significant cardiovascular disease, which includes but is not limited to New York Heart Association (NYHA) Heart Failure Class II or greater, myocardial infarction within the previous 3 months, unstable arrhythmias, unstable angina.

    a. Patients with known coronary artery disease, congestive heart failure not meeting the above criteria, or left ventricular ejection fraction \< 50% on a stable medical regimen that was optimized in the opinion of the treating physician, in consultation with a cardiologist if appropriate, are eligible.
19. Major surgical procedure other than for diagnosis within 28 days prior to Day 1 or anticipation of need for a major surgical procedure during the course of the trial.
20. Prior allogeneic stem cell or solid organ transplant.
21. Administration of a live, attenuated vaccine within 4 weeks before Day 1 or anticipation that such a live attenuated vaccine would be required during the trial

    a. Influenza vaccination may be given during influenza season only (approximately October to March). Patients cannot receive live, attenuated influenza vaccine (e.g., FluMist®) within 4 weeks prior to Day 1 or at any time during the trial.
22. Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicated the use of an investigational drug or that could affect the interpretation of the results or render the patient at high risk from treatment complications.
23. Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies
24. Treatment with systemic immunostimulatory agents (including but not limited to IFNs, interleukin \[IL\]-2) within 6 weeks or five half-lives of the drug, whichever was shorter, prior to Day 1.
25. Treatment with systemic corticosteroids or other systemic immunosuppressive medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, and anti-tumor necrosis factor \[anti-TNF\] agents) within 2 weeks prior to Day 1, or anticipated requirement for systemic immunosuppressive medications during the trial

    a. Patients who receive acute, low-dose, systemic corticosteroid medications (e.g., a one-time dose of dexamethasone for nausea) or for prevention of hypersensitivity reactions to contrast agents may be enrolled in the trial.
26. The use of inhaled, nasal, ophthalmic, intra-articular, auricular or topical corticosteroids, physiologic replacement doses of glucocorticoids (i.e., for adrenal insufficiency), and mineralocorticoids (e.g. Fludrocortisone for adrenal insufficiency) is allowed.