Details

Details

Title A Phase III, open-label, multicenter, randomized study of atezolizumab (Anti-PD-L1 antibody) versus observation as adjuvant therapy in patients with PD-L1-selected, high-risk muscle-invasive bladder cancer after cystectomy

IRB ROCH1815

CC 15-1059

Hospital Main Campus

Phase Phase 3

Disease Bladder

Drug Atezolizumab

Description

Description

EFFICACY OBJECTIVES
  • To evaluate the efficacy of adjuvant atezolizumab treatment in patients with PD-L1-selected muscle invasive bladder cancer (MIBC), as measured by disease-free survival (DFS)
  • To evaluate the efficacy of adjuvant atezolizumab treatment, as measured by overall survival (OS)
  • To evaluate the efficacy of adjuvant atezolizumab treatment, as measured by disease-specific survival (DSS)
  • To evaluate the efficacy of adjuvant atezolizumab treatment, as measured by distant metastasis-free survival (DMFS)
SAFETY OBJECTIVES
  • To evaluate the safety and tolerability of atezolizumab in the adjuvant setting
  • To evaluate the incidence of anti-therapeutic antibodies (ATAs) against atezolizumab and to explore the potential relationship of the immunogenicity response with pharmacokinetics, safety, and efficacy
PHARMACOKINETIC OBJECTIVE
  • To characterize the pharmacokinetics of MPDL32820A
PATIENT-REPORTED OUTCOME OBJECTIVE
  • To assess health status as measured by the EuroQol 5-dimension, 5-level version (EQ-5D-5L) questionnaire
EXPLORATORY OBJECTIVE
  • To assess predictive, prognostic, and pharmacodynamic exploratory biomarkers in archival and/or fresh tumor tissue and blood and their association with disease recurrence
COUNTRY-SPECIFIC OBJECTIVES
  • To evaluate the efficacy of atezolizumab adjuvant treatment in patients who are residents of China, with PD-L1-selected MIBC after cystectomy, as measured by DFS.
Inclusion Criteria

Inclusion Criteria

  1. Signed Informed Consent Form
  2. Ability to comply with protocol
  3. Age ≥ 18 years
  4. Histologically confirmed muscle-invasive TCC (also termed UC) of the bladder (excluding TCC of renal pelvis, ureters, or urethra). Patients with mixed histologies are required to have a dominant transitional cell pattern. Patients with disease of the upper tract will be excluded.
  5. TNM classification (UICC/AJCC 7th edition) at pathological examination of cystectomy specimen as follows: For patients treated with prior neoadjuvant chemotherapy: tumor stage of ypT2-T4a or ypN+. For patients who have not received prior neoadjuvant chemotherapy: tumor stage of pT3-T4a or pN+.
  6. Cystectomy with lymph node dissection. Surgeries may be performed by the open, laparoscopic, or robotic approach. Cystectomy must include bilateral lymph node dissection, the extent of which will be at the discretion of the treating surgeon but optimally should extend at a minimum from the mid common iliac artery proximally to Cooper's ligament distally, laterally to the genitofemoral nerve, and inferiorly to the obturator nerve. The method of urinary diversion for patients undergoing cystectomy will be at the discretion of the surgeon and choice of the patient. Patients must have a negative surgical margin (i.e., R0 resection). Positive surgical margin is defined as tumor identified at the inked perivesical fat margin surrounding the cystectomy specimen (R2) or evidence of microscopic disease at the tumor margin (R1).
  7. For patients who have not received prior neoadjuvant chemotherapy, refusal of or ineligibility (being "unfit") for cisplatin-based adjuvant chemotherapy; cisplatin ineligibility is defined by any one of the following criteria: Impaired renal function (glomerular filtration rate [GFR] > 30 but < 60 mL/min); GFR should be assessed by direct measurement (i.e., creatinine clearance or ethyldediaminetetra-acetate) or, if not available, by calculation from serum/plasma creatinine (Cockcroft-Gault formula). A hearing loss (measured by audiometry) of 25 dB at two contiguous frequencies. Grade 2 or greater peripheral neuropathy (i.e., sensory alteration or parasthesis including tingling). ECOG performance status of 2 (see Appendix 7).
  8. Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens from cystectomy in paraffin blocks (blocks preferred) or at least 15 unstained slides, with an associated pathology report, for central testing and determined to be evaluable for tumor PD-L1 expression prior to study enrollment. Patients with fewer than 15 unstained slides available at baseline (but no fewer than 10) may be eligible following discussion with Medical Monitor. Tumor tissue should be of good quality based on total and viable tumor content. Fine-needle aspiration, brushing, cell pellet from pleural effusion, bone metastases, and lavage samples are not acceptable. For core-needle biopsy specimens, at least three cores should be submitted for evaluation. Patients having additional tissue samples from procedures performed at different times during the course of their MIBC (e.g., a specimen from a prior transurethral resection of bladder tumor [TURBT]) or having lymph node involvement identified at cystectomy will be requested (but not required) to also submit these samples for central testing. Tissue samples obtained at multiple times or anatomical sites for individual patients will greatly contribute to an improved understanding of the dynamics of PD-L1 expression and relationship with intervening anti-cancer therapy. In situations where multiple specimens were received from different sites or at different times, the score from the cystectomy specimen will be used for both primary and secondary analyses.
  9. MIBC with a PD-L1 IHC score of IC2/3 prospectively determined on the cystectomy tumor specimens by a central laboratory. An IHC score of IC2/3 is defined by the presence of discernible PD-L1 staining of any intensity in tumor-infiltrating immune cells (ICs) covering ≥ 5% of tumor area occupied by tumor cells, associated intratumoral stroma, and contiguous peri-tumoral desmoplastic stroma.
  10. Absence of residual disease and absence of metastasis, as confirmed by a negative baseline computed tomography (CT) or magnetic resonance imaging (MRI) scan of the pelvis, abdomen, and chest no more than 4 weeks prior to randomization. Imaging of the upper urinary tracts may include one or more of the following: intravenous pyelogram (IVP), CT urography, renal ultrasound with retrograde pyelogram, ureteroscopy, or MRI urogram, and should be completed no more than 6 weeks prior to randomization. Other examinations should be performed as clinically indicated.
  11. Full recovery from cystectomy within 12 weeks following surgery.
  12. ECOG performance status of ≤ 2 (see Appendix 7).
  13. Life expectancy ≥ 12 weeks.
  14. Adequate hematologic and end-organ function, as defined by the following laboratory results obtained within 14 days prior to the first study treatment: ANC ≥ 1500 cells/μL (without granulocyte colony-stimulating factor support within 2 weeks prior to Cycle 1, Day 1). WBC counts > 2500/μL. Lymphocyte count ≥ 300/μL. Platelet count ≥ 100,000/μL (without transfusion within 2 weeks prior to Cycle 1, Day 1). Hemoglobin ≥ 9.0 g/dL. Patients may be transfused or receive erythropoietic treatment to meet this criterion. AST, ALT, and alkaline phosphatase ≤ 2.5 x the upper limit of normal (ULN). Serum bilirubin ≤ 1.0 xULN. Patients with known Gilbert disease who have serum bilirubin level. ≤ 3 x ULN may be enrolled. INR and aPTT ≤ 1.5 xULN. This applies only to patients who are not receiving therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be on a stable dose. Calculated creatinine clearance ≥ 30 mL/min (Cockcroft-Gault formula). Patients with a calculated creatinine clearance between 15-29 mL/min. (Cockcroft-Gault formula) may be eligible for study following discussion with the Medical Monitor.
  15. For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 90 days after the last dose of study drug. A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, established, proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
  16. For enrollment into the China extension cohort, residence in the People's Republic of China
Exclusion Criteria

Exclusion Criteria

Cancer-Specific Exclusion Criteria
  1. Any approved anti-cancer therapy, including chemotherapy, or hormonal therapy within 3 weeks prior to initiation of study treatment. Hormone-replacement therapy or oral contraceptives are allowed.
  2. Adjuvant chemotherapy or radiation therapy for UC following cystectomy. Patients who have received primary chemoradiation for bladder preservation before cystectomy are eligible and will be treated as the same as patients who have received prior neoadjuvant chemotherapy.
  3. Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 28 days or five half-lives of the drug, whichever is longer, prior to enrollment.
  4. Malignancies other than MIBC within 5 years prior to Cycle 1, Day 1. Patients with localized low risk prostate cancer (defined as stage ≤ T2b, Gleason score ≤ 7, and PSA at prostate cancer diagnosis ≤ 20 ng/mL) treated with curative intent and without prostate-specific antigen (PSA) recurrence are eligible Patients with low risk prostate cancer (defined as Stage T1/T2a,Gleason score ≤ 6 and PSA ≤ 10 ng/mL) who are treatment-na�ve and undergoing active surveillance are eligible. Patients with malignancies of a negligible risk of metastasis or death (e.g., risk of metastasis or death <5% at 5 years) are eligible provided they meet all of the following criteria: Malignancy treated with expected curative intent (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) No evidence of recurrence or metastasis by follow-up imaging and any disease-specific tumor markers.
General Medical Exclusion Criteria
  1. Pregnancy or breastfeeding.
  2. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins.
  3. Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation.
  4. 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 antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's syndrome, Guillain-Barre syndrome, multiple sclerosis, vasculitis, or glomerulonephritis (see Appendix 5 for a more comprehensive list of autoimmune diseases). Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone may be eligible for this study. Patients with controlled Type I diabetes mellitus on a stable dose of insulin regimen may be eligible for this study.
  5. 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. History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
  6. Serum albumin < 2.5 g/dL
  7. Positive test for HIV
  8. 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. Patients with past HBV infection or resolved HBV infection (defined as the presence of hepatitis B core antibody [HBc Ab] and absence of HBsAg) are eligible. HBV DNA must be obtained in these patients prior to Cycle 1, Day 1. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
  9. Active tuberculosis
  10. Severe infections within 4 weeks prior to Cycle 1, Day 1, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia.
  11. Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1.
  12. Receipt of therapeutic oral or IV antibiotics within 2 weeks prior to Cycle 1, Day 1. Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or to prevent chronic obstructive pulmonary disease exacerbation) are eligible.
  13. Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction within the previous 3 months, unstable arrhythmias, or unstable angina. Patients with known coronary artery disease, congestive heart failure not meeting the above criteria, or left ventricular ejection fraction < 50% must be on a stable medical regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist if appropriate.
  14. Major surgical procedure other than for diagnosis within 28 days prior to Cycle 1, Day 1 or anticipation of need for a major surgical procedure during the course of the study
  15. Prior allogeneic stem cell or solid organ transplant.
  16. Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1 or anticipation that such a live, attenuated vaccine will be required during the study Influenza vaccination should be given during influenza season only (approximately October through May in the Northern Hemisphere and approximately April through September in the Southern Hemisphere). Patients must agree not to receive live, attenuated influenza vaccine (e.g., FluMist�) within 28 days prior to randomization, during treatment or within 90 days following the last dose of atezolizumab (for patients randomized to atezolizumab).
  17. Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications
Medication-Related Exclusion Criteria
  1. Prior treatment with CD137 agonists or immune checkpoint-blockade therapies, including anti-CD40, anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies.
  2. Treatment with systemic immunostimulatory agents (including but not limited to interferons, IL-2) within 6 weeks or five half-lives of the drug, whichever is shorter, prior to Cycle 1, Day 1.
  3. Treatment with systemic corticosteroids or other systemic immunosuppressive medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) within 2 weeks prior to Cycle 1, Day 1, or anticipated requirement for systemic immunosuppressive medications during the trial. Patients who have received acute, low-dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled in the study after discussion with and approval by the Medical Monitor. The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone for adrenal insufficiency) is allowed.