IMVIGOR 011

INCLUSION CRITERIA FOR SURVEILLANCE PHASE:

Signed Informed Consent Form

• Age ≥ 18 years at time of signing Informed Consent Form

• Ability to comply with the study protocol

• TNM classification (UICC/AJCC 7th edition) at pathological examination of surgical resection specimen as follows:

– For patients treated with prior neoadjuvant chemotherapy: tumor stage of ypT2-4a or ypN+ and M0

– For patients who have not received prior neoadjuvant chemotherapy: tumor stage of pT3-4a or pN+ and M0

• Surgical resection of muscle-invasive UC of the bladder

– For patients with MIBC, radical cystectomy 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 with a negative surgical margin (i.e., R0 resection) or with carcinoma in situ at the distal ureteral or urethral margin will be eligible.

Patients with a positive R2 margin (which is defined as a tumor identified at the inked perivesical fat margin surrounding the cystectomy specimen) or R1 margin (which is defined as evidence of microscopic disease identified at the tumor margin), except for carcinoma in situ at the distal ureteral or urethral margin, will be excluded.

• Patients who have not received prior platinum-based neoadjuvant chemotherapy, have refused, or are ineligible (“unfit”) for cisplatin-based adjuvant chemotherapy

– Patients who have received at least two cycles of a platinum-containing regimen will be considered as those who have received prior neoadjuvant chemotherapy.

– Cisplatin ineligibility is defined by any one of the following criteria:

Impaired renal function (glomerular filtration rate [GFR] < 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

• Tumor PD-L1 expression per immunohistochemistry (IHC) and confirmed diagnosis of muscle-invasive UC as documented through central testing of a representative tumor tissue specimen

– A representative formalin-fixed paraffin-embedded (FFPE) tumor specimen from surgical resection (i.e., radical cystectomy, nephroureterectomy, or lymph node dissection) in a paraffin block (preferred) or at least 15 slides containing unstained, freshly cut, serial sections must be submitted along with an associated pathology report prior to study enrollment. If only 10-14 slides are available, the patient may still be eligible for the study, after Medical Monitor confirmation has been obtained

– 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.

– Tumor tissue of bladder should be of good quality based on total and viable tumor content and must contain a muscle invasive component (i.e., T2 or greater) of the tumor as verified by local pathology review. 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. In situations where multiple specimens were received from different sites or at different times, the score from the surgical resection of the primary tumor or lymph node dissection specimen will be used for both primary and secondary analyses.

• Availability of a surgical tumor specimen that is suitable (e.g., adequate quality and quantity) for use in determining ctDNA status, and for exploratory biomarker research assessed by central laboratory testing. Representative formalin-fixed, paraffin-embedded (FFPE) tumor block must be submitted along with an associated pathology report (two FFPE tumor blocks recommended if available). If an intact FFPE tumor block cannot be provided, then at least xx slides containing unstained, freshly cut, serial sections must be submitted along with an associated pathology report.

• A pre-surgery blood sample for the identification of somatic mutations in tumor tissue, and post-surgery blood sample for plasma preparation for determining ctDNA status must also be submitted for screening.

• Tumor tissue specimen submitted within 10 weeks of surgical resection for ctDNA assay development.

• ctDNA assay developed based on tumor tissue specimen and matched normal DNA from whole blood.

• 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 enrollment. Confirmation of disease-free status will be assessed by an independent central radiologic review of imaging data.

– Imaging of the upper urinary tracts must include one or more of the following: intravenous pyelogram (IVP), CT urography, renal ultrasound with retrograde pyelogram, ureteroscopy or MRI urogram, and must be completed no more than 4 weeks prior to enrollment.

– Other examinations should be performed as clinically indicated.

• Full recovery from cystectomy or nephroureterectomy and enrollment within 14 weeks following cystectomy or nephroureterectomy

– Minimum of 6 weeks must have elapsed from surgery.

INCLUSION CRITERIA FOR TREATMENT PHASE:

Patients enrolled in the surveillance phase must meet the following criteria for randomization into the Treatment Phase of the study:

• Histologically confirmed muscle-invasive UC (also termed TCC) of the bladder

– Patients with carcinomas showing mixed histologies are required to have a dominant transitional cell pattern.

• Plasma sample evaluated to be ctDNA-positive, defined as the presence of 2 or more mutations based on patient’s personalized ctDNA mPCR assay.

• Absence of residual disease and absence of metastasis, as confirmed by a negative baseline CT or MRI scan of the pelvis, abdomen, and chest no more than 4 weeks prior to randomization. Confirmation of disease-free status will be assessed by an independent central radiologic review of imaging data.

– Imaging of the upper urinary tracts must include one or more of the following: IVP, CT urography, renal ultrasound with retrograde pyelogram, ureteroscopy or MRI urogram, and must be completed no more than 4 weeks prior to randomization.

– Other examinations should be performed as clinically indicated.

• ECOG performance status of ≤ 2

• Life expectancy ≥ 12 weeks

• Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained within 14 days prior to initiation of study treatment:

– ANC ≥ 1.5 x 109/L (1500/μL) without granulocyte colony-stimulating factor support

– WBC counts > 2500/μL

– Lymphocyte count ≥ 0.3 x 109/L (300/μL)

– Platelet count ≥ 100 x 109/L (100,000/μL) without transfusion

– Hemoglobin ≥ 90 g/L (9 g/dL)

Patients may be transfused or receive erythropoietic treatment to meet this criterion.

– AST, ALT, and ALP ≤ 2.5 x upper limit of normal (ULN)

– Serum bilirubin ≤ 1.0 x ULN with the following exception:

Patients with known Gilbert disease: serum bilirubin ≤ 3 x ULN

– For patients not receiving therapeutic anticoagulation: PTT/PT ≤ 1.5 x ULN or INR < 1.7 x ULN

– For patients receiving therapeutic anticoagulation: stable anticoagulant regimen

– Creatinine clearance ≥ 20 mL/min (calculated using the Cockcroft-Gault formula)

• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception and agreement to refrain from donating eggs, as defined below:

Women must remain abstinent or use contraceptive methods with a failure rate of < 1% per year during the treatment period and for 5 months after the final dose of atezolizumab. Women must refrain from donating eggs during this same period.

A woman is considered to be of childbearing potential if she is postmenarchal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and is not permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined by the investigator (e.g., Müllerian agenesis). The definition of childbearing potential may be adapted for alignment with local guidelines or regulations.

Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, 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 adequate methods of contraception. If required per local guidelines or regulations, locally recognized adequate methods of contraception and information about the reliability of abstinence will be described in the local Informed Consent Form. 

Cancer-Specific Exclusion Criteria:

• Any approved anti-cancer therapy, including chemotherapy, or hormonal therapy within 3 weeks prior to study enrollment

– Hormone-replacement therapy or oral contraceptives are allowed.

• Adjuvant chemotherapy or radiation therapy for UC following surgical resection

– 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.

• 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

• Malignancies other than UC within 5 years prior to study enrollment

– Patients with high risk UTUC (defined as tumor stage ypT2-4a or ypN+) within 5 years prior to Cycle 1 Day 1 will be ineligible.

– Patients with localized low risk prostate cancer (defined as Stage ≤ T2c, Gleason score ≤ 7, and prostate-specific antigen (PSA) at prostate cancer diagnosis ≤ 20 ng/mL [if measured]) treated with curative intent and without PSA recurrence are eligible.

– Patients with low risk prostate cancer (defined as Stage T1/T2a, Gleason score ≤ 7 and PSA ≤ 10 ng/mL) who are treatment-naive 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:

• Pregnancy or breastfeeding

• History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins

• Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation

• 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, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis

– 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.

• 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.

• Serum albumin < 2.5 g/dL

• Positive test for HIV

• 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 and the absence of HBsAg) are eligible. HBV DNA must be obtained in these patients prior to enrollment.

– Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.

• Active tuberculosis

• 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.

• Prior allogeneic stem cell or solid organ transplant

• 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

2.3.2.3 Exclusion Criteria for the Treatment Phase

• Any approved anti-cancer therapy, including chemotherapy or hormonal therapy, within 3 weeks prior to randomization to the treatment phase

– Hormone-replacement therapy or oral contraceptives are allowed.

• Adjuvant chemotherapy or radiation therapy for UC following surgical resection

– Patients who have received primary chemoradiation for bladder preservation before cystectomy are eligible and will be treated the same as patients who have received prior neoadjuvant chemotherapy.

• 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 randomization to the treatment phase

• Malignancies other than UC within 5 years prior to Cycle 1, Day 1 (see cancer specific exclusion criteria above for details)

• 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

– Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1

• 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.

• 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

• 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 5 months following the last dose of atezolizumab (for patients randomized to atezolizumab). 

Research Nurse: Amanda Cook (x4656) Amanda.Cook@lthtr.nhs.uk

Administrator: Yecora Lecanda-Swarbrick (x3766)