BO44157

Potential participants are eligible to be included in the study only if all of the following criteria apply:

· Signed Informed Consent Form

· Age ≥ 18 years at the time of signing Informed Consent Form

· ECOG Performance Status of ≤ 2

· Ability to comply with protocol, in the investigator’s judgment

· Histologically or cytologically documented locally advanced (T4b, any N; or any T, N2-3) or metastatic (M1, Stage IV) TCC (also termed urothelial cell carcinoma) of the urothelium (including renal pelvis, ureters, urinary bladder, urethra)

- Patients with mixed histologies are required to have a dominant urothelial cell pattern.

- Locally advanced bladder cancer must be inoperable based on involvement of pelvic sidewall or adjacent viscera (clinical stage T4b) or bulky nodal metastasis (N2-N3).

· Considered to be ineligible ("unfit") to receive platinum-based chemotherapy as defined by one of the following criteria:

– ECOG Performance Status of 0 with baseline GFR ≥ 15 mL/min/1.73 m2 and ≤ 30 mL/min/1.73 m2

– ECOG Performance Status of 1 or 2 with baseline GFR ≥ 15 mL/min/1.73 m2 and ≤ 45 mL/min/1.73 m2

– ECOG Performance Status of 0-2 with G ≥ 2 neuropathy

- GFR should be assessed by calculation through use of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation:

CKD-EPI = 142 x (serum creatinine/A)B x 0.9938Age x (1.012 if female)

Where A and B are the following:

o Female serum creatinine ≤ 0.7: A = 0.7 and B = -0.241

o Female serum creatinine > 0.7: A = 0.7 and B = -1.2

o Male serum creatinine ≤ 0.9: A = 0.9 and B = -0.302

o Male serum creatinine > 0.9: A 0.9 and B = -1.2

– Patients for whom chemotherapy is not deemed appropriate

· No prior chemotherapy for inoperable locally advanced or metastatic or recurrent UC

For patients who received prior adjuvant/neoadjuvant chemotherapy or chemoradiation for UC, a treatment-free interval greater than 12 months between the last treatment administration and the date of recurrence is required in order to be considered treatment naïve in the metastatic setting.

Prior local intervesical chemotherapy or Bacillus Calmette-Guerin immunotherapy is allowed if completed at least 4 weeks prior to the initiation of study treatment.

· Measurable disease; at least one measurable lesion as defined by RECIST v1.1

Previously irradiated lesions should not 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.

· Availability of a representative leftover tumor specimen that meet the criteria outlined in Section 8.7 prior to study enrollment, and that is suitable for determination of PD-L1 status, for stratification and for exploratory biomarker research as assessed by a central laboratory

PD-L1 status will be centrally assessed by IHC using the investigational VENTANA PD-L1 (SP263) CDx assay (see Appendix 13). Positive PD-L1 expression status is defined as TAP ≥ 5% and negative PD-L1 status is defined as TAP < 5%. Patients with tumors that do not yield an evaluable PD-L1 status will not be eligible.

A representative formalin-fixed, paraffin-embedded (FFPE) tumor specimen in paraffin block (preferred) or at least 20 unstained slides, with an associated pathology report, containing freshly cut, serial sections. For the PD-L1 (SP263) CDx Assay, bone metastases and cytology samples are not acceptable.

In exceptional circumstances, 15-19 slides are acceptable provided that other eligibility requirements are met; however, a minimum of 20 slides is highly preferred. For China, the number of slides required for eligibility may also be governed by local regulations (e.g., Human Genetics Resources Administration of China [HGRAC]).

· 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 with the following exception: patients with benign ethnic neutropenia

(BEN) and ANC ≥ 1.3 x 109/L (≥ 1300/μL) are eligible.

BEN (also known as constitutional neutropenia) is an inherited cause of mild or moderate neutropenia that is not associated with any increased risk for infections or other clinical manifestations (Atallah-Yunes et al. 2019). BEN is referred to as ethnic neutropenia because of its increased prevalence in people of African descent and other specific ethnic groups.

– Lymphocyte count ≥ 0.5 x 109/L (≥ 500/μL)

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

– Hemoglobin ≥ 90 g/L (≥ 9 g/dL)

Patients may be transfused to meet this criterion.

– AST, ALT, and ALP ≤ 2.5 x upper limit of normal (ULN), with the following exceptions:

Patients with documented liver metastases: AST and ALT ≤ 5 x ULN

Patients with documented liver or bone metastases: ALP ≤ 5 x ULN

– Total bilirubin ≤ 1.5 x ULN with the following exception:

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

– Albumin ≥ 25 g/L (≥ 2.5 g/dL)

– For patients not receiving therapeutic anticoagulation: INR and aPTT ≤ 1.5 x ULN

· Negative HIV test at screening, with the following exception: individuals with a positive HIV test at screening are eligible provided they are stable on anti-retroviral therapy, have a CD4 count ≥ 200/μL, and have an undetectable viral load

· Negative hepatitis B surface antigen (HBsAg) test at screening

· Positive hepatitis B surface antibody (HBsAb) test at screening, or a negative HBsAb at screening accompanied by either of the following:

– Negative hepatitis B core antibody (HBcAb)

– Positive HBcAb test followed by quantitative hepatitis B virus (HBV) DNA < 500 IU/mL

The HBV DNA test must be performed for individuals who have a negative HBsAg test, a negative HBsAb test, and a positive HBcAb test.

· Negative hepatitis C virus (HCV) antibody test at screening, or a positive HCV antibody test followed by a negative HCV RNA test at screening

The HCV RNA test must be performed for individuals who have a positive HCV antibody test.

· Adequate cardiovascular function:

– New York Heart Association (NYHA) Heart Failure Class ≤ 2

· Baseline-corrected QT (QTcF) interval ≤ 480 ms. If the QTcF interval is longer than 480 ms but shorter than 500 ms, the participant may undergo a cardiac evaluation and be considered for treatment in case of no clinically significant findings

· Resting systolic blood pressure ≤ 150 mmHg and diastolic blood pressure 100 mmHg (average of ≥ 3 readings on ≥ 2 sessions with short break between sessions) (or no clinically significant hypertension)

· Resting heart rate between 45-100 bpm (or no clinically significant tachycardia)

· Left ventricular ejection fraction (LVEF) ≥ 50% assessed by either transthoracic echocardiogram (TTE) or multiple-gated acquisition (MUGA) scan (TTE preferred test) within 6 months prior to initiation of study treatment

· Troponin T (TnT) or troponin I (TnI) ≤ 3 x institutional ULN. Participants with TnT or TnI levels between > 1 and < 3 x ULN should have a further TnT or TnI reading within 3-6 hours and will be permitted to enter the study only if repeat levels remain ≤ 3 x ULN and have not changed by > 20% compared to the first reading. These participants should also undergo a cardiac evaluation and consider consulting a cardiologist to confirm no clinically significant findings before they receive study treatment.

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

Female participants 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, 4 months after the final dose of RO7247669, or 90 days after the final dose of tiragolumab.

Participants must refrain from donating eggs during this same period.

A female participant 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). Per this definition, a female participant with tubal ligation is considered to be of childbearing potential. 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.

Hormonal contraceptive methods must be supplemented by a barrier method.

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 individual. 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.

· For male participants: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods, and agreement to refrain from donating sperm, as defined below:

With a female partner of childbearing potential who is not pregnant, male participants must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and for 4 months after the final dose of RO7247669, or 90 days after the final dose of tiragolumab. Male participants must refrain from donating sperm during this same period.

Atezolizumab is not expected to be teratogenic or genotoxic. Data suggest that the anticipated concentrations of atezolizumab in seminal fluid as well as the potential risk to the developing conceptus is low following seminal transfer of atezolizumab to a female partner. Thus, the male contraception requirement for atezolizumab has not been presented.

With a pregnant female partner, male participants must remain abstinent or use a condom during the treatment period and for 4 months after the final dose of RO7247669, or 90 days after the final dose of tiragolumab to avoid exposing the embryo.

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 individual. 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. 

Potential participants are excluded from the study if any of the following criteria apply:

· Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or within 5 months after the final dose of atezolizumab, 4 months after the final dose of RO7247669, or 90 days after the final dose of tiragolumab

Female participants of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment.

· GFR < 15 mL/min/1.73 m2 as calculated through use of the CKD-EPI equation or receiving dialysis

· Symptomatic, untreated, or actively progressing CNS metastases

Asymptomatic patients with treated CNS lesions are eligible, provided that all of the following criteria are met:

– Measurable disease, per RECIST v1.1, must be present outside the CNS.

– The patient has no history of intracranial haemorrhage or spinal cord haemorrhage.

– The patient has not undergone stereotactic radiotherapy within 7 days prior to initiation of study treatment, whole-brain radiotherapy within 14 days prior to initiation of study treatment, or neurosurgical resection within 28 days prior to initiation of study treatment.

– The patient has no ongoing requirement for corticosteroids as therapy for CNS disease.

– If the patient is receiving anti-convulsant therapy, the dose is considered stable.

– Metastases are limited to the cerebellum or the supratentorial region (i.e., no metastases to the midbrain, pons, medulla, or spinal cord).

– No evidence of significant vasogenic edema.

– There is no evidence of interim progression between completion of CNS-directed therapy and initiation of study treatment.

Asymptomatic patients with CNS metastases newly detected at screening are eligible for the study after receiving radiotherapy and/or surgery, with no need to repeat the screening brain scan.

· History of leptomeningeal disease

· Uncontrolled tumor-related pain

Patients requiring pain medication must be on a stable regimen at study entry.

Symptomatic lesions (e.g., bone metastases or metastases causing nerve impingement) amenable to palliative radiotherapy should be treated prior to enrollment. Patients should be recovered from the effects of radiation. There is no required minimum recovery period.

Asymptomatic metastatic lesions that would likely cause functional deficits or intractable pain with further growth (e.g., epidural metastasis that is not currently associated with spinal cord compression) should be considered for loco-regional therapy, if appropriate, prior to enrollment.

· Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently)

Patients with indwelling catheters (e.g., PleurXâ) are allowed.

· Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12 mg/dL, or corrected calcium greater than ULN)

· Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, anti-phospholipid

antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis (see Appendix 8), with the following exceptions:

Patients with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible for the study.

Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study.

Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met:

– Rash must cover < 10% of body surface area.

– Disease is well controlled at baseline and requires only low-potency topical corticosteroids.

– There has been no occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months.

· History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan

History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

· Active tuberculosis (TB) (i.e., has signs and symptoms of TB)

· Active Epstein-Barr virus (EBV) infection or known or suspected chronic active EBV infection at screening

– Participants with a positive EBV viral capsid antigen IgM test at screening are excluded from this arm.

– An EBV PCR test should be performed as clinically indicated to screen for active infection or suspected chronic active infection. Participants with a positive EBV PCR test are excluded from this arm.

· Significant cardiovascular/cerebrovascular disease within 3 months prior to initiation of study treatment, including any of the following:

– Hypertensive crisis/encephalopathy

– Unstable angina

– Transient ischemic attack/stroke

– Congestive heart failure (for NYHA classification, refer to inclusion criteria)

– Serious cardiac arrhythmia requiring treatment (exceptions are atrial fibrillation, paroxysmal supraventricular tachycardia)

– History of thromboembolic events (such as myocardial infarction, stroke or pulmonary embolism)

· Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the study

· History of another primary malignancy other than urothelial carcinoma within 5 years prior to Cycle 1, Day 1, with the exception of malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate> 90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer with no plans for treatment intervention

– Participants with localized prostate cancer (defined as Stage ≤ pT2c, Gleason score ≤ 7, and prostate-specific antigen [PSA] at prostate cancer diagnosis £ 20 ng/mL) treated with curative intent and without PSA recurrence are eligible.

– Participants with pre-existing low-risk prostate cancer (defined as Stage cT1/T2a, Gleason score ≤ 6, and PSA ≤ 10 ng/mL) who are treatment-naïve and undergoing active surveillance are eligible.

· Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia, or any active infection that could impact patient safety

· Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment

Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease [COPD] exacerbation) are eligible for the study.

· Prior allogeneic stem cell or solid organ transplantation

· Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment

complications

· Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during treatment or within 5 months after the final dose of atezolizumab, 4 months after the final dose of RO7247669, or 90 days after the final dose of tiragolumab

· Current treatment with anti-viral therapy for HBV

· Treatment with any approved anti-cancer therapy, including chemotherapy or hormonal therapy, within 3 weeks prior to initiation of study treatment; the following exceptions are allowed:

Palliative radiotherapy for bone metastases or soft tissue lesions should be completed > 7 days prior to baseline imaging.

Hormone-replacement therapy or oral contraceptives.

· Treatment with investigational therapy within 28 days prior to initiation of study treatment

· Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including, but not limited to, anti-CTLA-4, anti-PD-1, anti-PD-L1, anti-TIGIT, and anti-LAG3 therapeutic antibodies or pathway-targeting agents

· Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin-2) within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior to initiation of study treatment

· Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [TNF] agents) within 2 weeks prior to initiation of study

treatment, or anticipation of need for systemic immunosuppressive medication during study treatment, with the following exceptions:

– Patients who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible for the study.

– Patients who received mineralocorticoids (e.g., fludrocortisone), inhaled or low-dose corticosteroids for COPD or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study.

· History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins

· Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab formulation. 

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

Administrator: Yecora Lecanda-Swarbrick (x3766)