MoST-TAP: This study will explore the effect of immunotherapy in people with locally advanced, solid cancers that cannot be removed by surgery, or have spread to other parts of the bodyA Single Arm, Open-label, Phase II Signal-seeking Trial of Tiragolumab and Atezolizumab in Patients With Advanced Solid Tumours

Exclusion

1. Involvement in the planning and/or conduct of the study (applies to both Roche staff and/or staff at the study site).
2. Patients with non-small cell lung cancer.
3. Participation in another clinical study with an investigational product during the last 4 weeks prior to study enrolment.
4. Any unresolved toxicity (>CTCAE grade 2) from previous anti-cancer therapy. Patients with irreversible toxicity that is not reasonably expected to be exacerbated by the investigational product may be included (e.g., hearing loss, peripherally neuropathy).
5. Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 electrocardiograms (ECGs) using Fredericia's Correction.

6. Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor-α [TNF-α] 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:

   • topical, intranasal, or inhaled corticosteroids or systemic corticosteroids at or below physiological doses (eg. ≤10 mg/day of prednisone);
   • use of dexamethasone up to 4mg/day within 14 days of initial treatment for patients with brain tumours.

7. Symptomatic or actively progressing central nervous system (CNS) metastases.

   Asymptomatic patients with treated or untreated 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).
   • There is no evidence of interim progression between completion of CNS directed therapy (if administered) 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.

8. Prior use of approved or investigational anti-TIGIT therapy.
9. Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies.
10. Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and IL-2) within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior to initiation of study treatment.
11. Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE >Grade 1.

12. 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, 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:

      i. Rash must cover < 10% of body surface area; ii. Disease is well controlled at baseline and requires only low-potency topical corticosteroids; and iii. 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.

13. Active or prior documented inflammatory bowel disease requiring systemic treatment within the past 2 years (e.g., Crohn's disease, ulcerative colitis).
14. History of primary immunodeficiency.
15. History of allogeneic organ transplant.
16. History of hypersensitivity to mAb to PD1/PD-L1 or any excipient.

17. Uncontrolled intercurrent illness including, but not limited to:

    • Ongoing or active infection
    • Symptomatic congestive heart failure
    • Uncontrolled hypertension
    • Unstable angina pectoris
    • Cardiac arrhythmia
    • Active peptic ulcer disease or gastritis
    • Active bleeding diatheses
    • 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 enrolment. 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 enrolment.

    • Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently) Patients with indwelling catheters (e.g., PleurX®) are allowed.
    • Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12 mg/dL, or corrected calcium greater than ULN)
    • Psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent.
18. Active tuberculosis.
19. Positive EBV viral capsid antigen (VCA) IgM test during screening. An EBV polymerase chain reaction (PCR) test should be performed as clinically indicated to screen for acute infection or suspected chronic active infection. Patients with a positive EBV PCR test are excluded.
20. History of leptomeningeal carcinomatosis.
21. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins; known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation
22. History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan.
23. Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving tiragolumab and atezolizumab.
24. Pregnant or breastfeeding.
25. No contraindication to study treatments as judged by the patient's responsible clinician.