Overview

This phase II study will explore the effect of 2 monoclonal antibodies, tiragolumab and atezolizumab, in patients with locally advanced solid cancers which cannot be removed by surgery or have spread. Their cancers will have characteristics which may predict immune response to the study treatment. PD-L1 and TIGIT are immune receptors which can help cancers grow by evading the immune response and inhibiting the action of some immune cells. By blocking these receptors, tiragolumab and atezolizumab may work together to re-activate the body's anti-tumour immune response and kill cancer cells.

Eligibility

Inclusion Criteria:

1. Provision of written informed consent.
2. Aged ≥18 years old.
3. Histologically or cytologically confirmed locally advanced unresectable or metastatic solid tumour.
4. Exhausted all available standard therapy or not suitable for standard therapy (including targeted therapies) for the tumour.
5. ECOG performance status score of 0-1.
6. Sufficient and accessible tumour tissue for panel sequencing, PD-L1 and TIL testing, and tertiary objectives.
7. Tumour biomarker criteria predictive of immune response defined by presence of one or more of the following;
   • tumour mutation burden ≥ 10 mutations per megabase.
   • tumour PD-L1 expression TAP score ≥ 5%
   • PD-L1 amplification >6 copy number alterations
   • tumour infiltrating lymphocytes (TILs) (CD3+CD8+) ≥ 5%.
8. Patient is willing to provide tumour biopsy samples on treatment at Week 4.
9. Life expectancy >12 weeks.
10. Measurable disease as defined by iRECIST or RANO criteria.
11. Adequate haematological and biochemical indices as defined by:
    • Absolute neutrophil count ≥1.0 x 10^9/L
    • Haemoglobin ≥100 g/L
    • Platelet count ≥100 x 10^9/L
    • Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of haemolysis or hepatic pathology), who will be allowed only in consultation with their physician.
    • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5x ULN; or ≤5.0x ULN if liver metastases are present.
    • International normalised ratio (INR) <1.3 in the absence of anticoagulation therapy.
    • Serum creatinine clearance >40 mL/min by the Cockcroft-Gault formula or by 24-hour urine collection for determination of creatinine clearance.
12. Negative HIV test at screening, with the following exception: patients with a positive

    HIV test at screening are eligible provided they are stable on antiretroviral therapy, have a CD4 count ≥ 200cells/mm3 , and have an undetectable viral load.

13. Negative hepatitis B surface antigen (HBsAg) test at screening.
14. Positive hepatitis B surface antibody (HBsAb) test at screening, or negative HBsAb at screening accompanied by either of the following:
    • Negative total hepatitis B core antibody (HBcAb);
    • Positive total HBcAb test followed by quantitative hepatitis B virus (HBV) DNA < 500 IU/mL.

             The HBV DNA test must be performed for patients who have a negative HBsAg test, a
             negative HBsAb test, and a positive total HBcAb test.
         15. Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody
             test followed by a negative HCV RNA test at screening. The HCV RNA test must be
             performed for patients who have a positive HCV antibody test.
         16. Women of childbearing potential must have a negative screening serum pregnancy test
             within 14 days prior to the first dose of study medication.
         17. Women of childbearing potential and men must remain abstinent or use contraceptive
             methods with a failure rate of <1% per year during the study and for at least 5 months
             after the last dose of study medication.
         18. Ability to adhere to the study visit schedule and understand and comply with all
             protocol requirements and instructions from study staff.
        Exclusion Criteria:
          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.