DETERMINE Trial Treatment Arm 02: Atezolizumab in Adult, Paediatric and Teenage/Young Adult Patients With Cancers With High Tumour Mutational Burden (TMB) or Microsatellite Instability-high (MSI-high) or Proven Constitutional Mismatch Repair Deficiency (CMMRD) Disposition

Exclusion Criteria

• •A. Diagnosis of urothelial cancer, non-small cell lung cancer, extensive-stage small cell lung cancer, hepatocellular carcinoma or triple negative breast cancer.
• •B. Patients with rapidly progressing or symptomatically deteriorating brain metastases and/or leptomeningeal disease. Patients with previously treated brain metastases are eligible, provided the patient has not experienced a seizure or had a clinically significant change in neurological status within 14 days (for adult patients) or 7 days (for paediatric patients) prior to the start of IMP administration. Such patients must be non-dependent on steroids or on a stable or reducing dose of steroid treatment for at least 14 days (or 7 days for paediatric patients) prior to the start of IMP administration. Primary brain or central nervous system (CNS) malignancies are allowed providing the patient is clinically stable (if requiring corticosteroids must be at stable or decreasing doses for at least 14 days for adults and 7 days for paediatric patients prior to the start of IMP administration). Patients who have received brain irradiation must have completed whole-brain radiotherapy and/or stereotactic radiosurgery at least 14 days prior to the start of IMP administration.
• •Paediatric patients with either primary brain tumours or extracranial solid tumours with intracranial metastases with one or more intracranial lesions should only be considered for inclusion if largest intracranial lesion is ≤6 cm in longest axis. Consideration should also be given to the intracranial location of the tumour and potential risk should swelling occur. This is because of the class risk of immune checkpoint inhibitors such as atezolizumab causing immune-mediated inflammatory response and 'tumour flare' which may result in acute neurological deterioration.
• •C. Female patients who are pregnant, breastfeeding or planning to become pregnant during the trial or within five months following their last dose of atezolizumab.
• •D. History or clinical evidence of current inflammatory lung disease:
• •History of idiopathic pulmonary fibrosis, organising pneumonia (e.g. bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis.
• •Evidence of active pneumonitis on screening chest computed tomography (CT) scan.
• •E. Active autoimmune disease that requires the use of systemic immunomodulatory therapy (i.e. with disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy for hypothyroidism and adrenal or pituitary insufficiency is acceptable.
• •F. Ongoing lung pathologies which, in the opinion of the Investigator present a compromise to safety (e.g. active tuberculosis).
• •G. Systemic immunomodulatory agents within 14 days prior to trial entry (immunostimulatory agents within four weeks). Exceptions to this are:
• •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 trial.
• •Patients who received corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma equivalent to ≤10 mg prednisolone a day or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the trial.
• •Patients with primary CNS disease can be receiving concurrent treatment with corticosteroids. Patients must be receiving a stable or decreasing dose for ≥14 days for adults and ≥7 days for paediatric patients prior to the screening magnetic resonance imaging (MRI) scan and at the time of drug initiation.
• •Patients who receive physiological doses of steroid replacement (e.g. hydrocortisone) are permitted.
• •H. Known to be serologically positive (as detected by polymerase chain reaction) for hepatitis B, hepatitis C or human immunodeficiency virus (HIV).
• •I. History of severe allergic anaphylactic reactions to chimeric, human or humanised antibodies, or fusion proteins including other immune checkpoint inhibitors.
• •J. Known hypersensitivity to Chinese hamster ovary cell products.
• •K. Known hypersensitivity to atezolizumab or any of the excipients.
• •L. Patients who were administered a live, attenuated vaccine within 28 days prior to enrolment, or anticipation of need for such a vaccine during atezolizumab treatment or within six months after the final dose of atezolizumab.
• •M. Patients with clinically significant pre-existing cardiac conditions, including uncontrolled or symptomatic angina, uncontrolled atrial or ventricular arrhythmias, or NYHA class III or IV congestive heart failure.
• •Patients with a cerebrovascular event (including stroke or transient ischaemic attacks \[TIA\]) or cardiovascular event (including acute myocardial infarction \[MI\]) within three months before the first dose of atezolizumab.
• •Patients with primary CNS tumours may be considered unless intra-tumoural bleeding has occurred within 2 weeks of the first dose of atezolizumab, and patients with punctate CNS haemorrhages \<3 mm may be considered.
• •Patients with a prior history of pericardial disorders, including pericarditis, pericardial effusion and cardiac tamponade.
• •N. Prior allogeneic stem cell or solid organ transplantation on immunosuppression.
• •O. Prior treatment with the same class of drug unless genetic profile demonstrates a mechanism of resistance known to be potentially sensitive to atezolizumab.
• •P. Uncontrolled diabetes.
• •Q. Any clinically significant concomitant disease or condition (or its treatment) that could interfere with the conduct of the trial or absorption of oral medications or that would, in the opinion of the Investigator, pose an unacceptable risk to the patient in this trial.
• •R. Severe infection within four weeks prior to the first IMP administration or the administration of antibiotics within two weeks prior to the first IMP administration, with the exemption of patients requiring prophylaxis.