Overview

This clinical trial is looking at a drug called atezolizumab. Atezolizumab is approved as standard of care treatment for adult patients with urothelial cancer, non-small cell lung cancer, extensive-stage breast small cell lung cancer, hepatocellular carcinoma and triple negative cancer. This means it has gone through clinical trials and been approved by the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK.

Atezolizumab works in patients with these types of cancers which have certain changes in the cancer cells called high tumour mutational burden (TMB) or high microsatellite instability (MSI) or proven (previously diagnosed) constitutional mismatch repair deficiency (CMMRD).

Investigators now wish to find out if it will be useful in treating patients with other cancer types which are also TMB/MSH-high or show CMMRD. If the results are positive, the study team will work with the NHS and the Cancer Drugs Fund to see if these drugs can be routinely accessed for patients in the future.

This trial is part of a trial programme called DETERMINE. The programme will also look at other anti-cancer drugs in the same way, through matching the drug to rare cancer types or ones with specific mutations.

Eligibility

THE PARTICIPANT MUST FULFIL THE ELIGIBILITY CRITERIA WITHIN THE DETERMINE MASTER PROTOCOL

(NCT05722886) AND WITHIN THE TREATMENT ARM 02 (ATEZOLIZUMAB) OUTLINED BELOW*

        *When atezolizumab-specific inclusion/exclusion criteria or precautions below differ from
        those specified in the Master Protocol, the atezolizumab-specific criteria will take
        precedence.
        Inclusion Criteria:
        A. Confirmed diagnosis of a malignancy that is high TMB (defined as ≥10 mut/Mb), MSI-high
        or of proven (previously diagnosed) CMMRD disposition using an analytically validated
        method.
        B. Women of childbearing potential are eligible provide they meet the following criteria:
          -  Have a negative serum or urine pregnancy test before enrolment and;
          -  Agree to use one form of effective birth control method such as:
        I. combined (oestrogen and progestogen containing) hormonal contraception associated with
        inhibition of ovulation [oral, intravaginal or transdermal]);
        II. progestogen-only hormonal contraception associated with or without inhibition of
        ovulation (oral, injectable or implantable);
        III. intrauterine device (IUD),
        IV. intrauterine hormone-releasing system (IUS),
        V. bilateral tubal occlusion,
        VI. vasectomised partner,
        VII. sexual abstinence,
        VIII. male or female condom with or without spermicide;
        IX. cap, diaphragm or sponge with spermicide.
        Effective from the first administration of atezolizumab, throughout the trial and for five
        months after the last administration of atezolizumab.
        C. Male patients with partners who are women of childbearing potential are eligible
        provided that they agree to the following, from the first administration of atezolizumab,
        throughout the trial and for five months after the last administration of atezolizumab:
          -  Agree to take measures not to father children by using a barrier method of
             contraception or sexual abstinence.
          -  Non-vasectomised male patients with partners who are women of childbearing potential
             must also be willing to ensure that their partner uses an effective method of
             contraception as in B.
          -  Male patients with pregnant or lactating partners must be advised to use barrier
             method contraception (e.g. condom) to prevent drug exposure of the foetus or neonate.
        D. Patients must be able and willing to undergo a fresh biopsy.
        E. ADULT PATIENTS: Adequate organ function as per haematological and biochemical indices
        within the ranges shown below. These measurements should be performed to confirm the
        patient's eligibility.
        Haemoglobin (Hb): ≥90 g/L (transfusion allowed)
        Lymphocyte count: ≥0.5×10^9/L
        Absolute neutrophil count (ANC): ≥1.5×10^9/L (no granulocyte colony-stimulating factor
        [GCSF] support in preceding 72 hours)
        Platelet count: ≥100×10^9/L
        Bilirubin: <1.5 × upper limit of normal (ULN). Patients with known Gilbert disease: total
        bilirubin ≤3 × ULN
        Serum albumin: ≥25 g/L (2.5 g/dL)
        Alanine aminotransferase (ALT) and aspartate aminotransferase (AST): ≤2.5 × ULN or ≤5 × ULN
        if raised due to metastases
        Coagulation - prothrombin (PT) (or international normalized ratio [INR]) and activated
        partial thromboplastin clotting time (aPTT): ≤1.5 × ULN (unless patient is on
        anticoagulants, e.g. warfarin [INR should be stable and within indicated therapeutic range]
        or direct oral anticoagulants [DOAC]).
        Amylase: ≤1.5 × ULN
        Estimated glomerular filtration rate (eGFR): ≥30 mL/mi
        F. Patients must have stable thyroid function tests. Patients on stable doses of thyroxine
        replacement are permitted
        G. PAEDIATRIC PATIENTS (there is no lower age limit for paediatric patients): Adequate
        organ function as per haematological and biochemical indices within the ranges shown below.
        These measurements should be performed to confirm the patient's eligibility.
        Haemoglobin (Hb): ≥80 g/L (transfusion allowed)
        Lymphocyte Count: ≥0.5×10^9/L
        Absolute neutrophil count (ANC): ≥1.0×10^9/L (no GCSF support in preceding 72 hours)
        Platelet count: ≥75×10^9/L (unsupported for 72 hrs)
        Bilirubin: ≤1.5 × ULN for age with the following exception: Patients with known Gilbert
        disease: total bilirubin ≤3 × ULN.
        Serum albumin: ≥25 g/L (2.5 g/dL)
        Alanine aminotransferase (ALT) and aspartate aminotransferase (AST): ≤2.5 × ULN for age or
        ≤5 × ULN if raised due to metastases.
        Coagulation - prothrombin (PT) (or international normalized ratio [INR]) and activated
        partial thromboplastin clotting time (aPTT): ≤1.5 × ULN (unless patient is on
        anticoagulants, e.g. warfarin [INR should be stable and within indicated therapeutic
        range], or DOAC).
        Amylase: ≤1.5 × ULN.
        Estimated glomerular filtration rate (eGFR): >60 mL/min (uncorrected value)
        H. Patients must have stable thyroid function tests. Patients on stable doses of thyroxine
        replacement are permitted
        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.
        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 the 14 days 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 five 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.
        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.