THE PATIENT 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 until the last administration of atezolizumab:
- - Agree to take measures not to father children by using a barrier method of
contraception (condom plus spermicide) 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.
- - 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.
All male patients must refrain from donating sperm for the same period.
D. Patients must be able and willing to undergo a fresh tissue biopsy.
E. ADULT PATIENTS (≥18 years): 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/min.F. PAEDIATRIC PATIENTS (<18 years): 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.
Hb: ≥80 g/L (transfusion allowed)
Lymphocyte Count: ≥0.5 × 10^9/L.ANC: ≥1.0 × 10^9/L (no GCSF support in preceding 72 hours)
Platelet count: ≥75 × 10^9/L (unsupported for 72 hours)
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)
ALT and AST: ≤2.5 × ULN for age or ≤5 × ULN if raised due to metastases.
Coagulation
- - PT (or INR) and 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.eGFR: >60 mL/min (uncorrected value)
G. 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 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 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 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.
