DETERMINE (Determining Extended Therapeutic Indications for Existing Drugs in Rare Molecularly Defined Indications Using a National Evaluation Platform Trial): An Umbrella-Basket Platform Trial to Evaluate the Efficacy of Targeted Therapies in Rare Adult, Paediatric and Teenage/Young Adult (TYA) Cancers With Actionable Genomic Alterations, Including Common Cancers With Rare Actionable Alterations. Treatment Arm 02: Atezolizumab in Adult, Paediatric and Teenage/Young Adult Patients With Cancers With High TMB or MSI-high or Proven CMMRD Disposition.
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 small cell lung cancer, hepatocellular carcinoma and triple negative breast 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.
⁃ 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