Cancer Clinical Trial
— DETERMINEOfficial title:
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, Teenage/Young Adults and Paediatric 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 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.
| Status | Recruiting |
| Enrollment | 30 |
| Est. completion date | October 2029 |
| Est. primary completion date | October 2029 |
| Accepts healthy volunteers | No |
| Gender | All |
| Age group | N/A and older |
| 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. |
| Country | Name | City | State |
|---|---|---|---|
| United Kingdom | Belfast City Hospital | Belfast | |
| United Kingdom | Birmingham Children's Hospital | Birmingham | |
| United Kingdom | University Hospital Birmingham | Birmingham | |
| United Kingdom | Bristol Haematology and Oncology Centre | Bristol | |
| United Kingdom | Bristol Royal Hospital for Children | Bristol | |
| United Kingdom | Addenbrooke's Hospital | Cambridge | |
| United Kingdom | Velindre Cancer Centre | Cardiff | |
| United Kingdom | Western General Hospital | Edinburgh | |
| United Kingdom | Royal Hospital for Children Glasgow | Glasgow | |
| United Kingdom | The Beatson Hospital | Glasgow | |
| United Kingdom | Leeds General Infirmary | Leeds | |
| United Kingdom | Leicester Royal Infirmary | Leicester | |
| United Kingdom | Alder Hey Hospital | Liverpool | |
| United Kingdom | Great Ormond Street Hospital | London | |
| United Kingdom | Guy's Hospital | London | |
| United Kingdom | University College London Hospital | London | |
| United Kingdom | The Royal Marsden Hospital | London Borough of Sutton | |
| United Kingdom | Royal Manchester Children's Hospital | Manchester | |
| United Kingdom | The Christie Hospital | Manchester | |
| United Kingdom | Freeman Hospital | Newcastle | |
| United Kingdom | Great North Children's Hospital | Newcastle | |
| United Kingdom | Churchill Hospital | Oxford | |
| United Kingdom | John Radcliffe Hospital | Oxford | |
| United Kingdom | Weston Park Hospital | Sheffield | |
| United Kingdom | Southampton General Hospital | Southampton | |
| United Kingdom | Clatterbridge Cancer Centre | Wirral |
| Lead Sponsor | Collaborator |
|---|---|
| Cancer Research UK | Hoffmann-La Roche, Royal Marsden NHS Foundation Trust, University of Birmingham, University of Manchester |
United Kingdom,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | Objective Response (OR) | An OR is defined as the confirmed occurrence of either a Complete Response (CR) or Partial Response (PR) according to Response Evaluation Criteria in Solid Tumours (RECIST) Version 1.1 criteria (or immune related (ir)-RECIST or standard imaging criteria for specific disease e.g. Response Evaluation in Neuro Oncology criteria (RANO)). In patients with leukaemia, OR will be defined as the occurrence of CR , CRi (CR incomplete neutrophil recovery) or CRp (CR with incomplete platelet recovery). The trial will report the proportion of patients with an OR and 95% credible interval. | Disease assessments to be performed up to 24 weeks from the start of trial treatment. | |
| Primary | Durable Clinical Benefit (DCB) | DCB is defined as the absence of disease progression for at least 24 weeks from the start of trial treatment according to RECIST Version 1.1 criteria (or ir-RECIST or standard imaging criteria for specific disease e.g. RANO criteria). Alternative definitions of DCB based on different time points may be pre-specified for particular sub-cohorts if 24 weeks is not clinically relevant. The trial will report the proportion of patients with a DCB and 95% credible interval. | Disease assessments to be performed up to 24 weeks from the start of trial treatment. | |
| Secondary | Duration of response (DR) | Duration of response, is defined as the time from the date of the first confirmed CR or PR according to RECIST 1.1 or ir-RECIST or standard imaging criteria for specific disease e.g. RANO criteria to the date of disease progression. The trial will report the median DR and 95% credible interval. | Disease assessment every 2 cycles of atezolizumab (each cycle is 28 days) and at EoT. After 24 weeks, it can be done every 3 cycles, on discussion with Sponsor. Follow-up visits are every 12 weeks after last dose of atezolizumab for up to 2 years. | |
| Secondary | Best percentage change in sum of target lesion / index lesion diameters (PCSD) | PCSD is defined as the greatest decrease or least increase in the sum of target lesion diameters (RECIST) or index lesion diameters (irRECIST) as a percentage compared to the baseline measurement. The trial will report the mean PCSD and 95% credible interval. | Disease assessment performed every 2 cycles (each cycle is 21 days). After 24 weeks, disease assessments can be repeated every 3 cycles, on discussion with Sponsor. Follow-up visits are every 12 weeks following last dose for a period of up to 2 years. | |
| Secondary | Time to treatment discontinuation (TTD) | TTD is defined as the time from date of starting trial treatment to date of discontinuing trial treatment, in days estimated by the median of the posterior inverse gamma probability distribution. The trial will report the median TTD and 95% credible interval. | From first dose of atezolizumab to discontinuation of trial treatment up to 5 years. | |
| Secondary | Progression-Free Survival time (PFS) | PFS is defined as the time from date of starting trial treatment to date of progression or date of death without a previous progression recorded estimated by the median of the posterior inverse gamma probability distribution. | Disease assessment performed every 2 cycles (each cycle is 21 days). After 24 weeks, it can be done every 3 cycles, on discussion with Sponsor. Follow-up visits take place every 12 weeks following last dose of atezolizumab for a period of up to 2 years. | |
| Secondary | Time to Progression (TTP) | TTP is defined as the time from date of starting trial treatment to date of progression or date of death without recorded progression censored rather than events. The trial will report the median TTP and 95% credible interval. | Disease assessment performed every 2 cycles (each cycle is 28 days). After 24 weeks, it can be done every 3 cycles, on discussion with Sponsor. Follow-up visits take place every 12 weeks following last dose of atezolizumab for a period of up to 2 years. | |
| Secondary | Growth Modulation Index (GMI) | GMI is defined as the ratio of TTP with the trial protocol treatment to TTP on the most recent prior line of therapy. The trial will report the mean GMI and 95% credible interval. | Disease assessment performed every 2 cycles (each cycle is 21 days). After 24 weeks, it can be done every 3 cycles, on discussion with Sponsor. Follow-up visits take place every 12 weeks following last dose of atezolizumab for a period of up to 2 years. | |
| Secondary | Overall Survival time (OS) | OS is defined as the time from date of starting trial treatment to date of death from any cause estimated by the median of the posterior normal probability distribution. | Time of death or up to 2 years after the End of Treatment (EoT) visit. | |
| Secondary | Occurrence of at least one Suspected Unexpected Serious Adverse Event (SUSAR) | The trial will report the number of patients who experience at least one SUSAR to atezolizumab. | From the time of consent until 90 days after last dose of atezolizumab (up to 5 years) or until patient starts another anti-cancer therapy, whichever came first. An average time frame will be presented with results entry. | |
| Secondary | Occurrence of at least one Grade 3, 4 or 5 atezolizumab related AE | Number of patients who experience at least one atezolizumab related Grade 3, 4 or 5 AE according to NCI CTCAE Version 5.0. | From the time of consent until 90 days after last dose of atezolizumab (up to 5 years) or until patient starts another anti-cancer therapy, whichever came first. An average time frame will be presented with results entry. | |
| Secondary | EORTC-QLQ-30 Standardised Area Under Summary Score Curve (QLQSAUC) in adult participants | For adult populations, multiple measures of QoL will be generated from patient completion of the European Organisation for Research and Treatment of Cancer QLQC30 (EORTC-QLQC30) questionnaire (30 measures). For each patient the Summary Score from the questionnaire will be generated at each time point and the area under the curve generated by these scores over time will be calculated and standardised by the time frame. The trial will report the mean QLQSAUC and 95% credible interval. | QoL surveys performed at baseline every 2 cycles (every cycle is 28 days) and after interrupting treatment (up to 5 years). | |
| Secondary | EQ-5D Standardised Area Under Index Value Curve (EQ5DSAUC) in adult participants | For adult populations, two measures of QoL will be generated from patient completion of the EQ-5D-5L questionnaire. For each measure, scores based on responses from the questionnaire will be generated at each time point and the area under the curve generated by these scores over time will be calculated and standardised by the time frame. The trial will report the mean EQ5DSAUC and 95% credible interval. | QoL surveys performed prior to inclusion, every 2 cycles (each cycle is 21 days) and at EoT visit (up to 5 years). | |
| Secondary | Mean change from baseline in the PedsQL 4.0 Standardised Area Under total Scale Score Curve (PedsSAUC) in paediatric participants. | For paediatric populations multiple measures of QoL will be generated from patient completion of the PedsQL 4.0 (4 measures). The Summary Score from the questionnaire will be generated at each time point and the area under the curve generated by these scores over time will be calculated and standardised by the time frame. The trial will report the mean PedsSAUC and 95% credible interval. | QoL surveys performed prior to inclusion, every 2 cycles (each cycle is 21 days) and at EoT visit (up to 5 years). | |
| Secondary | Mean change from baseline in the PedsQL 4.0 Standardised Area Under total Scale Score Curve (PedsSAUC) in parents from paediatric participants. | For paediatric populations multiple measures of QoL will be generated from patient's parent completion of the PedsQL 4.0 (4 measures). The Summary Score from the questionnaire will be generated at each time point and the area under the curve generated by these scores over time will be calculated and standardised by the time frame. The trial will report the mean PedsSAUC and 95% credible interval. | QoL surveys performed prior to inclusion, every 2 cycles (each cycle is 21 days) and at EoT visit (up to 5 years). |
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