DETERMINE Trial Treatment Arm 03: Entrectinib in Adult, Teenage/Young Adults and Paediatric Patients With ROS1 Gene Fusion-positive Cancers.

Study Overview
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Brief Summary
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This clinical trial is looking at a drug called entrectinib. Entrectinib is approved as standard of care treatment for adult patients with non-small cell lung cancer (NSCLC) which have a particular molecular alteration called ROS1-positive, and patients 12 years of age or older with solid tumours which have another type of change in the cancer cells. This means it has gone through clinical trials and been approved by the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK. Investigators now wish to find out if it will be useful in treating patients with other cancer types which have the same molecular alteration (ROS1-positive). 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.

Detailed Description
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DETERMINE Treatment Arm 03 (entrectinib) aims to evaluate the efficacy of entrectinib in ROS1 gene fusion-positive rare* adult, paediatric and teenage/young adult (TYA) cancers and in common cancers where a ROS1 mutation or amplification is considered to be infrequent. *Rare is defined generally as incidence less than 6 cases in 100,000 patients (includes paediatric and teenagers/young adult cancers) or common cancers with rare alterations. This treatment arm has a target sample size of 30 evaluable patients. Sub-cohorts may be defined and further expanded where promising activity is identified to a target of 30 evaluable patients each. The ultimate aim is to translate positive clinical findings to the NHS (Cancer Drugs Fund) to provide new treatment options for rare adult, paediatric and TYA cancers. OUTLINE: Pre-screening: The Molecular Tumour Board makes a treatment recommendation for the participant based on molecularly-defined cohorts. Screening: Consenting participants undergo biopsy and collection of blood samples for research purposes. Treatment: Participants will receive entrectinib until disease progression, unacceptable toxicity or withdrawal of consent. Participants will also undergo collection of blood samples at various intervals while receiving treatment and at the end of trial visit (EoT). After completion of study treatment, patients are followed up every 3 months for 2 years THE DETERMINE TRIAL MASTER (SCREENING) PROTOCOL: Please see DETERMINE Trial Master (Screening) Protocol record (NCT05722886) for information on the DETERMINE Trial Master Protocol and applicable documents.

Official Title
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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 03: Entrectinib in Adult, Teenage/Young Adults and Paediatric Patients With ROS1 Gene Fusion-positive Cancers.

Conditions
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Solid Tumor, Haematological Malignancy, Malignancy, Malignant Neoplasm, Neoplasms by Histologic Type, Neoplasms by Site, Cancer, Brain Neoplasms, Melanoma, Glioma, Lymphoproliferative Disorders

Intervention / Treatment
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* Drug: Entrectinib


Participation Criteria
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Eligibility Criteria
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THE PARTICIPANT MUST FULFIL THE ELIGIBILITY CRITERIA WITHIN THE DETERMINE MASTER PROTOCOL (NCT05722886) AND WITHIN THE TREATMENT ARM 03 (ENTRECTINIB) OUTLINED BELOW* *When entrectinib-specific inclusion/exclusion criteria or precautions below differ from those specified in the Master Protocol, the entrectinib-specific criteria will take precedence. Inclusion Criteria: A. Confirmed diagnosis of a ROS1 gene fusion-positive malignancy, other than NSCLC, that has been identified using an analytically validated sequencing technique. B. Patients must be able and willing to undergo a fresh biopsy. C. Patients with a BSA of 0.43m^2 and over. D. 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) 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 (unsupported for 72 hours) Bilirubin: <2.5 x upper limit of normal (ULN). Patients with known Gilbert's syndrome who have a serum bilirubin: ≤3 x ULN may be enrolled. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST): ≤2.5 x ULN or ≤5 x ULN if raised due to metastases. estimated glomerular filtration rate (eGFR): eGFR: ≥30 mL/min (uncorrected value) Coagulation - prothrombin (PT) (or international normalized ratio [INR]), and activated partial thromboplastin clotting time (aPTT): ≤1.5 x limit of normal (unless patient is on anticoagulants e.g. warfarin [INR should be stable and within indicated therapeutic range], or direct oral anticoagulants [DOAC]. E. 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) 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 x ULN for age ALT and AST: ≤2.5 x ULN for age or < 5xULN if raised due to metastases. estimated glomerular filtration rate (eGFR): eGFR >70 ml/min/1.73m^2 International Normalised Ratio (INR) or Prothrombin Time (PT) and activated Partial Thromboplastin Time (aPTT): ≤1.5 x ULN for age (unless patient is on anticoagulants e.g. warfarin [INR should be stable and within indicated therapeutic range], or DOAC). F. Women of childbearing potential are eligible provided that they meet the following criteria: - Have a negative serum or urine pregnancy test before enrolment and either: • Agree to use one form of highly effective birth control method such as: I. Oral, intravaginal or transdermal combined (oestrogen and progestogen containing) hormonal contraception II. Oral, injectable or implantable progestogen-only hormonal contraception associated with inhibition of ovulation III. Intrauterine device (IUD) IV. Intrauterine hormone-releasing system (IUS) V. Bilateral tubal occlusion VI. Vasectomised partner Plus a barrier method: male or female condom with or without spermicide; cap, diaphragm or sponge with spermicide. • Sexual abstinence; Effective from the first administration of entrectinib, throughout the trial and for five weeks after the last administration of entrectinib. G. Male patients with partners who are women of childbearing potential are eligible provided that they agree to the following, from the first administration of entrectinib, throughout the trial and for three months after the last administration of entrectinib: Agree to take measures not to father children by using a barrier method of contraception (condom plus spermicide) or to sexual abstinence. Non-vasectomised male patients with partners who are women of childbearing potential must also be willing to ensure that their partner uses a highly effective method of contraception as in F above. Male patients with pregnant or lactating partners must be advised to use barrier method contraception (for example, condom plus spermicidal gel) to prevent drug exposure of the foetus or neonate. Exclusion Criteria: A. Female patients who are pregnant, breastfeeding or planning to become pregnant during the trial or within five weeks following their last dose of entrectinib. B. Diagnosis of ROS1 fusion-positive Non-Small Cell Lung Cancer (NSCLC). C. Prior treatment with the same class of drug unless genetic profile demonstrates a mechanism of resistance known to be potentially sensitive to entrectinib. D. Patients with significant cardiovascular disease are excluded as defined by: i. Current congestive heart failure requiring therapy (New York Heart Association III or IV) or known left ventricular ejection fraction (LVEF) <50% (moderate to severe) ii. History of unstable angina pectoris or myocardial infarction (MI) up to three months prior to trial entry, or current poorly controlled angina (symptoms weekly or more) iii. Presence of symptomatic or severe valvular heart disease (severe by local echo graphic criteria or American Heart Association/American Cardiac College Stage C or D) iv. History of a clinically significant cardiac arrhythmia up to three months prior to trial entry (asymptomatic atrial fibrillation or asymptomatic first-degree heart block are permitted. v. History of stroke (ischaemic or haemorrhagic) within the last three months. E. Patients with a baseline QTcF (Corrected QT interval by Fridericia formula) interval longer than 450 millisecond (ms) for male patients and 470 ms for female patients, patients with congenital long QTcF syndrome, and patients taking medicinal products that are known to prolong the QTc interval. F. History of additional risk factors for Torsades de Pointes (e.g., family history of long QT syndrome). G. Grade ≥2 peripheral neuropathy. H. Known active infections that would interfere with the assessment of safety or efficacy of entrectinib (bacterial, fungal, or viral, including HIV positive). I. Known hypersensitivity to entrectinib or any of the excipients. J. Patient unable to swallow entrectinib intact, without chewing, crushing or opening the capsules (as per the dosing schedule and suitable dosing strengths available). Any active gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, or short gut syndrome) or other malabsorption syndromes that would reasonably affect drug absorption. K. 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 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. L. Patients with personal history of significant osteopenia (screening for osteopenia not required). M. Any clinically significant concomitant disease or condition (or its treatment) that could interfere with the conduct of the trial or absorption of oral medications that would, in the opinion of the Investigator, pose an unacceptable risk to the patient in this trial.
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Arm 03<br>This entrectinib treatment arm is for adult, teenage/young adult (TYA) and paediatric participants with ROS1 gene fusion-positive malignancies. | Drug: Entrectinib<br>* Adult and paediatric participants with body surface area (BSA) ≥1.51 m^2 will receive entrectinib orally at a dose of 600 mg daily dose (three 200 mg capsules per day). Paediatric participants with BSA <1.51 m^2 will receive entrectinib at a dose of 100 mg (BSA=0.43-0.50 m^2) or 200 mg (BSA=0.51-0.80m^2) or 300 mg (BSA=0.81-1.10 m^2) or 400 mg (BSA=1.11-1.50 m^2). Each cycle of treatment will consist of 28 days and participants may continue until disease progression, unacceptable toxicity or withdrawal of consent.<br>* Other names: Rozlytrek;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 entrectinib (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 entrectinib for up to 2 years. | 
| 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 28 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. | 
| 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 entrectinib to discontinuation of trial treatment up to 5 years. | 
| 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 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 entrectinib for a period of up to 2 years. | 
| 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 entrectinib for a period of up to 2 years. | 
| 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 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 entrectinib for a period of up to 2 years. | 
| 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. | 
| 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 entrectinib. | From the time of consent until 28 days after last dose of entrectinib (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. | 
| Occurrence of at least one Grade 3, 4 or 5 entrectinib related AE | Number of patients who experience at least one entrectinib related Grade 3, 4 or 5 AE according to NCI CTCAE Version 5.0. | From the time of consent until 28 days after last dose of entrectinib (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. | 
| 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). | 
| 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 28 days) and at EoT visit (up to 5 years). | 
| 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 28 days) and at EoT visit (up to 5 years). | 
| 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 28 days) and at EoT visit (up to 5 years). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neoplasms by Histologic Site, Rare, Adult, Antineoplastic Agents, Cancer, Child, Entrectinib, Malignancy, Malignant Neoplasms, Molecular Targeted Therapy, Mutation, Neoplasms by Site, Oncogene, Paediatric, Protein Kinase Inhibitors, ROS1 Protein, human, Tumour-agnostic, Young adult