DETERMINE Trial Treatment Arm 01: Alectinib in Adult, Teenage/Young Adults (TYA) and Paediatric Patients With ALK Positive Cancers

Study Overview
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Brief Summary
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This clinical trial is looking at a drug called alectinib. Alectinib is approved as standard of care treatment for adult patients with certain types of lung cancer. This means it has gone through clinical trials and been approved by the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK. Alectinib works in lung cancer patients with a particular mutation in their cancer known as ALK. Investigators now wish to find out if it will be useful in treating patients with other cancer types which have the same mutation. 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 01 (alectinib) aims to evaluate the efficacy of alectinib in ALK-positive rare* adult, paediatric and teenage/young adult (TYA) cancers and in common cancers where an ALK 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 (See information on Master Screening Protocol below). Screening: Consenting participants undergo biopsy and collection of blood samples for research purposes. Treatment: Participants will receive alectinib 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 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 01: Alectinib in Adult, Teenage/Young Adults (TYA) and Paediatric Patients With ALK Positive Cancers

Conditions
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Malignant Neoplasm, Solid Tumor, Haematological Malignancy, Lymphoproliferative Disorders, Neoplasms by Histologic Type, Neoplasms by Site, Cancer, Anaplastic Large Cell Lymphoma, Lymphoma, Renal Cell Carcinoma, Neuroblastoma

Intervention / Treatment
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* Drug: Alectinib


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 01 (ALECTINIB) OUTLINED BELOW* *When alectinib-specific inclusion/exclusion criteria or precautions below differ from those specified in the Master Protocol, the Alectinib-specific criteria will take precedence. Inclusion Criteria: A. Confirmed diagnosis of an ALK-positive malignancy using an analytically validated method. B. Women of childbearing potential are eligible, provided that they meet the following criteria: Have a negative serum or urine pregnancy test before enrolment and; Agree to use one form of highly 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 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 Effective from the first administration of alectinib, throughout the trial and for three months after the last administration of alectinib. C. Male patients with partners who are women of childbearing potential are eligible provided that they agree to the following, from first administration of alectinib, throughout the trial and for three months after the last administration of alectinib: 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 a highly effective method of contraception, as in criterion B, above. Male patients with pregnant or lactating partners must be advised to use barrier method contraception (for example, condom plus spermicide) 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) 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: <1.5 x upper limit of normal (ULN) or ≤2.5 x ULN if raised due to metastases Alanine aminotransferase (ALT) and aspartate aminotransferase (AST): ≤2.5 x 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 x lower limit of normal (LLN)/ULN (unless patient is on anticoagulants e.g. warfarin [INR should be stable and within indicated therapeutic range], or direct oral anticoagulants [DOAC]) Estimated glomerular filtration rate (eGFR): eGFR: ≥30 mL/min (uncorrected value) F. 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: ≥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 hrs) Bilirubin: ≤1.5 x ULN for age or <2.5 x ULN if raised due to metastases ALT and AST: ≤3.0 x ULN or ≤ 5 ULN if raised due to metastases Coagulation - PT or INR and aPTT: For patients not receiving therapeutic anticoagulation: INR and aPTT ≤1.5 x ULN for age. For patients receiving therapeutic anticoagulation: stable anticoagulant regimen, e.g. warfarin (INR should be stable and within indicated therapeutic range) or DOAC. eGFR: eGFR: ≥60 mL/min/1.73m^2 Exclusion Criteria: A. Diagnosis of ALK-positive non-small cell lung cancer. B. Female patients who are pregnant, breastfeeding or planning to become pregnant during the trial or for three months following their last dose of alectinib. C. 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 alectinib administration. Such patients must be nondependent on steroids or on a stable or reducing dose of steroid treatment for at least 14 days (or one week for paediatric patients) prior to the start of alectinib 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 alectinib 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 alectinib administration. D. Prior treatment with the same class of drug unless genetic profile demonstrates a mechanism of resistance known to be potentially sensitive to alectinib. E. History of or radiological evidence of interstitial lung disease and/or pneumonitis. Prior localised radiotherapy related pneumonitis is permitted if resolved and off steroids and asymptomatic for >6 months. F. Patients at risk of gastrointestinal (GI) perforation e.g. history of diverticulitis, concomitant use of medicinal product with a recognized risk of gastrointestinal perforation (unless patient has also been co-prescribed gastric protection). Patients who present with a GI primary tumour or metastases to the GI tract may be considered. G. Patient unable to swallow or tolerate oral medication or any GI disorder that may affect absorption of oral medications, such as malabsorption syndrome or following major bowel resection. Paediatric patients will be excluded if they are unable to swallow the capsules, as per the dosing schedule (150 mg dose strength). H. Patients with clinically significant pre-existing cardiac conditions, including uncontrolled or symptomatic angina, uncontrolled atrial or ventricular arrhythmias (within three months), or New York Heart Association (NYHA) class III or IV congestive heart failure. Patients with a cerebrovascular event (including stroke or transient ischaemic attack [TIA]), or cardiovascular event (including acute myocardial infarction [MI]), within three months before the first dose of alectinib. I. History of organ transplantation. J. Symptomatic bradycardia for age. K. Known hypersensitivity to alectinib or any of the excipients. L. Active hepatitis B or C virus or known human immunodeficiency virus (HIV) positivity or acquired immune deficiency syndrome related illness. M. Familial or personal history of congenital bone disorders, bone metabolism alterations or known osteopenia in the patient. N. Any clinically significant concomitant disease or condition (or it's 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 01: Alectinib<br>This alectinib treatment arm is for adult, teenage/young adult (TYA) and paediatric participants with ALK-positive cancers. | Drug: Alectinib<br>* Adult participants will be administered alectinib orally at a dose of 600 mg (four 150 mg capsules) twice daily. Paediatric participants with a body weight ≥40 kg and who are able to swallow the capsules, will be administered alectinib orally at a dose of 600 mg (four 150 mg capsules) twice daily. Each cycle of treatment will consist of 28 days and participants may continue on treatment until disease progression, unacceptable toxicity or withdrawal of consent.<br>* Other names: Alecensa;|

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 performed every 2 cycles of alectinib (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 alectinib 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 of alectinib for 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 alectinib to discontinuation of trial treatment up to 5 years with an average calculated and presented with results entry. | 
| 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 alectinib 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 alectinib 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. 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 alectinib 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 alectinib. | From the time of consent until 28 days after last dose of alectinib (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 alectinib related AE | Number of patients who experience at least one alectinib 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 alectinib (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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Adult, Alectinib, ALK Tyrosine Kinase Receptor, Antineoplastic Agents, Cancer, Child, Malignancy, Malignant Neoplasms, Molecular Targeted Therapy, Mutation, Neoplasms by Histologic Site, Neoplasms by Site, Paediatric, Precision Medicine, Protein Kinase Inhibitors, Rare, Tumour-agnostic, Young adult