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

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.

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.

Eligibility Criteria:
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.