Alectinib treatment for ALK-positive cancers in adults and children

THE PATIENT 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 next-generation sequencing 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 (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. Note that for patients with haematological malignancies or neuroblastomas, blood, bone marrow aspiration and/or trephine or lymph node biopsy samples may be taken.

E. Paediatric patients (patients aged \<18 years) must have a body weight ≥40kg.

F. ADULT PATIENTS (≥18 years): Adequate organ function as per haematological and biochemical indices within the ranges defined in the protocol. These measurements should be performed to confirm the patient's eligibility.

G. 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.

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. Prior treatment with the same class of drug unless genetic profile demonstrates a mechanism of resistance known to be potentially sensitive to alectinib. Patients who have previously received crizotinib (Xalkori\^\[®\]) and did not respond, or who responded inadequately or responded adequately and subsequently progressed, are allowed into the trial.

D. 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.

E. Patients at risk of gastrointestinal (GI) perforation e.g. history of diverticulitis, concomitant use of medicinal product with a recognized risk of GI 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.

F. 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).

G. 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.

• Patients with primary CNS tumours may be considered unless intra-tumoural bleeding has occurred within 2 weeks of the first dose of alectinib, and patients with punctate CNS haemorrhages \<3 mm may be considered.

H. History of organ transplantation.

I. Symptomatic bradycardia for age.

J. Known hypersensitivity to alectinib or any of the excipients. See the current alectinib (Alecensa® 150 mg hard capsules) SmPC for the full list.

K. Patients who were administered a live, attenuated vaccine within 28 days prior to enrolment, or anticipation of need for such a vaccine during alectinib treatment or within six months after the final dose of alectinib.

L. Active hepatitis B or C virus or known human immunodeficiency virus (HIV) positivity or acquired immune deficiency syndrome (AIDS) related illness. Patients with history of testing positive for HIV infection are eligible provided the each of the following conditions are met:

* CD4 count ≥350/μL;
* undetectable viral load;
* receiving antiretroviral therapy (ART) that does not interact with IMP (patients should be on established ART for at least four weeks); and
* no HIV/AIDS-associated opportunistic infection in the last 12 months.

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 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.