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

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.

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.

Eligibility Criteria:
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.