Overview

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.

Eligibility

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.