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

Launched by CANCER RESEARCH UK · Mar 14, 2023

Keywords

ClinConnect Summary

The DETERMINE Trial is studying a medication called entrectinib to see if it can help treat various types of cancers that have a specific genetic change known as ROS1 gene fusion. While entrectinib is already used for treating a certain lung cancer in adults, researchers want to find out if it can also be effective for other cancers with the same genetic feature, including in teenagers, young adults, and children. If the results show that entrectinib works well, the team hopes to make it available to patients through the NHS and the Cancer Drugs Fund.

To participate in this trial, patients need to have a confirmed diagnosis of a ROS1 gene fusion-positive cancer (not including the specific lung cancer mentioned) and be able to undergo a fresh biopsy. Both adults and children will be assessed for their overall health and organ function to ensure they can safely take the medication. Participants will receive entrectinib and will be closely monitored throughout the trial. It’s important to know that there are specific eligibility criteria to ensure safety, and potential participants should discuss these with their healthcare provider to see if they qualify.

Gender

ALL

Eligibility criteria

• • THE PATIENT 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 tissue biopsy.
• • C. Patients with a BSA of 0.43m\^2 and over.
• • D. ADULT 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.
• • 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 × upper limit of normal (ULN). Patients with known Gilbert's syndrome who have a serum bilirubin: ≤3 × ULN may be enrolled.
• • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST): ≤2.5 × ULN or ≤5 × ULN if raised due to metastases.
• • estimated glomerular filtration rate (eGFR): ≥30 mL/min (uncorrected value)
• • Coagulation - prothrombin (PT) (or international normalized ratio \[INR\]), and activated partial thromboplastin clotting time (aPTT): ≤1.5 × 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 (\<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.
• • 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 × ULN for age
• • ALT and AST: ≤2.5 × ULN for age or \<5 × ULN if raised due to metastases.
• • eGFR: \>70 ml/min/1.73 m\^2
• • INR or PT and 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 associated with inhibition of ovulation.
• • 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 if using a hormonal method: male or female condom with or without spermicide; cap, diaphragm or sponge with spermicide.
• • OR
• • • 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 (e.g condom) to prevent drug exposure of the foetus or neonate.
• • All male patients must refrain from donating sperm for the same period.
• 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 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.
• • • Patients with primary CNS tumours may be considered unless intra-tumoural bleeding has occurred within 2 weeks of the first dose of entrectinib, and patients with punctate CNS haemorrhages \<3 mm may be considered.
• • E. Patients with a baseline QTcF (Corrected QT interval by Fridericia formula) interval longer than 450 milliseconds (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 (bacterial, fungal or viral) that would interfere with the assessment of safety or efficacy of entrectinib, including human immunodeficiency virus (HIV) positivity. 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/ acquired immune deficiency syndrome (AIDS)-associated opportunistic infection in the last 12 months.
• • I. Known hypersensitivity to entrectinib or any of the excipients.
• • J. Patients who were administered a live, attenuated vaccine within 28 days prior to enrolment, or anticipation of need for such a vaccine during entrectinib treatment or within six months after the final dose of entrectinib.
• • K. 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.
• • 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.