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

Official title

DETERMINE (Determining Extended Therapeutic Indications for Existing Drugs in Rare Molecularly Defined Indications Using a National Evaluation Platform Trial): An Umbrella-Basket Platform Trial to Evaluate the Efficacy of Targeted Therapies in Rare Adult, Paediatric and Teenage/Young Adult (TYA) Cancers With Actionable Genomic Alterations, Including Common Cancers With Rare Actionable Alterations. Treatment Arm 03: Entrectinib in Adult, Paediatric and Teenage/Young Adult Patients With ROS1 Gene Fusion-Positive Cancers.

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 old or above 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.

Detailed description

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 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 patient based on molecularly-defined cohorts.

Screening: Consenting patients undergo biopsy and collection of blood samples for research purposes.

Treatment: Patients will receive entrectinib until disease progression without clinical benefit, unacceptable adverse events (AEs) or withdrawal of consent. Patients will also undergo collection of blood samples at various intervals while receiving treatment and at the end of treatment 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.

Interventions

• Drug Entrectinib
  Adult and paediatric patients with body surface area (BSA) ≥1.51 m\^2 will receive entrectinib orally at a dose of 600 mg daily dose (three 200 mg capsules per day). Paediatric patients with BSA \<1.51 m\^2 will receive entrectinib at a dose of 100 mg (BSA=0.43-0.50 m\^2) or 200 mg (BSA=0.51-0.80 m\^2) or 300 mg (BSA=0.81-1.10 m\^2) or 400 mg (BSA=1.11-1.50 m\^2). Each cycle of treatment will consist of 28 days and patients may continue until disease progression without clinical benefit, unacc

Primary outcome measures

• Objective Response (OR) [Time frame: Disease assessments to be performed up to 24 weeks from the start of trial treatment.]
• Durable Clinical Benefit (DCB) [Time frame: Disease assessments to be performed up to 24 weeks from the start of trial treatment.]

Secondary outcome measures (12)

• Duration of response (DR) [Time frame: Disease assessment every 2 cycles of entrectinib (each cycle is 28 days) and at EoT. After 24 weeks, it can be done every 12 weeks, on discussion with Sponsor. Follow-up visits are every 3 months after last dose of entrectinib for up to 2 years.]
• Best percentage change in sum of target lesion / index lesion diameters (PCSD) [Time frame: Disease assessment every 2 cycles of entrectinib (each cycle is 28 days) and at EoT. After 24 weeks, it can be done every 12 weeks, on discussion with Sponsor. Follow-up visits are every 3 months after last dose of entrectinib for up to 2 years.]
• Time to treatment discontinuation (TTD) [Time frame: From first dose of entrectinib to discontinuation of trial treatment up to 5 years.]
• Progression-Free Survival time (PFS) [Time frame: Disease assessment every 2 cycles of entrectinib (each cycle is 28 days) and at EoT. After 24 weeks, it can be done every 12 weeks, on discussion with Sponsor. Follow-up visits are every 3 months after last dose of entrectinib for up to 2 years.]
• Time to Progression (TTP) [Time frame: Disease assessment every 2 cycles of entrectinib (each cycle is 28 days) and at EoT. After 24 weeks, it can be done every 12 weeks, on discussion with Sponsor. Follow-up visits are every 3 months after last dose of entrectinib for up to 2 years.]
• Growth Modulation Index (GMI) [Time frame: Disease assessment every 2 cycles of entrectinib (each cycle is 28 days) and at EoT. After 24 weeks, it can be done every 12 weeks, on discussion with Sponsor. Follow-up visits are every 3 months after last dose of entrectinib for up to 2 years.]
• Overall Survival time (OS) [Time frame: Time of death or up to 2 years after the EoT visit.]
• Occurrence of at least one Suspected Unexpected Serious Adverse Reaction (SUSAR) [Time frame: From the time of consent until 28 days after last dose of entrectinib (up to 5 years) or until patient starts another anti-cancer therapy, whichever came first. An average time frame will be presented with results entry.]
• Occurrence of at least one Grade 3, 4 or 5 entrectinib related AE [Time frame: From the time of consent until 28 days after last dose of entrectinib (up to 5 years) or until patient starts another anti-cancer therapy, whichever came first. An average time frame will be presented with results entry.]
• EORTC-QLQ-C30 Standardised Area Under Summary Score Curve (QLQSAUC) in adult patients. [Time frame: QoL surveys performed prior to inclusion, every cycle (each cycle is 28 days) and at EoT visit (up to 5 years).]
• EQ-5D Standardised Area Under Index Value Curve (EQ5DSAUC) in adult patients [Time frame: QoL surveys performed prior to inclusion, every cycle (each cycle is 28 days) and at EoT visit (up to 5 years).]
• Mean change from baseline in the PedsQL 4.0 Standardised Area Under total Scale Score Curve (PedsSAUC) in paediatric patients [Time frame: QoL surveys performed prior to inclusion, every cycle (each cycle is 28 days) and at EoT visit (up to 5 years).]

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 next-generation sequencing method.

B. Patients must be able and willing to undergo a fresh tissue biopsy at baseline and blood samples for translational research. Note that for patients with haematological malignancies or neuroblastomas, blood, bone marrow aspiration and/or trephine or lymph node biopsy samples may be taken.

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 defined in the protocol. These measurements should be performed to confirm the patient's eligibility.

E. PAEDIATRIC 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.

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 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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United Kingdom · 27 centers

• Belfast City Hospital — Belfast
• University Hospital Birmingham — Birmingham
• Birmingham Children's Hospital — Birmingham
• Bristol Royal Hospital for Children — Bristol
• Bristol Haematology and Oncology Centre — Bristol
• Addenbrooke's Hospital — Cambridge
• Velindre Cancer Centre — Cardiff
• Cardiff Children's Hospital — Cardiff
• … and 19 more centers

Identifiers

NCT: NCT05770544 · CRUKD/21/004 - Treatment Arm 3 · IRAS ID: 1004057

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗