Clinical trial NCT05770544: 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.
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
PHASE3
Conditions: Haematological Malignancy
Malignancy
Malignant Neoplasm
Lymphoproliferative Disorders
Neoplasms by Histologic Type
Neoplasms by Site
Cancer
Brain Neoplasms
Melanoma
Glioma
Solid Tumour
Keywords: Adult
Antineoplastic Agents
Cancer
Child
Entrectinib
Malignancy
Malignant Neoplasms
Molecular Targeted Therapy
Mutation
Neoplasms by Histologic Site
Neoplasms by Site
Oncogene
Paediatric
Protein Kinase Inhibitors
Rare
ROS1 Protein, human
Tumour-agnostic
Young adult
Lead sponsor: Cancer Research UK
Sponsor class: OTHER
Collaborators: name: University of Manchester
name: University of Birmingham
name: Royal Marsden NHS Foundation Trust
name: Hoffmann-La Roche
First posted: 2023-03-15
Enrollment: 30
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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 toxicity 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.

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.

Primary outcomes:
measure: Objective Response (OR)
timeFrame: Disease assessments to be performed up to 24 weeks from the start of trial treatment.
measure: Durable Clinical Benefit (DCB)
timeFrame: Disease assessments to be performed up to 24 weeks from the start of trial treatment.
Secondary outcomes:
measure: Duration of response (DR)
timeFrame: 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.
measure: Best percentage change in sum of target lesion / index lesion diameters (PCSD)
timeFrame: 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.
measure: Time to treatment discontinuation (TTD)
timeFrame: From first dose of entrectinib to discontinuation of trial treatment up to 5 years.
measure: Progression-Free Survival time (PFS)
timeFrame: 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.
measure: Time to Progression (TTP)
timeFrame: 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.
measure: Growth Modulation Index (GMI)
timeFrame: 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.
measure: Overall Survival time (OS)
timeFrame: Time of death or up to 2 years after the EoT visit.
measure: Occurrence of at least one Suspected Unexpected Serious Adverse Reaction (SUSAR)
timeFrame: 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.
measure: Occurrence of at least one Grade 3, 4 or 5 entrectinib related AE
timeFrame: 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.
measure: EORTC-QLQ-C30 Standardised Area Under Summary Score Curve (QLQSAUC) in adult patients.
timeFrame: QoL surveys performed prior to inclusion, every cycle (each cycle is 28 days) and at EoT visit (up to 5 years).
measure: EQ-5D Standardised Area Under Index Value Curve (EQ5DSAUC) in adult patients
timeFrame: QoL surveys performed prior to inclusion, every cycle (each cycle is 28 days) and at EoT visit (up to 5 years).
measure: Mean change from baseline in the PedsQL 4.0 Standardised Area Under total Scale Score Curve (PedsSAUC) in paediatric patients
timeFrame: QoL surveys performed prior to inclusion, every cycle (each cycle is 28 days) and at EoT visit (up to 5 years).
measure: Mean change from baseline in the PedsQL 4.0 Standardised Area Under total Scale Score Curve (PedsSAUC) in parents of paediatric patients
timeFrame: QoL surveys performed prior to inclusion, every cycle (each cycle is 28 days) and at EoT visit (up to 5 years).
Other outcomes:
Locations:
city: Belfast
country: United Kingdom
facility: Belfast City Hospital
city: Birmingham
country: United Kingdom
facility: University Hospital Birmingham
city: Birmingham
country: United Kingdom
facility: Birmingham Children's Hospital
city: Bristol
country: United Kingdom
facility: Bristol Royal Hospital for Children
city: Bristol
country: United Kingdom
facility: Bristol Haematology and Oncology Centre
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital
city: Cardiff
country: United Kingdom
facility: Velindre Cancer Centre
city: Cardiff
country: United Kingdom
facility: Cardiff Children's Hospital
city: Edinburgh
country: United Kingdom
facility: Western General Hospital
city: Glasgow
country: United Kingdom
facility: The Beatson Hospital
city: Glasgow
country: United Kingdom
facility: Royal Hospital for Children Glasgow
city: Leicester
country: United Kingdom
facility: Leicester Royal Infirmary
city: Liverpool
country: United Kingdom
facility: Alder Hey Hospital
city: London Borough of Sutton
country: United Kingdom
facility: The Royal Marsden Hospital
city: London
country: United Kingdom
facility: University College London Hospital
city: London
country: United Kingdom
facility: Guy's Hospital
city: London
country: United Kingdom
facility: Great Ormond Street Hospital
city: Manchester
country: United Kingdom
facility: Royal Manchester Children's Hospital
city: Manchester
country: United Kingdom
facility: The Christie Hospital
city: Newcastle
country: United Kingdom
facility: Great North Children's Hospital
city: Newcastle
country: United Kingdom
facility: Freeman Hospital
city: Oxford
country: United Kingdom
facility: Churchill Hospital
city: Oxford
country: United Kingdom
facility: John Radcliffe Hospital
city: Sheffield
country: United Kingdom
facility: Weston Park Hospital
city: Sheffield
country: United Kingdom
facility: Sheffield's Children's Hospital
city: Southampton
country: United Kingdom
facility: Southampton General Hospital
city: Wirral
country: United Kingdom
facility: Clatterbridge Cancer Centre
Study officials:
affiliation: The Christie Hospital
name: Matthew Krebs, Dr
role: PRINCIPAL_INVESTIGATOR
References: