A Phase 2/3 interventional study of Entrectinib in Haematological Malignancy, Malignancy and Malignant Neoplasm, sponsored by Cancer Research UK. Recruiting at 27 sites in United Kingdom. Per ClinicalTrials.gov, last updated 2025-11-24.
Sponsored by Cancer Research UK · Phase 2/3, Interventional, and Treatment
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.
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.
1,444 studies on the registry are indexed under Hematologic Neoplasms; 420 are open to participants now.
This study's planned enrollment of 30 is below the median of 46 across 1,044 interventional studies indexed under Hematologic Neoplasms.
Browse Hematologic Neoplasms studies →Cancer Research UK is the lead sponsor of 83 studies on the registry; 12 are open to participants now.
Counted across the registry records on this site, refreshed daily.
Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
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 , 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 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 are eligible provided that they meet the following criteria:
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
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:
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 ( III or IV) or known (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 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 (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 (HIV) positivity. Patients with history of testing positive for HIV infection are eligible provided the each of the following conditions are met:
I. Known to entrectinib or any of the
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
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Malignancy means cancer. Criteria about another or earlier malignancy ask whether you have had a different cancer, usually within a set number of years.
Some are commonly allowed, such as treated skin cancers other than melanoma and early cancers removed completely — check the exceptions this study lists.
A biopsy takes a small piece of tissue to examine. “Archival tissue” is a sample already taken, for example at diagnosis, and kept by the hospital.
Whether a stored sample will do depends on when it was taken, how much there is and what the study needs. Ask whether the study accepts your stored sample or needs a new biopsy.
Able to become pregnant: from the first period until menopause, unless permanently unable to through surgery (removal of the womb, or of both ovaries or both fallopian tubes).
Criteria for people of childbearing potential usually ask for a negative pregnancy test and for contraception during the study and for a time after it.
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
The New York Heart Association’s four classes of how much heart failure limits physical activity.
Studies set their own limit — many outside heart failure leave out class III–IV, while heart failure studies may ask for a particular class. Check the class this study names.
The share of blood the heart’s main pumping chamber (the left ventricle) pushes out with each beat, measured by an echocardiogram (heart ultrasound) or a MUGA scan. About 50–70% is normal.
Judged by the study doctor to matter for your health or for the study. It is a doctor’s decision, so ask the study team if you are unsure whether something counts.
On an ECG, the QT interval is the time the heart’s lower chambers take to activate electrically and recover in each beat. QTc is that time adjusted for heart rate (QTcF by Fridericia’s formula, QTcB by Bazett’s). Some medicines lengthen it, and a long QTc can raise the risk of a dangerous heart rhythm.
The study may name a correction formula and a limit in milliseconds, often around 450–480.
The human immunodeficiency virus, which weakens the immune system.
Many studies now accept people whose HIV is controlled on treatment, judged by the viral load and the CD4 count. Check the limits this study sets.
The number of CD4 cells, a type of white blood cell, in a given amount of blood. It is used to follow how well the immune system is doing in HIV.
An allergy, or another reaction of the immune system, to a substance. “Hypersensitivity to the study drug” means a known allergic reaction to it — not every side effect a medicine can have.
The other ingredients in a medicine besides the active drug, such as fillers, colours or preservatives.
Cancer (malignancy)
Malignancy means cancer. Criteria about another or earlier malignancy ask whether you have had a different cancer, usually within a set number of years.
Some are commonly allowed, such as treated skin cancers other than melanoma and early cancers removed completely — check the exceptions this study lists.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Biopsy and archival tissue
A biopsy takes a small piece of tissue to examine. “Archival tissue” is a sample already taken, for example at diagnosis, and kept by the hospital.
Whether a stored sample will do depends on when it was taken, how much there is and what the study needs. Ask whether the study accepts your stored sample or needs a new biopsy.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Childbearing potential
Able to become pregnant: from the first period until menopause, unless permanently unable to through surgery (removal of the womb, or of both ovaries or both fallopian tubes).
Criteria for people of childbearing potential usually ask for a negative pregnancy test and for contraception during the study and for a time after it.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraception
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
NYHA class (heart failure)
The New York Heart Association’s four classes of how much heart failure limits physical activity.
Studies set their own limit — many outside heart failure leave out class III–IV, while heart failure studies may ask for a particular class. Check the class this study names.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
LVEF (left ventricular ejection fraction)
The share of blood the heart’s main pumping chamber (the left ventricle) pushes out with each beat, measured by an echocardiogram (heart ultrasound) or a MUGA scan. About 50–70% is normal.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Clinically significant
Judged by the study doctor to matter for your health or for the study. It is a doctor’s decision, so ask the study team if you are unsure whether something counts.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
QT and QTc
On an ECG, the QT interval is the time the heart’s lower chambers take to activate electrically and recover in each beat. QTc is that time adjusted for heart rate (QTcF by Fridericia’s formula, QTcB by Bazett’s). Some medicines lengthen it, and a long QTc can raise the risk of a dangerous heart rhythm.
The study may name a correction formula and a limit in milliseconds, often around 450–480.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
HIV
The human immunodeficiency virus, which weakens the immune system.
Many studies now accept people whose HIV is controlled on treatment, judged by the viral load and the CD4 count. Check the limits this study sets.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
CD4 count
The number of CD4 cells, a type of white blood cell, in a given amount of blood. It is used to follow how well the immune system is doing in HIV.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hypersensitivity
An allergy, or another reaction of the immune system, to a substance. “Hypersensitivity to the study drug” means a known allergic reaction to it — not every side effect a medicine can have.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Excipients
The other ingredients in a medicine besides the active drug, such as fillers, colours or preservatives.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
This entrectinib treatment arm is for adult, paediatric and TYA patients with ROS1 gene fusion-positive malignancies.
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, unacceptable AEs or withdrawal of consent.
Also known as: Rozlytrek
Objective Response (OR)
An OR is defined as the confirmed occurrence of either a Complete Response (CR) or Partial Response (PR) according to Response Evaluation Criteria in Solid Tumours (RECIST) Version 1.1 criteria (or immune related \[ir\]-RECIST or standard imaging criteria for specific disease e.g. Response Evaluation in Neuro Oncology criteria \[RANO\]). In patients with leukaemia, OR will be defined as the occurrence of CR, CRi (CR with incomplete neutrophil recovery) or CRp (CR with incomplete platelet recovery). The trial will report the proportion of patients with an OR and 95% credible interval.
Time frame: Disease assessments to be performed up to 24 weeks from the start of trial treatment.
Durable Clinical Benefit (DCB)
DCB is defined as the absence of disease progression for at least 24 weeks from the start of trial treatment according to RECIST Version 1.1 criteria (or ir-RECIST or standard imaging criteria for specific disease e.g. RANO criteria) and, where relevant (e.g. for haematological malignancies), by standard bone marrow response assessment criteria. Alternative definitions of DCB based on different time points may be pre-specified for particular sub-cohorts if 24 weeks is not clinically relevant. The trial will report the proportion of patients with a DCB and 95% credible interval.
Time frame: Disease assessments to be performed up to 24 weeks from the start of trial treatment.
Duration of response (DR)
DR is defined as the time from the date of the first confirmed CR or PR according to RECIST 1.1 (or ir-RECIST or standard imaging criteria for specific disease e.g. RANO criteria) to the date of disease progression. The trial will report the median DR and 95% credible interval.
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)
PCSD is defined as the greatest decrease or least increase in the sum of target lesion diameters (RECIST) or index lesion diameters (irRECIST) as a percentage compared to the baseline measurement. The trial will report the mean PCSD and 95% credible interval.
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)
TTD is defined as the time from date of starting trial treatment to date of discontinuing trial treatment, in days estimated by the median of the posterior inverse gamma probability distribution. The trial will report the median TTD and 95% credible interval.
Time frame: From first dose of entrectinib to discontinuation of trial treatment up to 5 years.
Progression-Free Survival time (PFS)
PFS is defined as the time from date of starting trial treatment to date of progression or date of death without a previous progression recorded estimated by the median of the posterior inverse gamma probability distribution.
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)
TTP is defined as the time from date of starting trial treatment to date of progression or date of death without recorded progression censored rather than events. The trial will report the median TTP and 95% credible interval.
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)
GMI is defined as the ratio of TTP with the trial protocol treatment to TTP on the most recent prior line of therapy. The trial will report the mean GMI and 95% credible interval.
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)
OS is defined as the time from date of starting trial treatment to date of death from any cause estimated by the median of the posterior normal probability distribution.
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)
The trial will report the number of patients who experience at least one SUSAR to entrectinib.
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
Number of patients who experience at least one entrectinib related Grade 3, 4 or 5 AE according to National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0.
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.
For adult populations, multiple measures of Quality of Life (QoL) will be generated from patient completion of the European Organisation for Research and Treatment of Cancer QLQ-C30 (EORTC-QLQ-C30) questionnaire (15 measures). For each patient the Summary Score from the questionnaire will be generated at each time point and the area under the curve generated by these scores over time will be calculated and standardised by the time frame. The trial will report the mean QLQSAUC and 95% credible interval.
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
For adult populations, two measures of QoL will be generated from patient completion of the EQ-5D-5L questionnaire. For each measure, scores based on responses from the questionnaire will be generated at each time point and the area under the curve generated by these scores over time will be calculated and standardised by the time frame. The trial will report the mean EQ5DSAUC and 95% credible interval.
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
For paediatric populations multiple measures of QoL will be generated from patient completion of the PedsQL 4.0 (4 measures and a Total Scale Score). The Summary Score from the questionnaire will be generated at each time point and the area under the curve generated by these scores over time will be calculated and standardised by the time frame. The trial will report the mean PedsSAUC and 95% credible interval.
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 parents of paediatric patients
For paediatric populations multiple measures of QoL will be generated from patient's parent completion of the PedsQL 4.0 (4 measures). The Summary Score from the questionnaire will be generated at each time point and the area under the curve generated by these scores over time will be calculated and standardised by the time frame. The trial will report the mean PedsSAUC and 95% credible interval.
Time frame: QoL surveys performed prior to inclusion, every cycle (each cycle is 28 days) and at EoT visit (up to 5 years).
Plan to share: Yes — Individual de-identified patient data will be shared with researchers whose proposed use of the data is approved by a review committee of the Sponsor.
Supporting information: Study protocol, Statistical analysis plan, Informed consent form
Time frame: All requests for data relating to this treatment arm that are made within 5 years from last patient last visit for the entrectinib treatment arm will be considered; requests made subsequently will be considered where possible.
Access criteria: When a request has been approved, Cancer Research UK will provide access to the de-identified individual patient-level data and appropriate supporting information. A signed Data Sharing Agreement must be in place before accessing requested information. Requests should be submitted to drugdev@cancer.org.uk.
Start is estimated for Nov 2025; primary completion for Oct 2029, 47 months later.
How these figures are worked out, and which studies are left out of them.
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Studies of the drug tested here: Entrectinib
Cancer Research UK