Trial Title:
DETERMINE Trial Treatment Arm 03: Entrectinib in Adult, Teenage/Young Adults and Paediatric Patients With ROS1 Gene Fusion-positive Cancers.
NCT ID:
NCT05770544
Condition:
Solid Tumor
Haematological Malignancy
Malignancy
Malignant Neoplasm
Lymphoproliferative Disorders
Neoplasms by Histologic Type
Neoplasms by Site
Cancer
Brain Neoplasms
Melanoma
Glioma
Conditions: Official terms:
Neoplasms
Brain Neoplasms
Neoplasms by Site
Hematologic Neoplasms
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Entrectinib
Conditions: 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
Study type:
Interventional
Study phase:
Phase 2/Phase 3
Overall status:
Recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Entrectinib
Description:
Adult and paediatric participants 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 participants 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=0.51-0.80m^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 participants may continue until
disease progression, unacceptable toxicity or withdrawal of consent.
Arm group label:
Treatment Arm 03
Other name:
Rozlytrek
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
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.
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 where promising activity is identified 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
participant based on molecularly-defined cohorts.
Screening: Consenting participants undergo biopsy and collection of blood samples for
research purposes.
Treatment: Participants will receive entrectinib until disease progression, unacceptable
toxicity or withdrawal of consent. Participants will also undergo collection of blood
samples at various intervals while receiving treatment and at the end of trial 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.
Criteria for eligibility:
Criteria:
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.
Gender:
All
Minimum age:
N/A
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Belfast City Hospital
Address:
City:
Belfast
Zip:
BT9 7AB
Country:
United Kingdom
Status:
Recruiting
Contact:
Last name:
Vicky Coyle, Prof
Email:
V.Coyle@qub.ac.uk
Investigator:
Last name:
Vicky Coyle, Prof
Email:
Principal Investigator
Facility:
Name:
University Hospital Birmingham
Address:
City:
Birmingham
Zip:
B15 2TT
Country:
United Kingdom
Status:
Recruiting
Contact:
Last name:
Gary Middleton, Prof
Phone:
0121 371 3573
Email:
G.Middleton@bham.ac.uk
Investigator:
Last name:
Gary Middleton, Prof
Email:
Principal Investigator
Facility:
Name:
Birmingham Children's Hospital
Address:
City:
Birmingham
Country:
United Kingdom
Status:
Not yet recruiting
Contact:
Last name:
Susanne Gatz, Dr
Phone:
0121 333 9999
Email:
Susanne.Gatz@nhs.net
Investigator:
Last name:
Susanne Gatz, Dr
Email:
Principal Investigator
Facility:
Name:
Bristol Royal Hospital for Children
Address:
City:
Bristol
Zip:
BS2 8BJ
Country:
United Kingdom
Status:
Not yet recruiting
Contact:
Last name:
Antony Ng, Dr
Phone:
0117 342 8044
Email:
Antony.Ng@uhbw.nhs.uk
Investigator:
Last name:
Antony Ng, Dr
Email:
Principal Investigator
Facility:
Name:
Bristol Haematology and Oncology Centre
Address:
City:
Bristol
Zip:
BS2 8ED
Country:
United Kingdom
Status:
Not yet recruiting
Contact:
Last name:
Antony Ng, Dr
Phone:
0117 342 8044
Email:
Antony.Ng@uhbw.nhs.uk
Investigator:
Last name:
Antony Ng, Dr
Email:
Principal Investigator
Facility:
Name:
Addenbrooke's Hospital
Address:
City:
Cambridge
Zip:
CB2 OQQ
Country:
United Kingdom
Status:
Recruiting
Contact:
Last name:
Bristi Basu, Dr
Phone:
01223 596105
Email:
bb313@medschl.cam.ac.uk
Investigator:
Last name:
Bristi Basu, Dr
Email:
Principal Investigator
Facility:
Name:
Velindre Cancer Centre
Address:
City:
Cardiff
Zip:
CF14 2TL
Country:
United Kingdom
Status:
Not yet recruiting
Contact:
Last name:
Robert Jones, Dr
Phone:
02920 615888
Phone ext:
6327
Email:
Robert.Hugh.Jones@wales.nhs.uk
Investigator:
Last name:
Robert Jones, Dr
Email:
Principal Investigator
Facility:
Name:
Western General Hospital
Address:
City:
Edinburgh
Zip:
EH4 2XU
Country:
United Kingdom
Status:
Recruiting
Contact:
Last name:
Stefan Symeonides, Dr
Investigator:
Last name:
Stefan Symeonides, Dr
Email:
Principal Investigator
Facility:
Name:
The Beatson Hospital
Address:
City:
Glasgow
Zip:
G12 OYN
Country:
United Kingdom
Status:
Recruiting
Contact:
Last name:
Patricia Roxburgh, Dr
Phone:
0141 301 7118
Email:
Patricia.Roxburgh@glasgow.ac.uk
Investigator:
Last name:
Patricia Roxburgh, Dr
Email:
Principal Investigator
Facility:
Name:
Royal Hospital for Children Glasgow
Address:
City:
Glasgow
Zip:
G51 4TF
Country:
United Kingdom
Status:
Not yet recruiting
Contact:
Last name:
Milind Ronghe, Dr
Phone:
0141 452 6692
Email:
Milind.Ronghe@ggc.scot.nhs.uk
Investigator:
Last name:
Milind Ronghe, Dr
Email:
Principal Investigator
Facility:
Name:
Leeds General Infirmary
Address:
City:
Leeds
Zip:
LS1 3EX
Country:
United Kingdom
Status:
Not yet recruiting
Contact:
Last name:
Martin Elliott, Dr
Phone:
0113 392 8779
Email:
martin.elliott1@nhs.net
Investigator:
Last name:
Martin Elliott, Dr
Email:
Principal Investigator
Facility:
Name:
Leicester Royal Infirmary
Address:
City:
Leicester
Zip:
LE1 5WW
Country:
United Kingdom
Status:
Recruiting
Contact:
Last name:
Anne Thomas, Dr
Phone:
0116 2587601
Email:
at107@le.ac.uk
Investigator:
Last name:
Anne Thomas, Dr
Email:
Principal Investigator
Facility:
Name:
Alder Hey Hospital
Address:
City:
Liverpool
Zip:
L14 5AB
Country:
United Kingdom
Status:
Not yet recruiting
Contact:
Last name:
Lisa Howell, Dr
Phone:
0151 293 3679
Email:
Lisa.Howell@alderhey.nhs.uk
Investigator:
Last name:
Lisa Howell, Dr
Email:
Principal Investigator
Facility:
Name:
The Royal Marsden Hospital
Address:
City:
London Borough of Sutton
Zip:
SM2 5PT
Country:
United Kingdom
Status:
Not yet recruiting
Contact:
Last name:
Lynley Marshall, Dr
Phone:
0208 661 3678
Email:
LynleyVanessa.Marshall@icr.ac.uk
Investigator:
Last name:
Lynley Marshall, Dr
Email:
Principal Investigator
Facility:
Name:
University College London Hospital
Address:
City:
London
Zip:
NW1 2BU
Country:
United Kingdom
Status:
Not yet recruiting
Contact:
Last name:
Martin Foster, Prof
Phone:
020 3447 5085
Email:
M.Forster@ucl.ac.uk
Investigator:
Last name:
Martin Foster, Prof
Email:
Principal Investigator
Facility:
Name:
Guy's Hospital
Address:
City:
London
Zip:
SE1 9RT
Country:
United Kingdom
Status:
Recruiting
Contact:
Last name:
James Spicer, Dr
Phone:
020 7188 4260
Email:
james.spicer@kcl.ac.uk
Investigator:
Last name:
James Spicer, Dr
Email:
Principal Investigator
Facility:
Name:
Great Ormond Street Hospital
Address:
City:
London
Zip:
WC1N 3JH
Country:
United Kingdom
Status:
Not yet recruiting
Contact:
Last name:
Darren Hargrave, Dr
Phone:
0207 813 8525
Email:
Darren.hargrave@gosh.nhs.uk
Investigator:
Last name:
Darren Hargrave, Dr
Email:
Principal Investigator
Facility:
Name:
Royal Manchester Children's Hospital
Address:
City:
Manchester
Zip:
M13 9WL
Country:
United Kingdom
Status:
Not yet recruiting
Contact:
Last name:
Guy Makin, Dr
Phone:
0161 701 8419
Email:
Guy.Makin@mft.nhs.uk
Investigator:
Last name:
Guy Makin, Dr
Email:
Principal Investigator
Facility:
Name:
The Christie Hospital
Address:
City:
Manchester
Zip:
M20 4BX
Country:
United Kingdom
Status:
Recruiting
Contact:
Last name:
Matthew Krebs, Prof
Phone:
0161 918 7672
Email:
Matthew.Krebs@nhs.net
Investigator:
Last name:
Matthew Krebs, Prof
Email:
Principal Investigator
Facility:
Name:
Great North Children's Hospital
Address:
City:
Newcastle
Zip:
NE1 4LP
Country:
United Kingdom
Status:
Recruiting
Contact:
Last name:
Alastair Greystoke, Dr
Phone:
0191 2138476
Email:
Alastair.Greystoke@newcastle.ac.uk
Investigator:
Last name:
Alastair Greystoke, Dr
Email:
Principal Investigator
Facility:
Name:
Freeman Hospital
Address:
City:
Newcastle
Zip:
NE7 7DN
Country:
United Kingdom
Status:
Recruiting
Contact:
Last name:
Alastair Greystoke, Dr
Phone:
0191 2138476
Email:
Greystoke@newcastle.ac.uk
Investigator:
Last name:
Alastair Greystoke, Dr
Email:
Principal Investigator
Facility:
Name:
Churchill Hospital
Address:
City:
Oxford
Zip:
OX3 7LE
Country:
United Kingdom
Status:
Recruiting
Contact:
Last name:
Sarah Pratap, Dr
Phone:
01865 235273
Email:
Sarah.Pratap@ouh.nhs.uk
Investigator:
Last name:
Sarah Pratap, Dr
Email:
Principal Investigator
Facility:
Name:
John Radcliffe Hospital
Address:
City:
Oxford
Zip:
OX3 9DU
Country:
United Kingdom
Status:
Recruiting
Contact:
Last name:
Sarah Pratap, Dr
Phone:
01865 235273
Email:
Sarah.Pratap@ouh.nhs.uk
Investigator:
Last name:
Sarah Pratap, Dr
Email:
Principal Investigator
Facility:
Name:
Weston Park Hospital
Address:
City:
Sheffield
Zip:
S10 2SJ
Country:
United Kingdom
Status:
Not yet recruiting
Contact:
Last name:
Sarah Danson, Dr
Phone:
0114 226 5068
Email:
s.danson@sheffield.ac.uk
Investigator:
Last name:
Sarah Danson, Dr
Email:
Principal Investigator
Facility:
Name:
Southampton General Hospital
Address:
City:
Southampton
Zip:
SO16 6YD
Country:
United Kingdom
Status:
Not yet recruiting
Contact:
Last name:
Juliet Gray, Prof
Phone:
0238 120 6639
Email:
Juliet.Gray@uhs.nhs.uk
Investigator:
Last name:
Juliet Gray, Prof
Email:
Principal Investigator
Facility:
Name:
Clatterbridge Cancer Centre
Address:
City:
Wirral
Zip:
CH63 4JY
Country:
United Kingdom
Status:
Not yet recruiting
Contact:
Last name:
Dan Palmer, Dr
Phone:
0151 706 4172 / 0151 706 4177
Email:
daniel.palmer@liverpool.ac.uk
Investigator:
Last name:
Dan Palmer, Dr
Email:
Principal Investigator
Start date:
June 2024
Completion date:
October 2029
Lead sponsor:
Agency:
Cancer Research UK
Agency class:
Other
Collaborator:
Agency:
University of Manchester
Agency class:
Other
Collaborator:
Agency:
University of Birmingham
Agency class:
Other
Collaborator:
Agency:
Royal Marsden NHS Foundation Trust
Agency class:
Other
Collaborator:
Agency:
Hoffmann-La Roche
Agency class:
Industry
Source:
Cancer Research UK
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05770544
http://CRUK.org/determine
https://clinicaltrials.gov/ct2/show/NCT05722886
