DETERMINE (Determining Extended Therapeutic Indications for Existing Drugs in Rare Molecularly Defined Indications Using a National Evaluation Platform Trial) - Master Screening Protocol
NCT ID: NCT05722886
Last Updated: 2025-11-24
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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RECRUITING
PHASE2/PHASE3
825 participants
INTERVENTIONAL
2023-03-01
2029-10-31
Brief Summary
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Detailed Description
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\*Rare is defined generally as incidence less than 6 cases in 100,000 patients (includes paediatric and TYA cancers) or common cancers with rare alterations.
The number of treatment arms opened will depend on the number of licensed medicines identified for inclusion. Each trial cohort 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.
This clinicaltrials.gov record refers to the Overall Trial Protocol (Master Screening Record), please refer to the references section for links to the individual treatment arm records.
The main aims of the clinical trial arms are:
* To describe the anti-cancer activity of licensed targeted drugs outside their licensed indication.
* To assess the safety and adverse event (AE) profile of licensed, targeted anti-cancer drugs in the target population.
* To understand biological mechanisms for response and resistance to targeted therapies.
* To evaluate the quality of life (QoL) of target populations receiving the licensed, targeted anti-cancer drugs.
This Master Screening Record will capture the number of patients with a cancer containing the appropriate genetic alteration that have been successfully allocated and consented to each arm. The trial results (according to the protocol defined outcome measures) will be reported per-arm for each treatment arm.
The ultimate aim is to translate positive clinical findings to the NHS to provide new treatment options for rare adult, paediatric and TYA cancers.
Conditions
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Study Design
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NON_RANDOMIZED
SINGLE_GROUP
TREATMENT
NONE
Study Groups
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Treatment Arm 1: Alectinib
This alectinib treatment arm is for adult, paediatric and TYA patients with ALK-positive cancers.
Alectinib
Adult patients will be administered alectinib orally at a dose of 600 mg (four 150 mg capsules) twice daily.
Paediatric patients with a body weight ≥40 kg and who are able to swallow the capsules will be administered alectinib orally at a dose of 600 mg (four 150 mg capsules) twice daily.
Each cycle of treatment will consist of 28 days and patients may continue on treatment until disease progression without clinical benefit, unacceptable AEs or withdrawal of consent.
Treatment Arm 2: Atezolizumab
This atezolizumab treatment arm is for adult, paediatric and TYA patients with cancers with high tumour mutational burden (TMB) or microsatellite instability high (MSI-high) or proven (previously diagnosed) constitutional mismatch repair deficiency (CMMRD).
Atezolizumab
Adult patients will receive 1200 mg of atezolizumab intravenously every 21 days.
Paediatric patients will receive atezolizumab at a dose of 15 mg/kg (maximum 1200 mg) every 21 days.
Patients may continue on treatment until disease progression without clinical benefit, unacceptable AEs or withdrawal of consent.
Treatment Arm 3: Entrectinib
This entrectinib treatment arm is for adult, paediatric and TYA patients with ROS1 gene fusion-positive cancers.
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 a dose adjusted for BSA. 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.
Treatment Arm 4: Trastuzumab in combination with pertuzumab
This trastuzumab and pertuzumab treatment arm is for adult, paediatric and TYA patients with cancers with HER2 amplification or activating mutations.
Trastuzumab in combination with pertuzumab
The initial loading dose of trastuzumab is 8 mg/kg body weight followed thereafter by a maintenance dose of 6 mg/kg body weight administered intravenously every 21 days.
The initial loading dose of pertuzumab is 840 mg followed thereafter by a maintenance dose of 420 mg administered intravenously every 21 days. Paediatric patients will receive a dose of pertuzumab adjusted by body weight.
Patients may continue until disease progression without clinical benefit, unacceptable AEs or withdrawal of consent.
Treatment Arm 5: Vemurafenib in combination with cobimetinib
This vemurafenib and cobimetinib treatment arm is for BRAF V600 mutation-positive cancers occurring in adults only.
Vemurafenib in combination with cobimetinib
Patients will receive vemurafenib at a dose of 960 mg (four tablets of 240 mg) orally on a twice daily schedule throughout a 28-day cycle.
Patients will receive cobimetinib at a dose of 60 mg (three tablets of 20 mg) to be taken orally, once daily for 21 consecutive days (days 1 to 21 in each 28-day cycle); followed by a 7-day break.
Patients may continue on treatment until disease progression without clinical benefit, unacceptable AEs or withdrawal of consent.
Treatment Arm 6: Capmatinib
This capmatinib treatment arm is for adult patients with cancers harbouring MET dysregulations.
Capmatinib
Patients will be administered capmatinib orally at a daily dose of 800 mg consisting of 400 mg (two 200 mg tablets) twice daily. Each cycle of treatment will consist of 28 days and patients may continue on treatment until disease progression without clinical benefit, unacceptable AEs or withdrawal of consent.
Interventions
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Alectinib
Adult patients will be administered alectinib orally at a dose of 600 mg (four 150 mg capsules) twice daily.
Paediatric patients with a body weight ≥40 kg and who are able to swallow the capsules will be administered alectinib orally at a dose of 600 mg (four 150 mg capsules) twice daily.
Each cycle of treatment will consist of 28 days and patients may continue on treatment until disease progression without clinical benefit, unacceptable AEs or withdrawal of consent.
Atezolizumab
Adult patients will receive 1200 mg of atezolizumab intravenously every 21 days.
Paediatric patients will receive atezolizumab at a dose of 15 mg/kg (maximum 1200 mg) every 21 days.
Patients may continue on treatment until disease progression without clinical benefit, unacceptable AEs or withdrawal of consent.
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 a dose adjusted for BSA. 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.
Trastuzumab in combination with pertuzumab
The initial loading dose of trastuzumab is 8 mg/kg body weight followed thereafter by a maintenance dose of 6 mg/kg body weight administered intravenously every 21 days.
The initial loading dose of pertuzumab is 840 mg followed thereafter by a maintenance dose of 420 mg administered intravenously every 21 days. Paediatric patients will receive a dose of pertuzumab adjusted by body weight.
Patients may continue until disease progression without clinical benefit, unacceptable AEs or withdrawal of consent.
Vemurafenib in combination with cobimetinib
Patients will receive vemurafenib at a dose of 960 mg (four tablets of 240 mg) orally on a twice daily schedule throughout a 28-day cycle.
Patients will receive cobimetinib at a dose of 60 mg (three tablets of 20 mg) to be taken orally, once daily for 21 consecutive days (days 1 to 21 in each 28-day cycle); followed by a 7-day break.
Patients may continue on treatment until disease progression without clinical benefit, unacceptable AEs or withdrawal of consent.
Capmatinib
Patients will be administered capmatinib orally at a daily dose of 800 mg consisting of 400 mg (two 200 mg tablets) twice daily. Each cycle of treatment will consist of 28 days and patients may continue on treatment until disease progression without clinical benefit, unacceptable AEs or withdrawal of consent.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
1. exhausted (or declined) standard-of-care treatment options.
2. or for whom no effective standard treatment is available.
3. and whose disease has progressed or is refractory. Exceptional circumstances may apply as described in the protocol.
2. Diagnosis of a rare cancer harbouring an actionable genomic alteration, or common cancer types with rare actionable genomic alterations, that has been identified using a validated next-generation sequencing method and for which there is a relevant open treatment arm within the DETERMINE trial.
3. Life expectancy of at least three months.
4. Patients are able to provide written (signed and dated) informed consent and be capable of co-operating with treatment and follow-up. For patients under 16 years old, the parent or legal guardian will be asked to provide written informed consent and the patient will be asked to provide age-appropriate assent (written or verbal, commensurate with age and level of understanding).
5. Patients with objectively evaluable or measurable disease, according to an assessment method appropriate for their cancer type.
6. Patients must provide a fresh tissue biopsy at baseline and blood samples for translational research. Note that for patients with haematological malignancies or neuroblastomas, blood, bone marrow and/or trephine or lymph node biopsy samples may be taken.
7. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (ECOG performance status 2 may be considered on an individual basis) (adults), Karnofsky score ≥50% (TYA) or Lansky Play scales ≥50% (\<12 years). Please see specific treatment arm appendices for any variations on this criterion and for definitions of adult and paediatric populations. Note: Paediatric patients: patients with Central Nervous System (CNS) tumours and a stable neurological deficit may be eligible with a performance status below 50%, at the discretion of the Investigator. In such cases, the deficit must be stable for at least 7 days prior to trial enrolment and be assessed by the local investigator as due to tumour or due to a post-surgical AE.
8. Women of childbearing potential are eligible provided that they meet the following criteria:
* Have a negative serum or urine pregnancy test before enrolment and
* Agree to the birth control methods and duration of use of those methods, as specified in each treatment arm appendix.
9. Male patients with partners of childbearing potential are eligible provided that they agree to the birth control methods and duration of use of those methods, as specified in each treatment arm appendix.
Exclusion Criteria
2. At high medical risk, in the opinion of the Investigator, because of non-malignant systemic disease (including active uncontrolled infection).
3. Female patients who are pregnant, breastfeeding or planning to become pregnant or male patients with a partner who is a woman of childbearing potential and is planning to become pregnant during the trial or following the last dose of IMP, as specified in each treatment arm appendix.
4. Is (or plans to be) a patient in another interventional clinical trial, whilst taking part in this trial. Participation in an observational trial which does not involve administration of an Investigational Medicinal Product (IMP) and which, in the opinion of the local Investigator, would not place an unacceptable burden on the patient would be acceptable e.g. sample collection\* or QoL studies.
\*for paediatric patients participating in other studies involving tissue/circulating tumour (ct) DNA/other blood collection, consideration would need to be given to the total blood volumes collected (as per the European Medicines Agency blood volume limits for children).
5. Co-administration of anti-cancer therapies other than those administered in this trial (with the exception of lifelong hormone suppression such as luteinising hormone agonists/analogues in prostate cancer).
6. Radiotherapy (except for palliative reasons) or chemotherapy, endocrine therapy (except when given for conditions other than malignant disease; e.g. thyroid replacement for hypothyroidism, hydrocortisone for cortisol deficiency/panhypopituitarism), nitrosoureas, mitomycin-C, immunotherapy and molecularly targeted agents or other IMPs within 4 weeks or 5 half-lives (whichever is the shorter).
7. 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 (for adult patients) or 7 days (for paediatric patients) 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.
8. Any other condition which, in the opinion of the local Investigator, would not be in the best interests of the patient.
ALL
No
Sponsors
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University of Manchester
OTHER
University of Birmingham
OTHER
Royal Marsden NHS Foundation Trust
OTHER
Hoffmann-La Roche
INDUSTRY
Novartis Pharmaceuticals
INDUSTRY
Cancer Research UK
OTHER
Responsible Party
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Principal Investigators
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Matthew Krebs, Dr
Role: PRINCIPAL_INVESTIGATOR
The Christie Hospital
Locations
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Belfast City Hospital
Belfast, , United Kingdom
University Hospital Birmingham
Birmingham, , United Kingdom
Birmingham Children's Hospital
Birmingham, , United Kingdom
Bristol Royal Hospital for Children
Bristol, , United Kingdom
Bristol Haematology and Oncology Centre
Bristol, , United Kingdom
Addenbrooke's Hospital
Cambridge, , United Kingdom
Velindre Cancer Centre
Cardiff, , United Kingdom
Cardiff Children's Hospital
Cardiff, , United Kingdom
Western General Hospital
Edinburgh, , United Kingdom
The Beatson Hospital
Glasgow, , United Kingdom
Royal Hospital for Children Glasgow
Glasgow, , United Kingdom
Leicester Royal Infirmary
Leicester, , United Kingdom
Alder Hey Hospital
Liverpool, , United Kingdom
University College London Hospital
London, , United Kingdom
Guy's Hospital
London, , United Kingdom
Great Ormond Street Hospital
London, , United Kingdom
Royal Manchester Children's Hospital
Manchester, , United Kingdom
The Christie Hospital
Manchester, , United Kingdom
Clatterbridge Cancer Centre
Metropolitan Borough of Wirral, , United Kingdom
Great North Children's Hospital
Newcastle, , United Kingdom
Freeman Hospital
Newcastle, , United Kingdom
Churchill Hospital
Oxford, , United Kingdom
John Radcliffe Hospital
Oxford, , United Kingdom
Weston Park Hospital
Sheffield, , United Kingdom
Sheffield's Children's Hospital
Sheffield, , United Kingdom
Southampton General Hospital
Southampton, , United Kingdom
The Royal Marsden Hospital
Sutton, , United Kingdom
Countries
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Central Contacts
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Facility Contacts
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Stefan Symeonides, Dr
Role: primary
Related Links
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Overview of the DETERMINE trial.
ClinicalTrials.gov record for DETERMINE Trial Treatment Arm 01 (alectinib) (NCT05770037)
ClinicalTrials.gov record for DETERMINE Trial Treatment Arm 02 (atezolizumab) (NCT05770102)
ClinicalTrials.gov record for DETERMINE Trial Treatment Arm 03 (entrectinib) (NCT05770544)
ClinicalTrials.gov record for DETERMINE Trial Treatment Arm 04 (trastuzumab in combination with pertuzumab) (NCT05786716)
ClinicalTrials.gov record for DETERMINE Trial Treatment Arm 05 (vemurafenib in combination with cobimetinib) (NCT05768178)
ClinicalTrials.gov record for DETERMINE Trial Treatment Arm 06 (capmatinib) (NCT06988475)
Other Identifiers
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IRAS ID: 1004057
Identifier Type: OTHER
Identifier Source: secondary_id
CRUKD/21/004
Identifier Type: -
Identifier Source: org_study_id
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