DETECTION Trial: Using blood tests to guide early treatment of relapse in early stage melanoma
| ISRCTN | ISRCTN94991276 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN94991276 |
| EudraCT/CTIS number | 2020-000234-17 |
| IRAS number | 270318 |
| ClinicalTrials.gov number | NCT4901988 |
| Secondary identifying numbers | CPMS 48994, Grant codes C26937/A28891 |
- Submission date
- 09/07/2021
- Registration date
- 17/08/2021
- Last edited
- 06/03/2023
- Recruitment status
- Stopped
- Overall study status
- Stopped
- Condition category
- Cancer
Plain English Summary
https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-of-a-blood-test-to-monitor-for-early-signs-of-melanoma-coming-back-detection (added 26/01/2022)
Background and study aims
We are looking for new and better ways to treat melanoma. We have developed a blood test that tells us whether cancer cells are still present or cancer is becoming active, even if a scan looks normal. The test looks for pieces of DNA that are known to have come from the cancer, which we call ‘circulating tumour DNA’, or ctDNA. If we do not find ctDNA patients will stay on the study having blood tests either until the study ends (and we have not found ctDNA in their blood) or until we find ctDNA in the blood. If we find ctDNA, patients will be allocated to either receive the standard of care, which is ongoing follow up or nivolumab, an immune-boosting drug which we know is effective at treating melanoma. A doctor will inform patients of the possible benefits and risks when taking nivolumab. We do not know whether treating early with nivolumab, on the evidence of ctDNA alone, is of benefit to patients, and this is what we need to find out.
Who can participate?
Patients who have been diagnosed with early-stage melanoma which has been removed by surgery.
What does the study involve?
The study will begin with screening to check that it is safe for participants to be involved in the trial.
Then the primary tumour (tissue removed from your recent melanoma surgery) will be tested for the presence of faulty genes. If faulty genes are present then participants will undergo regular blood tests for the presence of ctDNA every 3 months. If ctDNA is detected participants will be allocated into 1 of 2 groups (Arm A or Arm B) Participants will be allocated to one of two groups, with an equal chance of being in either group (like tossing a coin).
For the first 3 years participants in Arm A will receive medical assessment (physical examination, vital signs, weight) and blood tests for ctDNA every 3 months; scans and questionnaires every 6 months; and an ECG and urine test yearly. In years 4 and 5 of the study participants in Arm A will receive medical assessment, ctDNA blood test, scans, and questionnaires every 6 months, and the ECG and urine test yearly. At the last visit there will be final a medical assessment, ctDNA blood test, ECG and urine test.
Over 2 years, participants in Arm B will receive medical assessments, administration of nivolumab (over a period of 1 h), ctDNA blood test every 4 weeks, scans and questionnaire every 6 months and ECG and urine test yearly. After the 2 year period of receiving nivolumab participants will receive medical assessments, ctDNA test, urine test, ECG, then scan and questionnaires every 6 months and ECG and urine test yearly.. At the last visit there will be final a medical assessment, ctDNA blood test, ECG and urine test.
What are the possible benefits and risks of participating?
We hope the treatments (nivolumab) will help you. The information from the study may help improve future treatments of patients with early-stage melanoma.
There is a small possibility that ctDNA could be detected with no disease and therefore nivolumab could be administered unnecessarily. There are side effects associated with treatment with nivolumab, exposure to radiation during CT scanning, MRI scans, and having blood tests taken.
Where is the study run from?
The Christie NHS Foundation Trust (UK)
When is the study starting and how long is it expected to run for?
From November 2019 to April 2029
Who is funding the study?
Cancer Research UK
Who is the main contact?
Professor Paul Lorigan
Detection@liverpool.ac.uk
Contact information
Scientific
University of Manchester
Dept of Medical Oncology
The Christie NHS Foundation Trust
Wilmslow Road
Manchester
M20 4BX
United Kingdom
 ORCID ID |
0000-0002-8875-2164 |
|---|---|
| Phone | +44 (0)161 446 8002 |
| detection@liverpool.ac.uk |
Public
LCTC Senior Trial Manager
Liverpool Clinical Trials Centre
University of Liverpool
1st Floor Block C, Waterhouse Building
3 Brownlow Street
Liverpool
L69 3GL
United Kingdom
| Phone | No telephone contact available |
|---|---|
| Silviya.balabanova@liverpool.ac.uk |
Study information
| Study design | Interventional randomized controlled trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | 40140_PIS_v5.0_14Jul2021.pdf |
| Scientific title | Circulating tumour DNA guidEd Therapy for stage IIB/C mElanoma after surgiCal resecTION (DETECTION) |
| Study acronym | DETECTION |
| Study hypothesis | 1. Null Hypothesis: Treating with immune therapy at the point of ctDNA detection has no impact on overall survival 2. Alternative Hypothesis: Treating with immune therapy at the point of ctDNA detection improves overall survival with a hazard ratio of 0.7 |
| Ethics approval(s) | Approved 23/07/2021, London Harrow Research Ethics Committee (**Currently being held remotely via Teleconference/ZOOM** Education Centre, Northwick Park Hospital, HA1 3UJ; +44 (0)207 104 8098, +44 (0)207 104 8306, +44 (0)207 104 8356; harrow.rec@hra.nhs.uk), ref: 21/LO/0318 |
| Condition | Skin Cancer |
| Intervention | DETECTION will regularly test patients who have had their cancer removed by surgery (every three months for three years and then every six months for a further two years) using blood tests to check for ctDNA. If we do not find ctDNA, the patient will stay on the study having blood tests either until the study ends (and we have not found ctDNA in their blood) or until we do find ctDNA. If we find ctDNA, the patient will be randomised into one of two Arms. Arm A will continue to have blood tests for ctDNA, and also scans and appointments as part of normal care. Patients will only get treatment if their scan shows that the cancer has returned as part of normal patient care. The patient and their doctor will not be told that the test has shown ctDNA in the blood. We need an equal number of patients to those receiving treatment to NOT receive treatment to compare our results against (controls). We do not know whether the presence of ctDNA in the blood means that cancer will return or not. Arm A must be treated in the same way as a patient not on the trial and knowing that ctDNA is present may mean patients act differently, for example requesting extra checkups. We also want to avoid these patients from having additional anxiety. Arm B will have checks to see if it is safe for them to start receiving treatment and the patient will have a discussion with their doctor to see if they are still happy to take part in the trial. If it is safe to do so, patients will receive a drug called nivolumab 480mg intravenously every 4 weeks for 2 years. Trial visits: All Patients will have the following type of visits: screening, baseline, ctDNA monitoring, and Last visit/Withdrawal. If the ctDNA test comes back negative the patient will continue on the trial having visits and procedures. If they relapse they will be managed with standard of care therapy. Arm A – Standard Care: If the patient is randomised into Arm A, neither they nor their doctor will be told that ctDNA has been detected. Patients will continue coming to hospital for visits as per the same schedule to prior to the randomisation. The doctor will only offer further treatment if the melanoma re-appears on scan or is observed to have reappeared on the skin. Arm B – Early treatment based on the ctDNA result: If a patient is randomised into Arm B, they will be telephoned by the clinical team to return to the clinic, where they will be told the results of their ctDNA blood test. They will receive early treatment for melanoma with a drug that helps the immune system kill the cancer called nivolumab for 2 years. They will have the drug through the vein, every 4 weeks for 2 years. They will be monitored for side effects from the treatment as well as for any sign of the cancer returning. They will also continue to have blood taken for ctDNA testing to assess the response in hte blood. In addition they will continue to have a CT scan every 6 months on the maintaining the original timings of every 6 months from when they started on the study. End of Treatment due to side effects or choice (Arm B only): If the patient has any severe side effects from the drug or if they choose to stop treatment they will no longer receive therapy. They will continue to attend visits (post treatment follow-up) every 3 months for 3 years and then every 6 months for a further 2 years after that until the trial closes. If their melanoma returns they will have standard of care therapy. Follow-up after return of melanoma for all study patients: If the patient is on Arm B and the disease re-appears whilst patients are receiving treatment they will stop having nivolumab. They will have further therapy according to the standard of care. If they have already completed nivolumab they will also have treatment according to standard of care. If the patient is on Arm A and their melanoma re-appears they will be managed as standard of care and will continue to have bloods for ctDNA taken at the start of each treatment cycle until they progress on that first treatment. For both arms, we will continue to collect data about the health and the treatments received by the patients along with their response to these treatments. We will collect this data through their regular clinic appointment or through telephone conversations with them and clinical note review. In addition, in order to understand better why the melanoma came back to improve our management we will take further blood tests at the time of relapse and if the patient is planned to have surgery to remove the melanoma we will collect left-over tissue for our research. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Not Applicable |
| Drug / device / biological / vaccine name(s) | Nivolumab |
| Primary outcome measure | Overall Survival (OS) defined as the time from randomisation until death from any cause measured as the incidence of death at follow up after relapse (every 12 weeks after the date of confirmed relapse) |
| Secondary outcome measures | 1. Recurrence free survival (RFS) defined as the time from randomisation to radiological or clinical progression measured using scans evaluated using the RECIST v1.1 criteria at screening, every 6 months for years 1 to 5, and at follow up from the date of confirmed relapse as part of standard of care, with up to 3 per year after this based on clinical need; or histological data (i.e. biopsies) when clinically indicated 2. Distant metastasis-free survival (DMFS) defined as the time from randomisation to distant metastatic relapse or death measured using scans evaluated using the RECIST v1.1 criteria at screening, every 6 months for years 1 to 5, and at follow up from the date of confirmed relapse as part of standard of care, with up to 3 per year after this based on clinical need; or histological data (i.e. biopsies) when clinically indicated 3. Progression Free Survival (PFS) for participants on first-line therapy (from relapse for participants in Arm A, from randomisation for participants in Arm B) defined as the time from start of treatment (day of the first dose) until disease progression as clinical or radiological progression or death measured using scans evaluated using the RECIST v1.1 criteria at screening, every 6 months for years 1 to 5, and at follow up from the date of confirmed relapse as part of standard of care, with up to 3 per year after this based on clinical need; or histological data (i.e. biopsies) when clinically indicated 4. Time from randomisation to disease progression of first-line therapy (from relapse for participants in Arm A, from randomisation for participants in Arm B) measured using scans evaluated using the RECIST v1.1 criteria at screening, every 6 months for years 1 to 5, and at follow up from the date of confirmed relapse as part of standard of care, with up to 3 per year after this based on clinical need; or histological data (i.e. biopsies) when clinically indicated 5. Radiological response in Arm A (Complete Response, Partial Response, Stable Disease, and Progressive Disease) vs no Progressive Disease in Arm B to first-line systemic therapy measured using scans evaluated using the RECIST v1.1 criteria at screening, every 6 months for years 1 to 5, and at follow up from the date of confirmed relapse as part of standard of care, with up to 3 per year after this based on clinical need 6. Time from registration to ctDNA detection measured using ctDNA test every three months for years 1 to 3, and every 6 months for years 4 to 5 7. Number of participants with undetectable ctDNA but clinical/radiological progression and site of progression measured using ctDNA test every three months for years 1 to 3, and every 6 months for years 4 to 5; and scans evaluated using the RECIST v1.1 criteria at screening, every 6 months for years 1 to 5, and at follow up from the date of confirmed relapse as part of standard of care, with up to 3 per year after this based on clinical need; or histological data (i.e. biopsies) when clinically indicated 8. RFS of participants with undetectable ctDNA (not randomised) compared to participants with detectable ctDNA in Arm A measured using ctDNA test every three months for years 1 to 3, and every 6 months for years 4 to 5; and scans evaluated using the RECIST v1.1 criteria at screening, every 6 months for years 1 to 5, and at follow up from the date of confirmed relapse as part of standard of care, with up to 3 per year after this based on clinical need; or histological data (i.e. biopsies) when clinically indicated 9. DMFS of participants with undetectable ctDNA (not randomised) compared to participants with detectable ctDNA in Arm A measured using ctDNA test every three months for years 1 to 3, and every 6 months for years 4 to 5; and scans evaluated using the RECIST v1.1 criteria at screening, every 6 months for years 1 to 5, and at follow up from the date of confirmed relapse as part of standard of care, with up to 3 per year after this based on clinical need; or histological data (i.e. biopsies) when clinically indicated 10. OS defined as time from registration (commenced on study) until death of participants with undetectable ctDNA (not randomised) compared to participants in Arm A measured as the incidence of death at follow up after relapse (every 12 weeks after the date of confirmed relapse) 11. Treatment-free survival as defined as area between Kaplan-Meier curves between time from initiation of first-line therapy until its cessation and time from initiation of first-line therapy and subsequent therapy initiation or death in Arm A compared to Arm B S calculated during statistical analysis at interim and final study analyses 12. Toxicity measured according to Common Terminology Criteria for Adverse Events (CTCAE v5.0) at pre-randomisation for all participants; at baseline, every 3 months for years 1 to 3, every 6 months for years 4 to 5, within 28 days of confirmed disease relapse and at the end of the study for participants in Arm A; and at the post-randomisation visit, every 4 weeks in years 1 to 2, at the end of treatment, every 6 months during follow up in years 3 to 5, within 28 days of confirmed disease relapse, and at the end of study for participants in Arm B 13. Health economics assessment by the EuroQol 5-dimension 5-level quality of life questionnaire (EQ-5D-5L) and resource use questionnaires at baseline, every 3 months for years 1 to 5, within 28 days of confirmed disease relapse, then every 6 months during follow up, and at the end of the study for participants in Arm A; and at the post-randomisation visit, every 4 weeks in years 1 to 2, every 6 months during follow up in years 3 to 5, and within 28 days of confirmed disease relapse for participants in Arm B |
| Overall study start date | 01/11/2019 |
| Overall study end date | 30/04/2029 |
| Reason abandoned (if study stopped) | Objectives no longer viable |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | Planned Sample Size: 1,050; UK Sample Size: 1,050 |
| Total final enrolment | 8 |
| Participant inclusion criteria | 1. Signed written informed consent 2. Patients must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests and other requirements of the study 3. Histological confirmation of cutaneous melanoma 4. Age ≥18 years 5. Stage IIB or IIC melanoma (sentinel lymph node (SNLB) staged) according to AJCC version 8 (4) 6. Complete resection (including SNLB) must have been performed within 12 weeks prior to registration 7. Disease-free status documented both clinically and radiologically within 4 weeks prior to registration 8. Mutation confirmed in at least one of the following BRAF (p.V600E/p.V600K/p.V600R) /NRAS (p.Q61R/p.Q61K, p.Q61L/p.G12D), which can be tracked in ctDNA with exact point mutation known 9. ECOG performance status 0/1 10. Adequate organ function and screening laboratory values must meet the following criteria: WBC ≥ 2.0x109/L, Absolute neutrophil count (ANC) ≥1.5x10⁹/l, Platelets ≥100 x10⁹/l, Haemoglobin ≥90 g/l, Creatinine ≤1.5 x ULN or creatinine clearance >30 ml/min using Cockcroft-Gault, AST ≤1.5 x ULN, ALT ≤1.5 x ULN, Bilirubin ≤1.5 x ULN unless the patient has familial hyperbilirubinaemia 11. LDH ≤1.5 x ULN as per local institution parameters 12. Patients who are pregnant or breastfeeding will be eligible to join the trial. However, if they are allocated to Arm B, women of childbearing potential (WOCBP) must agree to have a serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) and must be withdrawn if pregnant or breastfeeding. WOCBP and males who are sexually active with WOCBP must also agree to follow instructions for method(s) of contraception for the duration of treatment plus 5 months if randomised to Arm B (or while receiving any systemic treatment and to follow local guidance if given on Arm A). |
| Participant exclusion criteria | 1. If previously received prior immunotherapy, chemotherapy, cancer directed vaccine therapy or BRAF/MEK targeted therapy for cancer 2. Patients with active, known or suspected autoimmune disease. Patients with type 1 diabetes mellitus, rheumatoid arthritis not requiring disease modifying drugs, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger will be permitted to enrol. 3. Current other malignancy or history of another malignancy within the last 3 years. Patients who have been disease-free for 3 years, (i.e. patients with second malignancies that have been definitively treated at least 3 years ago) or patients with a history of completely resected non-melanoma skin cancer are eligible 4. Any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), psychiatric disorders, or other conditions that could interfere with the patient’s safety, obtaining informed consent, or compliance with study procedures 5. Patients with a condition requiring ongoing/long-term (> 3 months) systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications. Inhaled or topical steroids and adrenal replacement steroid doses ≤10 mg daily prednisolone equivalent are permitted in the absence of active autoimmune disease 6. Patients with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity 7. History of allergies or adverse drug reaction to any of the study drug components or to any monoclonal antibody 8. Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection 9. Prisoners or patients who are involuntarily incarcerated |
| Recruitment start date | 20/10/2021 |
| Recruitment end date | 31/08/2026 |
Locations
Countries of recruitment
- England
- Northern Ireland
- Scotland
- United Kingdom
- Wales
Study participating centres
Withington
Manchester
M20 4BX
United Kingdom
Freeman Road
High Heaton
Newcastle Upon Tyne
NE7 7DN
United Kingdom
Headley Way
Headington
Oxford
OX3 9DU
United Kingdom
Campus
Hills Road
Cambridge
CB2 0QQ
United Kingdom
London
SW3 6JJ
United Kingdom
Clatterbridge Road
Bebington
Wirral
CH63 4JY
United Kingdom
Coreys Mill Lane
Stevenage
SG1 4AB
United Kingdom
Infirmary Square
Leicester
LE1 5WW
United Kingdom
Sharoe Green Lane North
Fulwood
Preston
PR2 9HT
United Kingdom
Mindelsohn Way
Edgbaston
Birmingham
B15 2GW
United Kingdom
Herries Road
Sheffield
S5 7AU
United Kingdom
London
SW17 0QT
United Kingdom
Charnwood Court
Heol Billingsley
Cardiff
CF15 7QZ
United Kingdom
Barrack Road
Exeter
EX2 5DW
United Kingdom
Westcliff-On-Sea
SS0 0RY
United Kingdom
Colney
Norwich, Norfolk
NR4 7UY
United Kingdom
Westminster Bridge Road
London
SE1 7EH
United Kingdom
Gartnavel Royal Hospital
1055 Great Western Road
Glasgow
G12 0XH
United Kingdom
Beckett Street
Leeds
LS9 7TF
United Kingdom
Guildford
GU2 7XX
United Kingdom
Saintfield Road
Belfast
BT8 8BH
United Kingdom
Sponsor information
Hospital/treatment centre
550 Wilmslow Road
Withington
Manchester
M20 4BX
England
United Kingdom
| Phone | +44 (0)161 918 7432 |
|---|---|
| Wes.Dale@nhs.net | |
| Website | http://www.christie.nhs.uk/ |
"ROR" |
https://ror.org/03v9efr22 |
Funders
Funder type
Industry
Government organisation / For-profit companies (industry)
- Alternative name(s)
- Bristol-Myers Squibb Company, BMS
- Location
- United States of America
Private sector organisation / Other non-profit organizations
- Alternative name(s)
- CR_UK, Cancer Research UK - London, CRUK
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 30/04/2030 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | Planned publication in a high-impact peer reviewed journal. |
| IPD sharing plan | The datasets generated during and/or analysed during the current study are/will be available upon request from detection@liverpool.ac.uk at the end of the trial after primary results have been published, and after review from an internal committee at LCTC and discussion with the CI. It must also be authorised by the Sponsor. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Participant information sheet | version 5.0 | 14/07/2021 | 17/08/2021 | No | Yes |
| HRA research summary | 28/06/2023 | No | No |
Additional files
Editorial Notes
06/03/2023: Due to changes in standard of care guidelines for the patient population (https://www.nice.org.uk/guidance/TA837) a substantial redesign of the protocol is required. Recruitment was halted on 11/11/2022 in order to allow for the redesign to be implemented as a substantial amendment. Since this halt it has been agreed by sponsor and CI that, given the extent of the changes required, the most appropriate course is to terminate the current protocol and to submit a new protocol. Termination of the study has been declared prior to any patient being randomised which prohibits any evaluation of efficacy and by extension and risk/benefit comparison. Total final enrolment added.
26/01/2022: The Cancer Research UK plain English summary has been added.
23/09/2021: The following changes have been made:
1. The recruitment start date has been changed from 01/09/2021 to 20/10/2021.
2. The ClinicalTrials.gov number has been added.
21/09/2021: The study contacts have been updated.
09/07/2021: Trial's existence confirmed by the National Institute for Health Research (NIHR) (UK).
