MelanomaPhase 2DyNAMIcNCT06470880
Circulating Tumour DNA Guided Adaptive BRAF and MEK Inhibitor Therapy
A Phase 2 study testing Adaptive Therapy in people with Melanoma, run by The Christie NHS Foundation Trust.
Trial summary
The goal of this clinical trial is to investigate adaptive therapy in late-stage cutaneous melanoma. The main question it aims to answer are: If the patient having breaks in their treatment allows the less resistant cells to continue to grow, this would result in a tumour with a lower proportion of resistant cells… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Melanoma
- What is being tested?
- Adaptive Therapy
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 40 participants
- Where
- No sites listed yet
- Study dates
- Jun 2024to Jun 2027
- Phase
- Phase 2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- At Screening
- Written and informed consent obtained from participant and agreement of participant to comply with the requirements of the study
- Histological confirmation of cutaneous melanoma
- ≥ 18 years of age
- Stage III un-resectable/ IV disease
- Measurable disease on CT (thorax, abdomen and pelvis, ± neck if indicated) and/or PET-CT, and CT or MRI (brain) scan (RECIST v1.1)
Show all 17Show fewer
- BRAF p.V600E/K/R/D mutation confirmed (exact point mutation must be known)
- ECOG performance status 0/1/2
- Prior radiotherapy or radiosurgery must have been completed at least 2 weeks prior to the first dose of study drugs
- Adequate organ function as defined below:
- Haemoglobin ≥ 9 g/dL ii. White blood count ≥ 2 x109/L iii. ANCa ≥ 1.2 x109/L iv. Platelet count ≥ 75 x109/L v. Albumin ≥ 2.5 g/dL vi. Total bilirubinb ≤ 1.5 x ULNa vii. ASTa or ALTa ≤ 3 x ULNa viii. Calculated creatinine clearance ≥ 30ml/min
- Women of childbearing potential participating in the study (WOCBP see Appendix B for definition) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of study drug.
- WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drugs plus at least 28 days following last dose of drug (either encorafenib or binimetinib), (see Appendix B).
- Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment plus 90 days (duration of sperm turnover) from last dose of drug (either encorafenib or binimetinib), (see Appendix B).
- At randomisation:
- Left Ventricular Ejection fraction (LVEF) ≥ 50% or ≥LLNa by ECHO
- BRAF ctDNA TAB level of ≥15 copies/ml of plasma
Who cannot join
- Prior systemic targeted BRAF/MEKi therapy for stage IV (metastatic) melanoma (treatment for stage III allowed as long as RFS ≥26 weeks following discontinuation of drugs)
- BRAF wild-type malignant melanoma
- Metastasis to the brain or leptomeninges
- Any contraindication to treatment with encorafenib or binimetinib as per the local Summary of Product Characteristics
- Hypersensitivity to the active substance or to any of the excipients of encorafenib or binimetinib
- Current use of a prohibited medication as described in Section 8.9
Show all 19Show fewer
- History of another malignancy. Exception: Patients who have been disease-free for 3 years, (i.e. patients with second malignancies that are indolent or definitively treated at least 3 years ago), curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS); stage 1, grade I endometrial carcinoma, or patients with a history of completely resected non-melanoma skin cancer. No additional therapy should be required whilst the patient is on study
- 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
- Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection
- Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption
- Child Pugh B or C liver disease
- Coronary syndromes (including myocardial infarction within 6 months or unstable angina)
- A history or evidence of current ≥ Class II congestive heart failure as defined by the NYHA guidelines with an ejection fraction of <50% (see appendix C)
- Treatment refractory hypertension defined as a blood pressure of systolic >150 mmHg and/or diastolic >95 mm Hg on >3 occasions which cannot be controlled by anti-hypertensive therapy
- Uncorrectable electrolyte abnormalities > CTCAE v5 Grade 1 (e.g. hypokalaemia, hypomagnesaemia, hypocalcaemia), long QT syndrome (baseline 1 QTC interval ≥ 480msec) or taking medicinal products known to prolong the QT interval
- A history or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR) including presence of predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled hypertension, uncontrolled diabetes mellitus, or a history of hyperviscosity or hypercoagulability syndromes)
- Females who are pregnant or breast-feeding and are not able to stop breast-feeding prior to first dose of study drugs (see section 7.5)
- Prisoners or patients who are involuntarily incarcerated
- Patients who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness
Trial locations and contacts
No sites are listed yet. Contact the study team or a site near you to ask about taking part.
Research Group Project Manager contact
About this study
The goal of this clinical trial is to investigate adaptive therapy in late-stage cutaneous melanoma. The main question it aims to answer are:
If the patient having breaks in their treatment allows the less resistant cells to continue to grow, this would result in a tumour with a lower proportion of resistant cells, making the tumour less resistant to the treatment, an increasing the time it takes for the disease to progress?
Read more
Participants will
- Receive their allocated treatment regimen until their cancer progresses, they or their doctor withdraw them from the study, or until the study ends, whichever happens first.
- Attend fortnightly visits to hospital.
- Complete EORTC QLQ-C30 and PRO-CTCAE questionnaires, prior to treatment, every 12 weeks and at the point of cancer progression, to assess quality of life.
Researchers will compare the adaptive therapy participant arm with a standard of care arm to answer the research question described above.
Read the detailed description
Encorafenib and binimetinib given in combination ("the treatment") is a standard of care treatment in the UK for late stage cutaneous melanoma, a skin cancer that starts in the cells that produce skin pigmentation. 'Late stage' means it can't be surgically removed, or has spread. The treatment is taken daily. Resistance to the treatment can develop after about 12-15 months. During this period, the treatment will kill the less resistant cells, meaning the tumour has a greater proportion of cells that are resistant to the treatment.
This study aims to investigate if the patient having breaks in their treatment allows the less resistant cells to continue to grow, this would result in a tumour with a lower proportion of resistant cells, making the tumour as a whole less resistant to the treatment, and increasing the time it takes for the disease to progress. A blood test that measures the amount of tumour DNA circulating in the patient's blood (known as ctDNA) will be conducted every two weeks to check if the cancer cells are still present, and if they are becoming active. The result of this test will allow doctors to monitor the activity of the tumour and judge when to pause and resume treatment. This intermittent treatment is called 'adaptive therapy'. The investigators intend to recruit 40 participants with late stage cutaneous melanoma from NHS hospitals in the UK. Ten will receive the standard, daily treatment, and thirty will receive adaptive therapy. Patients will receive their allocated treatment regimen until their cancer progresses, they or their doctor withdraw them from the study, or until the study ends, whichever happens first. As well as the fortnightly visits to hospital, patients will required to complete EORTC QLQ-C30 and PRO-CTCAE questionnaires in order for their quality of life to be assessed. These will be completed before their treatment starts; every 12 weeks from when they start treatment; and again if their cancer progresses.
- Conditions
- Melanoma
- Being tested
- Adaptive Therapy, Standard of Care
- Keywords
- Adaptive Therapy
- Medical subject headings
- Melanoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Adaptive TherapyDrug
A blood test that measures the amount of tumour DNA circulating in the patient's blood (known as ctDNA) will be conducted every two weeks to check if the cancer cells are still present, and if they are becoming active. The result of this test will allow doctors to monitor the activity of the tumour and judge when to pause and resume encorafenib and binimetinib treatment. This intermittent treatment is called 'adaptive therapy'.
Standard of CareDrug
Encorafenib and binimetinib delivered to UK standard of care.
| Study group | Role | What they receive |
|---|---|---|
| ARM A: Standard of care | Active comparator | Continuous dosing of encorafenib 450mg once daily plus binimetinib 45mg twice daily. Receives: Drug: Standard of Care |
| ARM B: Adaptive therapy | Experimental | 4 weeks of encorafenib 450mg once daily plus binimetinib 45mg twice daily, followed by adaptive cycles based on ctDNA TAB level Receives: Drug: Adaptive Therapy |
What is being measured
The primary outcome is the main question the study is designed to answer.
To measure tumour response to re-introduction of encorafenib plus binimetinib following the first "drug off " period.
Specific measure: Maximal reduction in percentage ctDNA mutant BRAF copies/ml of plasma from baseline 2 TAB level upon restart of E+B following first drug off period.
Measured: 3 years (Longitudinally throughout the study)
Secondary outcomes (12)
To measure the thresholds of percentage reduction in TAB level in ctDNA as a measure of response to stop drugs and the percentage increase in TAB as a decision to restart drugs.
Specific measure: ctDNA mutant BRAF copies/ml of plasma
Measured: 3 years (Longitudinally throughout the study)
To measure maximal response (complete response (CR)/partial response (PR)/stable disease (SD)/progressive disease (PD)) to therapy in Arm A vs. Arm B
Specific measure: Maximal radiological response (complete response (CR)/partial response (PR)/stable disease (SD)/progressive disease (PD)) using RECIST v1.1 criteria
Measured: Randomisation until RECIST progression/clinical deterioration (estimated 12 months)
To measure progression free survival (PFS) in Arm A vs. Arm B
Specific measure: Percentage of participants who have experienced disease progression or death. PFS defined as time from randomisation to radiological (RECIST v1.1 and in Arm B defined as radiological progression whilst on targeted therapy unless stopped due to toxicity/choice) progression
Measured: 3 years (Continuously throughout the study)
To measure time to clinical deterioration in Arm A vs. Arm B.
Specific measure:Time to clinical deterioration. Defined as either the point of radiological progression (defined as per RECIST v1.1) or in participants treated beyond radiological progression, at the time of clinically determined deterioration defined at the discretion of the treating clinician, specifically due to progression of the underlying cancer
Measured: 3 years (Continuously throughout the study)
To measure overall survival in Arm A vs. Arm B
Specific measure: Overall survival (OS) defined as time from randomisation until death from any cause
Measured: 3 years (Continuously throughout the study)
To measure melanoma specific overall survival in Arm A vs. Arm B
Specific measure: Overall survival (OS) defined as time from randomisation until death from melanoma
Measured: 3 years (Continuously throughout the study)
To measure number of adaptive therapy cycles completed by participants on Arm B
Specific measure: Number of adaptive therapy cycles completed
Measured: 3 years (Longitudinally throughout the study)
To measure median duration of adaptive therapy cycles completed by participants on Arm B
Specific measure: Median duration of adaptive therapy cycles
Measured: 3 years (Longitudinally throughout the study)
To measure whether ctDNA result can be provided within 5 working days from sample receipt into NBC
Specific measure: Percentage of ctDNA results reported within 5 days from sample receipt into NBC
Measured: 3 years (Longitudinally throughout the study)
To measure quality of life in Arm A vs. Arm B
Specific measure: EORTC QLQ-C30 (standardised tool, scored as outlined by EORTC)
Measured: 3 years (Longitudinally throughout the study)
To measure quality of life in Arm A vs. Arm B
Specific measure: PRO-CTCAE (standardised tool, scored as outlined by NIH)
Measured: 3 years (Longitudinally throughout the study)
To measure toxicity (all grade adverse events) in Arm A vs. Arm B
Specific measure: Adverse Events and Serious Adverse Events defined by CTCAE version 5
Measured: 3 years (Continuously throughout the study)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Jun 2024
- Study startJun 2024 (estimated)
- Primary completionJun 2026 (estimated)
- Study completionJun 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for MelanomaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind
- Who is masked
- Participant
- Enrolment
- 40 participants (estimated)
Sponsor and investigators
- Lead sponsor
- The Christie NHS Foundation Trust
- Sponsor type
- University, hospital or other
- Collaborators
- University of Manchester, University of Liverpool
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06470880
- Sponsor's protocol ID
- CFTSp175
- Acronym
- DyNAMIc
- Status last verified
- Jun 2024
- First submitted
- 13 May 2024
- Last updated
- 24 Jun 2024
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No: Grouped, anonymised data will be made available after the study has ended.
Study at a glance
From the registry record, last updated by the sponsor on 24 Jun 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Circulating Tumour DNA Guided Adaptive BRAF and MEK Inhibitor Therapy
- ClinicalTrials.gov ID
- NCT06470880
- Acronym / sponsor ID
- DyNAMIc / CFTSp175
- Conditions
- Melanoma
- Keywords
- Adaptive Therapy
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Not yet recruiting
- Enrolment
- 40 participants (estimated)
- Lead sponsor
- The Christie NHS Foundation TrustUniversity, hospital or other
- Collaborators
- University of Manchester, University of Liverpool
- Study start
- Jun 2024 (estimated)
- Primary completion
- Jun 2026 (estimated)
- Study completion
- Jun 2027 (estimated)
- First posted
- 24 Jun 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The goal of this clinical trial is to investigate adaptive therapy in late-stage cutaneous melanoma. The main question it aims to answer are:
If the patient having breaks in their treatment allows the less resistant cells to continue to grow, this would result in a tumour with a lower proportion of resistant cells, making the tumour less resistant to the treatment, an increasing the time it takes for the disease to progress?
Participants will
- Receive their allocated treatment regimen until their cancer progresses, they or their doctor withdraw them from the study, or until the study ends, whichever happens first.
- Attend fortnightly visits to hospital.
- Complete EORTC QLQ-C30 and PRO-CTCAE questionnaires, prior to treatment, every 12 weeks and at the point of cancer progression, to assess quality of life.
Researchers will compare the adaptive therapy participant arm with a standard of care arm to answer the research question described above.
Detailed description
Encorafenib and binimetinib given in combination ("the treatment") is a standard of care treatment in the UK for late stage cutaneous melanoma, a skin cancer that starts in the cells that produce skin pigmentation. 'Late stage' means it can't be surgically removed, or has spread. The treatment is taken daily. Resistance to the treatment can develop after about 12-15 months. During this period, the treatment will kill the less resistant cells, meaning the tumour has a greater proportion of cells that are resistant to the treatment.
This study aims to investigate if the patient having breaks in their treatment allows the less resistant cells to continue to grow, this would result in a tumour with a lower proportion of resistant cells, making the tumour as a whole less resistant to the treatment, and increasing the time it takes for the disease to progress. A blood test that measures the amount of tumour DNA circulating in the patient's blood (known as ctDNA) will be conducted every two weeks to check if the cancer cells are still present, and if they are becoming active. The result of this test will allow doctors to monitor the activity of the tumour and judge when to pause and resume treatment. This intermittent treatment is called 'adaptive therapy'. The investigators intend to recruit 40 participants with late stage cutaneous melanoma from NHS hospitals in the UK. Ten will receive the standard, daily treatment, and thirty will receive adaptive therapy. Patients will receive their allocated treatment regimen until their cancer progresses, they or their doctor withdraw them from the study, or until the study ends, whichever happens first. As well as the fortnightly visits to hospital, patients will required to complete EORTC QLQ-C30 and PRO-CTCAE questionnaires in order for their quality of life to be assessed. These will be completed before their treatment starts; every 12 weeks from when they start treatment; and again if their cancer progresses.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (participant)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| ARM A: Standard of care | Active comparator | Drug: Standard of CareContinuous dosing of encorafenib 450mg once daily plus binimetinib 45mg twice daily. |
| ARM B: Adaptive therapy | Experimental | Drug: Adaptive Therapy4 weeks of encorafenib 450mg once daily plus binimetinib 45mg twice daily, followed by adaptive cycles based on ctDNA TAB level |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (17 listed)
- At Screening
- Written and informed consent obtained from participant and agreement of participant to comply with the requirements of the study
- Histological confirmation of cutaneous melanoma
- ≥ 18 years of age
- Stage III un-resectable/ IV disease
Key exclusion criteria (19 listed)
- Prior systemic targeted BRAF/MEKi therapy for stage IV (metastatic) melanoma (treatment for stage III allowed as long as RFS ≥26 weeks following discontinuation of drugs)
- BRAF wild-type malignant melanoma
- Metastasis to the brain or leptomeninges
- Any contraindication to treatment with encorafenib or binimetinib as per the local Summary of Product Characteristics
- Hypersensitivity to the active substance or to any of the excipients of encorafenib or binimetinib
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Adaptive TherapyA blood test that measures the amount of tumour DNA circulating in the patient's blood (known as ctDNA) will be conducted every two weeks to check if the cancer cells are still present, and if they are becoming active. The result of this test will allow doctors to monitor the activity of the tumour and judge when to pause and resume encorafenib and binimetinib treatment. This intermittent treatment is called 'adaptive therapy'. | Drug | ARM B: Adaptive therapy |
| Standard of CareEncorafenib and binimetinib delivered to UK standard of care. | Drug | ARM A: Standard of care |
Primary outcome
To measure tumour response to re-introduction of encorafenib plus binimetinib following the first "drug off " period.
Time frame: 3 years (Longitudinally throughout the study)
Specific measure: Maximal reduction in percentage ctDNA mutant BRAF copies/ml of plasma from baseline 2 TAB level upon restart of E+B following first drug off period.
12 secondary outcomes
To measure the thresholds of percentage reduction in TAB level in ctDNA as a measure of response to stop drugs and the percentage increase in TAB as a decision to restart drugs.
Time frame: 3 years (Longitudinally throughout the study)
To measure maximal response (complete response (CR)/partial response (PR)/stable disease (SD)/progressive disease (PD)) to therapy in Arm A vs. Arm B
Time frame: Randomisation until RECIST progression/clinical deterioration (estimated 12 months)
To measure progression free survival (PFS) in Arm A vs. Arm B
Time frame: 3 years (Continuously throughout the study)
To measure time to clinical deterioration in Arm A vs. Arm B.
Time frame: 3 years (Continuously throughout the study)
To measure overall survival in Arm A vs. Arm B
Time frame: 3 years (Continuously throughout the study)
To measure melanoma specific overall survival in Arm A vs. Arm B
Time frame: 3 years (Continuously throughout the study)
To measure number of adaptive therapy cycles completed by participants on Arm B
Time frame: 3 years (Longitudinally throughout the study)
To measure median duration of adaptive therapy cycles completed by participants on Arm B
Time frame: 3 years (Longitudinally throughout the study)
To measure whether ctDNA result can be provided within 5 working days from sample receipt into NBC
Time frame: 3 years (Longitudinally throughout the study)
To measure quality of life in Arm A vs. Arm B
Time frame: 3 years (Longitudinally throughout the study)
To measure quality of life in Arm A vs. Arm B
Time frame: 3 years (Longitudinally throughout the study)
To measure toxicity (all grade adverse events) in Arm A vs. Arm B
Time frame: 3 years (Continuously throughout the study)
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 24 Jun 2024.
- Individual participant dataSharing planned: No. Grouped, anonymised data will be made available after the study has ended.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Research Group Project Manager contact
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Adaptive Therapy in people with Melanoma, run by The Christie NHS Foundation Trust.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 17 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: opening soon, as of the sponsor's last update on 24 Jun 2024. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Trial Project Manager (0000, dynamic_study@liverpool.ac.uk), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
To measure tumour response to re-introduction of encorafenib plus binimetinib following the first "drug off " period. (time frame: 3 years (Longitudinally throughout the study)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Jun 2024.