MelanomaPhase 2CAcTUSNCT03808441
CAcTUS - Circulating Tumour DNA Guided Switch
A Phase 2 study testing ctDNA analysis in people with Melanoma, run by The Christie NHS Foundation Trust at 1 site in United Kingdom.
Trial summary
The stay aims to determine whether switching from targeted therapy to immunotherapy based on a decrease in levels of circulating tumour DNA in the blood, will improve the outcome in melanoma patients. Read more about this study
- Who is it for?
- Ages 16 years and older
- Conditions the study is for
- Melanoma
- What is being tested?
- ctDNA analysis
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 21 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- 2 May 2019to 2 May 2024
- Phase
- Phase 2
- Are there results?
- None posted in the registry
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 16 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- Patient capable of giving written informed consent
- Patients must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests and other requirements of the study.
- Histological confirmation of cutaneous melanoma
- ≥ 16 years
- Stage III un-resectable/ IV disease
- BRAF p.V600E/K/R mutation confirmed (exact point mutation must be provided to the investigators)
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- At least one target lesion measurable by CT or MRI as per RECIST 1.1
- Baseline ctDNA (as defined by the mutant BRAF VAF in plasma) ≥1.5%
- Adequate organ function
- ECOG performance status 0/1
- Prior radiotherapy or radiosurgery must have been completed at least 2 weeks prior to the first dose of study drug
- Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 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 5 half-lives of the drugs they are taking at treatment completion (5 times the half-life = 125 days [nivolumab]; 5 times the half-life = 90 days [ipilimumab]; 5 times the half life = 40 hours [dabrafenib]; 5 times the half life = 50 days [trametinib]) plus 30 days (duration of ovulatory cycle).
- Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment plus 5 half-lives of the study drug as above plus 90 days (duration of sperm turnover).
- Azoospermic males and WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements
Who cannot join
- Prior systemic anti-cancer treatment (immune therapy, targeted therapy, vaccine therapy, or investigational treatment) for unresectable Stage III or Stage IV melanoma.
- Prior adjuvant therapy with BRAF +/- MEK inhibitor or adjuvant therapy with combination PD-1 inhibitor plus CTLA-4 inhibitor. Prior adjuvant therapy with PD-1 inhibitor is allowed so long as relapse occurred > 6 months from discontinuation of treatment and treatment not stopped due to grade 3 or 4 toxicity.
- Current use of a prohibited medication
- 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) 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 patients 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 laboratory evidence of cleared or chronic (not active) HBV and HCV infection will be permitted).
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- A history of glucose-6-phosphate dehydrogenase (G6PD) deficiency.
- Patients with active, known or suspected autoimmune disease. Patients with type 1 diabetes mellitus, 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.
- Patients with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement steroid doses > 10 mg daily prednisone equivalent are permitted in the absence of active autoimmune disease.
- Patients with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity.
- Brain metastases and leptomeningeal metastases are excluded unless:
- Asymptomatic and untreated at presentation, OR
- Symptomatic lesions have been definitively treated with surgery or stereotactic surgery (whole-brain radiation may be given as adjuvant treatment), and do not require steroids for control of symptoms
- Symptomatic metastases, treated or untreated, or metastases requiring steroids to control symptoms, are excluded
- No enzyme inducing anticonvulsants for ≥ 4 weeks prior to randomisation
- 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 New York Heart Association (NYHA) guidelines with an ejection fraction of <50%
- 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;
- Known cardiac metastases;
- Uncorrectable electrolyte abnormalities (e.g. hypokalaemia, hypomagnesaemia, hypocalcaemia), long QT syndrome 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)
- Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments including monoclonal antibodies, their excipients, and/or dimethyl sulfoxide (DMSO) and/or Polysorbate-80-containing infusions.
- Females who are breast-feeding.
- 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
1 site in 1 country.
United Kingdom1 site
The Christie NHS Foundation Trust
Manchester, M20 4BX
About this study
Official title: A Parallel Arm, Biomarker Driven, Phase II Trial to Determine the Role of Circulating Tumour DNA in Guiding a Switch Between Targeted Therapy and Immune Therapy in Patients With Advanced Cutaneous Melanoma
The stay aims to determine whether switching from targeted therapy to immunotherapy based on a decrease in levels of circulating tumour DNA in the blood, will improve the outcome in melanoma patients.
Read the detailed description
The optimal scheduling of targeted and immune therapies in metastatic melanoma is unknown. At present, patients are treated with targeted therapy until acquired resistance develops, and then switched to immune therapy. Pre-clinical data has revealed that BRAF inhibition results in an environment that can enhance immune responses. Tumours responding to BRAF inhibitors but not resistant have been shown to have increased T cell infiltration, improved T cell recognition of melanoma associated antigens and reduced production of immunosuppressive cytokines. Furthermore, in response to targeted therapy LDH levels, which are associated with decreased response to immune therapy reduces, which may improve efficacy of immunotherapy.
A precise definition of response is required in order to decide upon a switch to immune therapy. A radiological definition of response is currently the standard assessment. However a scan at a fixed time point of 2 or 3 months does not reflect the wide range of response dynamics or allow decision making on an individual patient basis. The investigators have developed techniques using circulating tumour DNA (ctDNA) in the metastatic setting, which are able to accurately monitor tumour burden over time.
The aim of this pilot study is to provide a signal as to whether:
- In BRAF mutant melanoma the efficacy of immune therapy is enhanced by response to pre-treatment with MAPK pathway inhibition with dabrafenib + trametinib.
- Changes in ctDNA levels can be used to accurately inform when to switch from targeted to immune therapy.
Data from this study will provide the basis for follow on studies with sufficient power to assess whether tumours responding to BRAF inhibition as defined by response in ctDNA can improve efficacy of immune therapy.
- Conditions
- Melanoma
- Being tested
- ctDNA analysis
- Keywords
- Circulating tumour DNA, targeted therapy, immune therapy, dabrafenib, trametinib, ipilimumab, nivolumab
- Medical subject headings
- Melanoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ctDNA analysisOther
Regular ctDNA analysis, which upon a decrease in mutant BRAF VAF (variant allele frequency) level of ≥80% the switch to N+I is triggered.
| Study group | Role | What they receive |
|---|---|---|
| Standard Arm | No intervention | Dabrafenib + Trametinib Switch to N+I at first progression |
| ctDNA Guided Switch | Active comparator | Dabrafenib + Trametinib
Switch to N+I when ctDNA levels in the blood have dropped by ≥80%. Receives: Other: ctDNA analysis |
What is being measured
The primary outcome is the main question the study is designed to answer.
CtDNA result critical (red) blood samples returned within 7 working days of samples being received in the laboratory
Feasibility of returning samples to hospitals from the laboratory to inform clinical decisions
Measured: 12 months from last patient starting trial treatment
Decrease in ctDNA level of mutant BRAF≥80%
To assess whether a decrease in ctDNA levels of mutant BRAF by ≥80% on targeted therapy is an appropriate cut off for switching to immune therapy
Measured: Through study completion, an average of 1 year
Secondary outcomes (5)
Screen failure due to ctDNA levels of mutant BRAF VAF <1.5% Efficacy
To assess whether BRAF VAF (within the ctDNA) of ≥1.5% is an appropriate target for study inclusion (by assessing the number and proportion of screen failures
Measured: Through study completion, an average of 1 year
First progression free survival (PFS) at 12 months
To explore whether PFS at 12 months would improve in patients switching from targeted to immune therapy on response to treatment as guided by ctDNA levels of mutant BRAF VAF
Measured: Through study completion, an average of 1 year
First progression free survival
Time to first progression in both arms
Measured: When all patients finished follow up, 4 years after last patient starting treatment
Second progression free survival
Time to second progression in both arms
Measured: When all patients finished follow up, 4 years after last patient starting treatment
Overall survival
Explore whether survival outcomes would improve in patients switching from targeted to immune therapy on response to treatment as guided by ctDNA levels of mutant BRAF VAF
Measured: When all patients finished follow up, 4 years after last patient starting treatment
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 Jan 2019
- Study start2 May 2019
- Primary completion26 Apr 2023
- Study completion2 May 2024 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- 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
- None (open label)
- Enrolment
- 21 participants (actual)
Sponsor and investigators
- Lead sponsor
- The Christie NHS Foundation Trust
- Sponsor type
- University, hospital or other
- Collaborators
- Bristol-Myers Squibb, University of Manchester, Manchester Academic Health Science Centre
- Responsible party
- Sponsor
- Investigators
- Paul Lorigan, Principal investigator, The Christie National Health Service (NHS) Foundation Trust
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03808441
- Sponsor's protocol ID
- CFTSp129
- Acronym
- CAcTUS
- Status last verified
- Aug 2023
- First submitted
- 7 Nov 2018
- Last updated
- 25 Aug 2023
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Lee RJ, Rothwell DG, Smith N, Chow S, Delgado-SanMartin J, Mistry H, Sylvestre Y, Chiang SC, Clarke H, Gremel G, Gupta A, Hockenhull K, Kelso N, Kochhar R, Mullan D, Plummer R, Serra P, Shaw H, Summersgill H, Turajlic S, Mouliere F, Marais R, Dive C, Lorigan P. Use of circulating tumour DNA to prospectively guide a switch from targeted to immune therapy in BRAF mutant advanced melanoma: the randomised phase II CAcTUS trial. Nat Commun. 2026 May 21;17(1):6850. doi: 10.1038/s41467-026-72735-8.
PubMed 42168180
Study at a glance
From the registry record, last updated by the sponsor on 25 Aug 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Parallel Arm, Biomarker Driven, Phase II Trial to Determine the Role of Circulating Tumour DNA in Guiding a Switch Between Targeted Therapy and Immune Therapy in Patients With Advanced Cutaneous Melanoma
- ClinicalTrials.gov ID
- NCT03808441
- Acronym / sponsor ID
- CAcTUS / CFTSp129
- Conditions
- Melanoma
- Keywords
- Circulating tumour DNA, targeted therapy, immune therapy, dabrafenib, trametinib, ipilimumab, nivolumab
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 21 participants (actual)
- Lead sponsor
- The Christie NHS Foundation TrustUniversity, hospital or other
- Collaborators
- Bristol-Myers Squibb, University of Manchester, Manchester Academic Health Science Centre
- Study start
- 2 May 2019 (actual)
- Primary completion
- 26 Apr 2023 (actual)
- Study completion
- 2 May 2024 (estimated)
- First posted
- 17 Jan 2019 (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 stay aims to determine whether switching from targeted therapy to immunotherapy based on a decrease in levels of circulating tumour DNA in the blood, will improve the outcome in melanoma patients.
Detailed description
The optimal scheduling of targeted and immune therapies in metastatic melanoma is unknown. At present, patients are treated with targeted therapy until acquired resistance develops, and then switched to immune therapy. Pre-clinical data has revealed that BRAF inhibition results in an environment that can enhance immune responses. Tumours responding to BRAF inhibitors but not resistant have been shown to have increased T cell infiltration, improved T cell recognition of melanoma associated antigens and reduced production of immunosuppressive cytokines. Furthermore, in response to targeted therapy LDH levels, which are associated with decreased response to immune therapy reduces, which may improve efficacy of immunotherapy.
A precise definition of response is required in order to decide upon a switch to immune therapy. A radiological definition of response is currently the standard assessment. However a scan at a fixed time point of 2 or 3 months does not reflect the wide range of response dynamics or allow decision making on an individual patient basis. The investigators have developed techniques using circulating tumour DNA (ctDNA) in the metastatic setting, which are able to accurately monitor tumour burden over time.
The aim of this pilot study is to provide a signal as to whether:
- In BRAF mutant melanoma the efficacy of immune therapy is enhanced by response to pre-treatment with MAPK pathway inhibition with dabrafenib + trametinib.
- Changes in ctDNA levels can be used to accurately inform when to switch from targeted to immune therapy.
Data from this study will provide the basis for follow on studies with sufficient power to assess whether tumours responding to BRAF inhibition as defined by response in ctDNA can improve efficacy of immune therapy.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Standard Arm | No intervention | –Dabrafenib + Trametinib Switch to N+I at first progression |
| ctDNA Guided Switch | Active comparator | Other: ctDNA analysisDabrafenib + Trametinib Switch to N+I when ctDNA levels in the blood have dropped by ≥80%. |
Who may qualify
- Ages
- 16 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (15 listed)
- Patient capable of giving written informed consent
- Patients must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests and other requirements of the study.
- Histological confirmation of cutaneous melanoma
- ≥ 16 years
- Stage III un-resectable/ IV disease
Key exclusion criteria (25 listed)
- Prior systemic anti-cancer treatment (immune therapy, targeted therapy, vaccine therapy, or investigational treatment) for unresectable Stage III or Stage IV melanoma.
- Prior adjuvant therapy with BRAF +/- MEK inhibitor or adjuvant therapy with combination PD-1 inhibitor plus CTLA-4 inhibitor. Prior adjuvant therapy with PD-1 inhibitor is allowed so long as relapse occurred > 6 months from discontinuation of treatment and treatment not stopped due to grade 3 or 4 toxicity.
- Current use of a prohibited medication
- 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) 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 patients safety, obtaining informed consent, or compliance with study procedures.
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 |
|---|---|---|
| ctDNA analysisRegular ctDNA analysis, which upon a decrease in mutant BRAF VAF (variant allele frequency) level of ≥80% the switch to N+I is triggered. | Other | ctDNA Guided Switch |
Primary outcome
CtDNA result critical (red) blood samples returned within 7 working days of samples being received in the laboratory
Time frame: 12 months from last patient starting trial treatment
Feasibility of returning samples to hospitals from the laboratory to inform clinical decisions
Decrease in ctDNA level of mutant BRAF≥80%
Time frame: Through study completion, an average of 1 year
To assess whether a decrease in ctDNA levels of mutant BRAF by ≥80% on targeted therapy is an appropriate cut off for switching to immune therapy
5 secondary outcomes
Screen failure due to ctDNA levels of mutant BRAF VAF <1.5% Efficacy
Time frame: Through study completion, an average of 1 year
First progression free survival (PFS) at 12 months
Time frame: Through study completion, an average of 1 year
First progression free survival
Time frame: When all patients finished follow up, 4 years after last patient starting treatment
Second progression free survival
Time frame: When all patients finished follow up, 4 years after last patient starting treatment
Overall survival
Time frame: When all patients finished follow up, 4 years after last patient starting treatment
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 Aug 2023.
- Derived from this study: PubMed 42168180Lee RJ, Rothwell DG, Smith N, Chow S, Delgado-SanMartin J, Mistry H, Sylvestre Y, Chiang SC, Clarke H, Gremel G, Gupta A, Hockenhull K, Kelso N, Kochhar R, Mullan D, Plummer R, Serra P, Shaw H, Summersgill H, Turajlic S, Mouliere F, Marais R, Dive C, Lorigan P. Use of circulating tumour DNA to prospectively guide a switch from targeted to immune therapy in BRAF mutant advanced melanoma: the randomised phase II CAcTUS trial. Nat Commun. 2026 May 21;17(1):6850. doi: 10.1038/s41467-026-72735-8.
- Individual participant dataSharing planned: No
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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. This study is not recruiting at the moment.
Paul Lorigan principal investigator
The Christie National Health Service (NHS) Foundation Trust
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing ctDNA analysis in people with Melanoma, run by The Christie NHS Foundation Trust at 1 site in United Kingdom.
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 15 inclusion and 25 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: status not confirmed, as of the sponsor's last update on 25 Aug 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
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?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
CtDNA result critical (red) blood samples returned within 7 working days of samples being received in the laboratory (time frame: 12 months from last patient starting trial treatment). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03808441, which also lists 1 linked publication.
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 25 Aug 2023.