Power of Liquid Biopsy Tracking in Immunotherapy Treated Stage IV Melanoma (PerceIVe)

The advent of immune ICI has remarkably improved survival in advanced melanoma patients in the last decade. Long term responders following 2 years of treatment with immunotherapy go on to surveillance with frequent radiological imaging every 3-6 months up to 5-10 years. This not only exposes patients with a relatively low risk of recurrence to significant amounts of ionising radiation, but also increases the burden and cost on already stretched radiology departments. Therefore, this study aims to assess the feasibility and patient experience of using ctDNA with minimally invasive liquid biopsy assays as a biomarker for detecting disease relapse or progression at the point of radiological progression. Data from this pilot study will help to design a future validation study for establishing optimal liquid biopsy for surveillance in advanced melanoma patients.

Study Overview

• Status: Not yet recruiting
• Conditions: Metastatic Melanoma

Detailed Description

This prospective study will measure ctDNA in a simple plasma sample and using a dried blood spot assay, collected at the time of radiological disease progression. We will investigate the use of tumour informed and tumour naïve approaches, assessing targeted sequencing, copy number variations using whole genome low depth sequencing, fragmentomics and methylation as potential methods to improve molecular recurrence detection. We will also collect urine samples to investigate the use of cfDNA to detect relapse in the brain, which has been noted to be more challenging to detect using ctDNA in the blood than other sites of relapse.

In addition, we will investigate the use of novel immunophenotyping technology through a collaboration with MelioHealth (IMU) in the same setting. The IMU platform combines high resolution cellular analysis and machine learning to enable high-content, high-throughput and real-time cellular immunophenotyping from less than 2ml of whole blood. We hypothesize that disease relapse following immunotherapy may detectably trigger a patient's immune system memory, which may be particularly important for those patients who do not shed ctDNA.

• Study Type: Observational
• Enrollment (Estimated): 100

Contacts and Locations

• Study Contact: Name: Arjun Modi, MSc; Phone Number: 020 7352 8171; Email: arjun.modi@rmh.nhs.uk
• Study Contact Backup: Name: Laura Boddy; Phone Number: 020 7352 8171; Email: laura.boddy@rmh.nhs.uk

Study Locations

• United Kingdom
  • London
    • Chelsea, London, United Kingdom, SW3 6JJ
      • The Royal Marsden
      • Contact: Kate Young, MD
      • Contact: Javi Pozas, MD; Phone Number: 020 7352 8171; Email: javi.pozas@rmh.nhs.uk
      • Contact: Laura Boddy; Email: laura.boddy@rmh.nhs.uk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients are being enrolled from either relapsed unresectable Stage III or Stage IV melanomas

Description

Inclusion Criteria:

• Histologically proven melanoma
• Unresectable stage III or stage IV disease, with confirmed radiological disease progression within 1 month of recruitment
• Patient has received at least 1 cycle of immunotherapy with checkpoint inhibitors for melanoma
• Undergoing standard of care active treatment with regular interval imaging or routine imaging surveillance following treatment completion/cessation
• Age over 16
• Not previously diagnosed with HIV, Hepatitis B or C (does not need testing)

Exclusion Criteria:

• Not on routine surveillance with interval imaging per standard of care
• Unable to provide informed consent due to psychological, medical or cognitive conditions.
• Unable to comply with schedule of study samples to be collected. Concurrent active malignancies needing treatment

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Histologically proven melanoma; Unresectable stage III or stage IV disease, with confirmed radiological disease progression within 1 month of recruitment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients with measurable ctDNA at the point of radiological disease progression	Proportion positive of ctDNA assays vs. standard imaging including CT, MRI or PET scans depending upon site of disease relapse	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Patient acceptance of liquid biopsy measured by proportion of enrolled patients to those invited to participate in the study	Patient satisfaction with using liquid biopsy for each assay measured by a question on satisfaction (Yes/No/Undecided)	1 year
Cost of standard imaging pathway and additional cost of using liquid biopsy testing	To assess the cost of standard imaging pathway and additional cost of using liquid biopsy testing	1 year
Proportion of patients with positive tests in the different liquid biopsy assays to detect disease relapse	To assess the sensitivity of different liquid biopsy assays, including plasma vs blood spot for measuring ctDNA at point of disease progression	1 year

Collaborators and Investigators

• Sponsor: Royal Marsden NHS Foundation Trust

Publications and helpful links

General Publications

• Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, Cowey CL, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hogg D, Hill A, Marquez-Rodas I, Haanen J, Guidoboni M, Maio M, Schoffski P, Carlino MS, Lebbe C, McArthur G, Ascierto PA, Daniels GA, Long GV, Bastholt L, Rizzo JI, Balogh A, Moshyk A, Hodi FS, Wolchok JD. Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med. 2019 Oct 17;381(16):1535-1546. doi: 10.1056/NEJMoa1910836. Epub 2019 Sep 28.
• MANDEL P, METAIS P. [Nuclear Acids In Human Blood Plasma]. C R Seances Soc Biol Fil. 1948 Feb;142(3-4):241-3. No abstract available. French.
• Eroglu Z, Krinshpun S, Kalashnikova E, Sudhaman S, Ozturk Topcu T, Nichols M, Martin J, Bui KM, Palsuledesai CC, Malhotra M, Olshan P, Markowitz J, Khushalani NI, Tarhini AA, Messina JL, Aleshin A. Circulating tumor DNA-based molecular residual disease detection for treatment monitoring in advanced melanoma patients. Cancer. 2023 Jun 1;129(11):1723-1734. doi: 10.1002/cncr.34716. Epub 2023 Mar 4.
• Lee RJ, Gremel G, Marshall A, Myers KA, Fisher N, Dunn JA, Dhomen N, Corrie PG, Middleton MR, Lorigan P, Marais R. Circulating tumor DNA predicts survival in patients with resected high-risk stage II/III melanoma. Ann Oncol. 2018 Feb 1;29(2):490-496. doi: 10.1093/annonc/mdx717.
• Pascual J, Attard G, Bidard FC, Curigliano G, De Mattos-Arruda L, Diehn M, Italiano A, Lindberg J, Merker JD, Montagut C, Normanno N, Pantel K, Pentheroudakis G, Popat S, Reis-Filho JS, Tie J, Seoane J, Tarazona N, Yoshino T, Turner NC. ESMO recommendations on the use of circulating tumour DNA assays for patients with cancer: a report from the ESMO Precision Medicine Working Group. Ann Oncol. 2022 Aug;33(8):750-768. doi: 10.1016/j.annonc.2022.05.520. Epub 2022 Jul 6.
• Teixido C, Castillo P, Martinez-Vila C, Arance A, Alos L. Molecular Markers and Targets in Melanoma. Cells. 2021 Sep 5;10(9):2320. doi: 10.3390/cells10092320.
• Lee JH, Menzies AM, Carlino MS, McEvoy AC, Sandhu S, Weppler AM, Diefenbach RJ, Dawson SJ, Kefford RF, Millward MJ, Al-Ogaili Z, Tra T, Gray ES, Wong SQ, Scolyer RA, Long GV, Rizos H. Longitudinal Monitoring of ctDNA in Patients with Melanoma and Brain Metastases Treated with Immune Checkpoint Inhibitors. Clin Cancer Res. 2020 Aug 1;26(15):4064-4071. doi: 10.1158/1078-0432.CCR-19-3926. Epub 2020 Apr 22.
• Syeda MM, Wiggins JM, Corless BC, Long GV, Flaherty KT, Schadendorf D, Nathan PD, Robert C, Ribas A, Davies MA, Grob JJ, Gasal E, Squires M, Marker M, Garrett J, Brase JC, Polsky D. Circulating tumour DNA in patients with advanced melanoma treated with dabrafenib or dabrafenib plus trametinib: a clinical validation study. Lancet Oncol. 2021 Mar;22(3):370-380. doi: 10.1016/S1470-2045(20)30726-9. Epub 2021 Feb 12.
• Tan L, Sandhu S, Lee RJ, Li J, Callahan J, Ftouni S, Dhomen N, Middlehurst P, Wallace A, Raleigh J, Hatzimihalis A, Henderson MA, Shackleton M, Haydon A, Mar V, Gyorki DE, Oudit D, Dawson MA, Hicks RJ, Lorigan P, McArthur GA, Marais R, Wong SQ, Dawson SJ. Prediction and monitoring of relapse in stage III melanoma using circulating tumor DNA. Ann Oncol. 2019 May 1;30(5):804-814. doi: 10.1093/annonc/mdz048.
• Tan AC, Emmett L, Lo S, Liu V, Kapoor R, Carlino MS, Guminski AD, Long GV, Menzies AM. FDG-PET response and outcome from anti-PD-1 therapy in metastatic melanoma. Ann Oncol. 2018 Oct 1;29(10):2115-2120. doi: 10.1093/annonc/mdy330.

Helpful Links

• Recommendations | Melanoma: assessment and management | Guidance | NICE

Study record dates

Study Major Dates

• Study Start (Estimated): February 1, 2025
• Primary Completion (Estimated): January 1, 2028
• Study Completion (Estimated): January 1, 2029

Study Registration Dates

• First Submitted: November 22, 2024
• First Submitted That Met QC Criteria: November 25, 2024
• First Posted (Actual): November 29, 2024

Study Record Updates

• Last Update Posted (Actual): November 29, 2024
• Last Update Submitted That Met QC Criteria: November 25, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: advanced melanoma; ctDNA testing; immune checkpoint inhibitors (ICI)
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Skin Diseases; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Skin Neoplasms; Melanoma
• Other Study ID Numbers: CCR6083

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Observational Pilot study, no plans to share the IPD.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No