226TiP - CLEAR-Me: Interception trial to detect and clear molecular residual disease in patients with high-risk melanoma

Background

Adjuvant treatment with single-agent anti-PD-1 immune checkpoint blockade (ICB) is the standard of care for patients (pts) with high-risk melanoma (IIB-IV) following surgical resection. However, a significant proportion of pts still experience disease relapse. To date, no prognostic or predictive biomarker has been established for this patient population. Highly sensitive techniques applied to circulating tumour DNA (ctDNA) have shown promising results as prognostic markers for identifying molecular residual disease following curative treatment in various tumour types. We previously evaluated the longitudinal use of a bespoke ctDNA assay in high-risk melanoma pts following surgical treatment (Sofia Genta et al., JCO [ES1] 40, 9579-9579, 2022) and showed a marked increase in the median overall survival (OS) in pts with undetectable ctDNA post-operatively, compared to pts with detectable ctDNA. Building on this knowledge, we aim to leverage personalized ctDNA testing for early cancer interception and as a surrogate to guide the treatment of high-risk melanoma pts.

Trial design

CLEAR-Me is an investigator-initiated, open-label, ctDNA-based, phase II cancer interception study. This study evaluates whether the combination of an anti-LAG-3 (relatlimab) and an anti-PD-1 (nivolumab) agents is superior to anti-PD-1 inhibition alone in high-risk melanoma pts with detectable ctDNA following definitive surgery. A personalized, amplicon-based NGS assay by NeoGenomics (RaDaR®) is used for ctDNA detection. Pts are randomly assigned (2:1) to receive treatment with BMS-986213 (Arm A: nivolumab/relatlimab) IVQ4W or monotherapy with anti-PD-1 (Arm B: nivolumab) IVQ4W for up to 12 doses. The primary endpoint is clearance of ctDNA at 12 months after starting adjuvant treatment (defined as no detection of plasma ctDNA). Secondary endpoints are relapse-free survival at 12 and 36 months, and safety. Exploratory endpoints include ctDNA methylation (cfMeDIPSeq) pattern dynamics in both arms and their correlation with RaDaR® results. Study enrolment is ongoing. A total of 270 pts will be pre-screened for ctDNA detection with a target accrual of 54 ctDNA-positive pts, of whom 36 will be randomized to Arm A and 18 to Arm B.

Clinical trial identification

NCT06319196.

Editorial acknowledgement

Legal entity responsible for the study

BRAS Drug Development Program - Phase 1 Central Office.

Funding

BMS.

Disclosure

C.G. Smith, B. Ambasager: Other, Institutional, Affiliate: NeoGenomics Inc. A. Carter, C. Pipinikas: Non-Financial Interests, Institutional, Affiliate: NeoGenomics Inc. M.O. Butler: Financial Interests, Personal, Advisory Board: BMS, Merck, Novartis, Adaptimmune, Iovance, GSK, Sanofi, La Roche Posay, Pfizer, Medison, Ideaya, Regeneron; Financial Interests, Personal, Invited Speaker: BMS, Merck, Novartis, Sanofi, Pfizer; Financial Interests, Personal, Advisory Board, Safety Review Committee: Adaptimmune; Financial Interests, Institutional, Other, Conduct Clinical Trial: TCR2, Novartis, Sanofi, Immunocore, GSK, Pfizer, Merck, Bristol Myers Squibb, Regeneron, AstraZeneca, Adaptimmune, Ideaya Biosciences, Amgen, Instil Bio, Turnstone Biologics, Iovance, Ankara; Financial Interests, Institutional, Research Grant, support clinical trial: Merck; Financial Interests, Institutional, Funding, support clinical trial: Takara Bio; Financial Interests, Institutional, Funding, support quality improvement project: Novartis. S. Saibil: Financial Interests, Personal, Invited Speaker: Medison, Novartis. P.L. Bedard: Financial Interests, Institutional, Local PI: AstraZeneca, Bicara, BMS, Amgen, Novartis, Genentech/Roche, Merck, Pfizer, Zymeworks, Lilly, Seagen, Medicenna, DayOneBiopharmaceuticals, LegoChem, Takeda, Gilead; Financial Interests, Institutional, Research Grant: Pfizer; Non-Financial Interests, Member of Board of Directors, Executive Board Member: Breast International Group; Non-Financial Interests, Leadership Role, Chair: AACR Project GENIE; Non-Financial Interests, Leadership Role, Past Chair IND Committee Member, Breast Site Steering Committee: Canadian Clinical Trials Group; Non-Financial Interests, Advisory Role: Seagen, Lilly, Amgen, Merck, BMS, Pfizer, Gilead, Janssen, Repare Therapeutics, Roche. L.L. Siu: Financial Interests, Personal, Advisory Board: Merck, AstraZeneca, Roche, Voronoi, Arvinas, Navire, Relay Therapeutics, Amgen, Marengo, Medicenna, Tubulis, LTZ Therapeutics, Pangea, GSK, Daiichi Sankyo; Financial Interests, Personal, Other, Spouse is co-founder: Treadwell Therapeutics; Financial Interests, Personal, Stocks/Shares, Spouse has stock ownership: Agios; Financial Interests, Institutional, Local PI: Novartis, Bristol Myers Squibb, Pfizer, Boehringer Ingelheim, GSK, Roche/Genentech, AstraZeneca, Merck, Bayer, Amgen, EMD Serono, Biontech, Gilead, Daiichi Sankyo; Financial Interests, Institutional, Coordinating PI: EMD Serono; Non-Financial Interests, Advisory Role: ICR, Dana Farber Harvard Cancer Center, Cancer Grand Challenge, Break Through Cancer. A. Spreafico: Financial Interests, Personal, Advisory Board: Janssen, Merck, BMS, Oncorus, Alentis; Financial Interests, Coordinating PI, Funding paid to the Institutions for trial conduct: Merck, BMS, Roche, Novartis, Oncorus, Janssen, AstraZeneca, Bayer, Treadwell, Nubiyota; Financial Interests, Coordinating PI, Funding paid to the Institution for trial conduct: Symphogen; Financial Interests, Coordinating PI, Funding paid to the Institution for clinical trial conduct: Janssen Oncology/Johnson & Johnson, Regeneron, Alkermes, ArrayBiopharma/Pfizer, GSK, Amgen, ALX Oncology; Financial Interests, Institutional, Local PI, Funding paid to the Institution for trial conduct: Alentis, Servier, Seagen; Financial Interests, Institutional, Local PI, Funding paid to the Institution for trail conduct: Incyte. All other authors have declared no conflicts of interest.