A Multicenter Randomized Open-Label Trial Evaluating ctDNA-Guided Interruption Versus Standard of Care Immune-Checkpoint Inhibitor (ICI) Therapy In Patients With Advanced / Metastatic Solid Tumors.

Official title

A Multicenter Randomized Open-Label Trial Evaluating ctDNA-Guided Interruption Versus Standard of Care Continuous Immune-Checkpoint Inhibitor (ICI) Therapy In Patients With Advanced/Metastatic Solid Tumors

Overview

This is a multicenter, open-label, randomized (1:1) trial designed to evaluate whether ctDNA-guided interruption of immune-checkpoint inhibitor (ICI) therapy provides comparable survival to standard of care (SoC) continuous ICI therapy in patients with histologically confirmed advanced/metastatic non-small cell lung cancer (NSCLC), melanoma, microsatellite instability-high (MSI-High)/Deficient Mismatch Repair (dMMR) colorectal cancer (CRC), renal cell carcinoma (RCC) and other solid tumors. This study will be conducted in up to 100 sites.

Interventions

• Device Signatera Genome ultra-sensitive ctDNA blood test
  The test is used to monitor for disease recurrence.

Primary outcome measures

• To demonstrate that ctDNA-guided intermittent ICI therapy results in at least 50% of patients who do not reinitiate systemic therapy prior to 6 months from randomization. [Time frame: 6 months from randomization]
• To demonstrate that ctDNA-guided intermittent ICI therapy is non-inferior to SoC continuous ICI therapy as measured by 36 month OS in advanced/metastatic solid tumor patients. [Time frame: 3 years from randomization to death from any cause]

Secondary outcome measures (2)

• To compare ctDNA-guided intermittent ICI therapy to SoC continuous ICI therapy as measured by 36 month progression-free survival (PFS) (blinded independent central review [BICR] assessed) in advanced/metastatic solid tumor patients. [Time frame: 3 years from randomization to the first occurrence of disease progression measured by RECIST 1.1 or death from any cause, whichever occurs first]
• To compare the tolerability between the ctDNA-guided intermittent ICI therapy and SoC continuous ICI therapy using the Common Terminology Criteria for Adverse Events (CTCAE) v6.0. [Time frame: From randomization to Year 3]

Eligibility criteria

Inclusion criteria

General inclusion criteria includes the following selection criteria to be eligible for inclusion in any aspect of the study. Eligibility will be assessed by the investigator:

• Signed Informed consent
• Age ≥ 18 years
• ECOG 0-2.
• Histologically confirmed advanced/metastatic solid tumors including:

• Melanoma: Unresectable recurrent, advanced, or metastatic
• NSCLC: Advanced or metastatic
• MSI-High/dMMR CRC: Metastatic
• RCC: Unresectable recurrent, advanced, or metastatic
• Other: Metastatic solid tumors
• Received first line ICI monotherapy or dual-ICI therapy (e.g., PD-1/CTLA-4 combination therapy) for a minimum of 12 months (maximum of 15 months) for NSCLC, RCC \& other metastatic solid tumors, or for a minimum of 6 months (maximum of 9 months) for melanoma and MSI-High /dMMR CRC. Exceptions permitted:

• For patients with NSCLC: First line platinum-based chemo-ICI regimens if on maintenance ICI +/- pemetrexed.
• For patients with melanoma: nivolumab/relatlimab is permissible.
• Radiographic CR/PR: Participants must have CR or PR at the last assessment performed within 6 weeks before randomization according to RECIST v1.1 using a diagnostic CT and/or MRI. Radiographic assessment must be confirmed by the BICR prior to randomization.
• Known ctDNA-negative with a tissue-informed assay

• ≥ 2 consecutive ctDNA-negative results at least 6 weeks apart; last test within 1 month of enrollment.
• Note: A confirmatory Signatera Genome negative test must be completed at enrollment if previous ctDNA testing performed for clinical care was done with a test other than Signatera Genome.
• Adequate organ function:

• Hematology: ANC ≥1500/μL; Platelets ≥100000/μL;Hemoglobin ≥9.0g/dL;
• Renal: Serum Cr ≤1.5×ULN or calculated CrCl ≥60 mL/min (using Cock-Gault formula);
• Hepatic: Total bilirubin ≤1.5 ×ULN or, for participants with total bilirubin levels >1.5×ULN, direct bilirubin within normal limits; AST (SGOT) and ALT (SGPT) ≤2.5×ULN;
• Coagulation: INR or PT, activated partial thromboplastin time (APTT) ≤1.5×ULN Note: Laboratory assessments performed as part of standard of care evaluations during immunotherapy treatment administration may be used to satisfy these eligibility criteria, provided they are obtained within 28 days of enrollment.
• Recovery to baseline or ≤ Grade 1 common terminology criteria for adverse events (CTCAE) v6 from AE(s) related to any prior treatments unless AE(s) are deemed clinically non-significant (e.g., Grade 2 alopecia) by the Investigator and/or stable on supportive therapy.
• No prior malignancy, with the exception of basal cell carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the skin, or in situ cancer, or has undergone potentially curative therapy with no evidence of that disease recurrence for 5 years since completion of definitive therapy
• Participants must be willing and able to comply with study visits, treatment plans, laboratory tests, and other study procedures
• Women of child-bearing potential (WOCBP) and male participants partnering with WOCBP must agree to use highly effective contraception during the treatment phase and at least 180 days post last dose
• Patients must be willing to discontinue clinically-directed ctDNA testing for treatment response monitoring during the period of clinical trial testing as dictated by the protocol.

Exclusion criteria

Patients are not eligible for the study if they meet any of the following criteria, as assessed by the investigator:

• Available alternate treatment options with curative intent, e.g. surgery and / or RT and / or Chemotherapy.
• Symptomatic or progressing CNS metastases; or presence of leptomeningeal disease.
• Patient has active autoimmune disease that required systemic treatment in the past 2 years, is immunocompromised in the opinion of the Investigator, or is receiving systemic immunosuppressive treatment. (Note: Participants with splenectomy are allowed.) Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc) is not considered a form of systemic treatment.
• Patient is receiving systemic steroid therapy ≤3 days prior to enrollment or receiving any other form of immunosuppressive medication with the exception of daily steroid replacement therapy. Note: Use of inhaled corticosteroids, local steroid injection, or steroid eye drops is allowed.
• Had allogeneic tissue/solid organ transplantation.
• Interstitial lung disease or history of pneumonitis that has required oral or IV steroids. Note: Patients with lymphangitic carcinomatosis secondary to NSCLC can be considered as eligible.
• Has received or will receive a live vaccine within 30 days prior to enrollment (seasonal flu vaccines that do not contain live vaccine are permitted).
• Active infection requiring intravenous systemic therapy.
• Known history of human immunodeficiency virus (HIV).
• Known active Hepatitis B or C.
• Pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the study.
• Currently participating or has participated in a study of an investigational agent or using an investigational device within 4 weeks of enrollment.
• Use of any commercial ctDNA or liquid biopsy monitoring outside of the study protocol during the treatment monitoring phase within the protocol.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Publications

• Zalcman G, Madroszyk A, Guenzi E, Dayen C, Molinier O, Egenod T, Pote N, Debieuvre D, Beaucaire-Danel S, Dixmier A, Pichon E, Galland-Girodet S, Giroux-Leprieur E, Cloarec N, Cadranel J, Otto J, Romand P, Favier L, Martinez S, Mascaux C, Odier L, Cortot A, Audigier-Valette C, Langlais A, Amour E, Morin F, Antoine M, Gounant V, Westeel V, Toffart AC. Four-Year Outcomes of First-Line Nivolumab Plus PMID 41690366
• Vokes NI, Pan K, Le X. Efficacy of immunotherapy in oncogene-driven non-small-cell lung cancer. Ther Adv Med Oncol. 2023 Mar 18;15:17588359231161409. doi: 10.1177/17588359231161409. eCollection 2023. PMID 36950275
• Vokes N, Gandara D, Sezer A, Kilickap S, Gümüş M, Bondarenko I, Özgüroğlu M, Gogishvili M, Turk HM, Cicin I, Bentsion D. Circulating tumor DNA (ctDNA) dynamics and survival outcomes in patients with advanced NSCLC and high (> 50%) PD-L1 expression, randomized to cemiplimab vs chemotherapy. In ASCO Annual Meeting, Chicago, IL 2023 Jun.
• Sun L, Bleiberg B, Hwang WT, Marmarelis ME, Langer CJ, Singh A, Cohen RB, Mamtani R, Aggarwal C. Association Between Duration of Immunotherapy and Overall Survival in Advanced Non-Small Cell Lung Cancer. JAMA Oncol. 2023 Aug 1;9(8):1075-1082. doi: 10.1001/jamaoncol.2023.1891. PMID 37270700
• Nakamura Y, Watanabe J, Akazawa N, Hirata K, Kataoka K, Yokota M, Kato K, Kotaka M, Kagawa Y, Yeh KH, Mishima S, Yukami H, Ando K, Miyo M, Misumi T, Yamazaki K, Ebi H, Okita K, Hamabe A, Sokuoka H, Kobayashi S, Laliotis G, Aushev VN, Sharma S, Jurdi A, Liu MC, Aleshin A, Rabinowitz M, Bando H, Taniguchi H, Takemasa I, Kato T, Kotani D, Mori M, Yoshino T, Oki E. ctDNA-based molecular residual disea PMID 39284954
• Martinez-Vila C, Teixido C, Martin R, Aya F, Sudhaman S, Budde GL, Gonzalez-Navarro EA, Alos L, Castrejon N, Ortiz JB, Krainock M, Liu MC, Arance A. Personalized Circulating Tumor DNA Assay to Assess Long-Term Clinical Benefit in Patients with Advanced Melanoma. Cancers (Basel). 2025 Nov 27;17(23):3804. doi: 10.3390/cancers17233804. PMID 41375005
• Larkin J, Sileni VC, Marqueste CG, Rutkowski P, Medina TM, Lao CD, Cowey CL, Schadendorf D, Wagstaff J, Dummer R, Queirolo P. LBA43 10-y survival outcomes from the phase III CheckMate 067 trial of nivolumab plus ipilimumab in advanced melanoma. Annals of Oncology. 2024 Sep 1;35:S1234-5.
• 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. PMID 36869646

Identifiers

NCT: NCT07689812 · 26-107-NCP

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗