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.

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.

Patients meeting eligibility criteria are randomized into two arms:

Arm A (SoC Continuous ICI): Participants will continue current ICI therapy per SoC.

Arm B (ctDNA-Guided Intermittent ICI): Participants will interrupt ICI therapy upon randomization and pursue monitoring that includes serial ctDNA testing. They will reinitiate the same ICI therapy (monotherapy or dual-ICI therapy as documented at enrollment) if they become ctDNA-positive without evidence of radiographic progression. Following reinitiation, ICI therapy may again be interrupted after achievement of ≥ 2 consecutive ctDNA-negative results and subsequently re-initiated upon recurrence of ctDNA positivity without evidence of radiographic progression. This cycle of ctDNA-guided interruption and reinitiation (maximum of 2 ICI interruptions) may continue until radiographic progression is documented. Upon radiographic progression, treatment will be determined by the treating physician in accordance with SoC.

Participants will be followed prospectively from randomization through the end of the treatment monitoring phase for up to 36 months and then survival follow-up, up to 5 years. Participants in both arms will undergo response assessments including imaging (CT/MRI) (BICR review) and ctDNA testing performed q12 weeks; PRO (QLQ-C30, FACT-ICM, PRO-CTCAE & EQ-5D-5L) data collection (q12 weeks); and continued toxicity assessment reviewed per CTCAE v6.0 at each visit and unscheduled contacts.

All data are collected under a unified electronic data-capture (EDC) system with site entry verified by central data management. Core data streams include clinical visits, imaging, ctDNA testing, safety events, PROs, and healthcare resource consumption.

Digitized slides of tissues (obtained either from commercial Signatera tests or upon confirmatory Signatera testing) may be collected for future research. Imaging data collected as part of study procedures may also be centrally archived for exploratory imaging and radiomic analyses.

Optional biobanking: Two 10 mL Streck blood samples may be collected at enrollment and at confirmed disease progression, defined as radiographic progression (per RECIST 1.1), for exploratory biomarker analyses.

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.