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.

Prior treatment

• Available alternate treatment options with curative intent, e.g. surgery and / or RT and / or Chemotherapy (patient is considered a candidate for curative-intent therapy, including but not limited to surgical resection, radiotherapy, and/or systemic chemotherapy, as determined by the investigator).
• 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.
• Currently participating or has participated in a study of an investigational agent or using an investigational device within 4 weeks of enrollment.

Other illness

• Symptomatic or progressing CNS metastases; or presence of leptomeningeal disease.
• 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.
• Active infection requiring intravenous systemic therapy.
• History of human immunodeficiency virus (HIV), Hepatitis B, or Hepatitis C infection that is untreated and/or with a detectable viral load.

Other

• Patients are not eligible for the study if they meet any of the following criteria, as assessed by the investigator:
• Pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the study.
• Use of any commercial ctDNA or liquid biopsy monitoring outside of the study protocol during the treatment monitoring phase within the protocol.

• Patients must meet all the following selection criteria to be eligible for 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.
  • Participants with melanoma, NSCLC, or history of CNS lesions require MRI brain scan to confirm CNS disease status and response.
  • For participants with metastatic skin or dermal lesions (e.g., melanoma) not adequately accessible by imaging, standardized photographic documentation may be used to support confirmation of PR or CR.
• 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 ≥1000/μL; Platelets ≥75000/μL;Hemoglobin ≥8.0g/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 \>3×ULN, direct bilirubin within normal limits; AST (SGOT) and ALT (SGPT) ≤3×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 3 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.