A Multicenter Randomized Open-Label Trial Evaluating MRD-Guided Interruption Versus Standard of Care Immune-Checkpoint Inhibitor (ICI) Therapy In Patients With Advanced / Metastatic Solid Tumors. (SIGNAL-IO 301)

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:

1. Signed Informed consent
2. Age ≥ 18 years
3. ECOG 0-2.

4. Histologically confirmed 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

5. Received First line ICI monotherapy or combo for a minimum of 12 months for NSCLC, RCC & other metastatic solid tumors, or for a minimum of 6 months for melanoma and MSI-High /dMMR CRC.
6. 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 will be confirmed by the BICR.

7. Known ctDNA negative with Signatera

   ≥ 2 consecutive ctDNA-negative results (from Natera's tissue-informed Signatera whole genome test) at least 6 wks apart; last test within 1 month of enrollment.

8. 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 subjects 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.

9. 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 by the Investigator and/or stable on supportive therapy.

10. 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.

    Subjects must be willing and able to comply with study visits, treatment plans, laboratory tests, and other study procedures.

11. WOCBP and male subjects partnering with WOCBP must agree to use highly effective contraception during the treatment phase and at least 180 days post last dose.

Exclusion Criteria:

1. Documented presence of a sensitizing EGFR, ALK, ROS-1, or BRAF V600E mutation or other genomic aberration for which an approved targeted therapy is available.
2. Available alternate treatment options with curative intent, e.g. surgery and / or RT with or without Chemotherapy.
3. Symptomatic or progressing CNS mets; or presence of leptomeningeal disease.
4. 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 (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc) is not considered a form of systemic treatment.
5. 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.
6. Had allogeneic tissue/solid organ transplantation.
7. 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.
8. 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).
9. Active infection requiring intravenous systemic therapy.
10. Known history of human immunodeficiency virus (HIV).
11. Known active Hepatitis B or C.
12. Pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the study.
13. Currently participating or has participated in a study of an investigational agent or using an investigational device within 4 weeks of enrollment.
14. Use of any commercial ctDNA or liquid biopsy monitoring outside of the study protocol during the primary 36-month monitoring period.