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. (SIGNAL-IO 301)

July 31, 2026 updated by: Natera, Inc.

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

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.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Estimated)

920

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

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 advanced/metastatic solid tumors including:

    1. Melanoma: Unresectable recurrent, advanced, or metastatic
    2. NSCLC: Advanced or metastatic
    3. MSI-High/dMMR CRC: Metastatic
    4. RCC: Unresectable recurrent, advanced, or metastatic
    5. Other: Metastatic solid tumors

  5. 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.
  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 must be confirmed by the BICR prior to randomization.

  7. 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.

  8. Adequate organ function:

    1. Hematology: ANC ≥1500/μL; Platelets ≥100000/μL;Hemoglobin ≥9.0g/dL;
    2. Renal: Serum Cr ≤1.5×ULN or calculated CrCl ≥60 mL/min (using Cock-Gault formula);
    3. 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;
    4. 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.
  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 (e.g., Grade 2 alopecia) 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
  11. Participants must be willing and able to comply with study visits, treatment plans, laboratory tests, and other study procedures
  12. 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
  13. 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:

  1. Available alternate treatment options with curative intent, e.g. surgery and / or RT and / or Chemotherapy.
  2. Symptomatic or progressing CNS metastases; or presence of leptomeningeal disease.
  3. 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.
  4. 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.
  5. Had allogeneic tissue/solid organ transplantation.
  6. 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.
  7. 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).
  8. Active infection requiring intravenous systemic therapy.
  9. Known history of human immunodeficiency virus (HIV).
  10. Known active Hepatitis B or C.
  11. Pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the study.
  12. Currently participating or has participated in a study of an investigational agent or using an investigational device within 4 weeks of enrollment.
  13. Use of any commercial ctDNA or liquid biopsy monitoring outside of the study protocol during the treatment monitoring phase within the protocol.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: SOC Continuous ICI

Participants will continue the current ICI therapy, per approved product label and / or treating investigator's clinical judgement.

Standard infusion visits are maintained for the total of 2 years or until radiographic progression, unacceptable toxicity, or withdrawal of consent.
Device: Signatera Genome ultra-sensitive ctDNA blood test
The test is used to monitor for disease recurrence.
Experimental: 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.
Device: Signatera Genome ultra-sensitive ctDNA blood test
The test is used to monitor for disease recurrence.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
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
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
3 years from randomization to death from any cause

Secondary Outcome Measures

Outcome Measure
Time Frame
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
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
From randomization to Year 3

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Natera, Inc.

Investigators

  • Study Director: Caitlin Shonewolf, MD, Natera, Inc.

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

December 1, 2026

Primary Completion (Estimated)

December 1, 2033

Study Completion (Estimated)

March 1, 2034

Study Registration Dates

First Submitted

July 1, 2026

First Submitted That Met QC Criteria

July 1, 2026

First Posted (Actual)

July 8, 2026

Study Record Updates

Last Update Posted (Actual)

August 4, 2026

Last Update Submitted That Met QC Criteria

July 31, 2026

Last Verified

June 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 26-107-NCP

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

Yes

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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