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)

July 1, 2026 updated by: Natera, Inc.

A Multicenter, Open-label, Randomized (1:1) Trial Designed to Evaluate Whether MRD-guided Intermittent ICI Therapy Provides Comparable Survival to SOC Continuous ICI Therapy in Subjects With Histologically Confirmed Advanced / Metastatic NSCLC, Melanoma, MSI-High/dMMR CRC, RCC and Other Solid Tumors.

This is an open-label, randomized study evaluating whether MRD-guided intermittent ICI therapy provides comparable survival to SOC continuous ICI therapy in subjects with histologically confirmed advanced / metastatic NSCLC, melanoma, MSI-High/dMMR CRC, 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 multi-center, open-label, randomized study evaluating whether MRD-guided intermittent ICI therapy provides non-inferior overall survival to SOC continuous ICI therapy in subjects with histologically confirmed advanced / metastatic NSCLC, melanoma, MSI-High/dMMR CRC, RCC and other solid tumors. Participants will be assigned to receive standard of care continuous ICI therapy, or molecular-residual disease (MRD)-guided intermittent immune-checkpoint inhibitor (ICI) therapy.

Participants meeting eligibility criteria are randomized into two arms:

Arm A (SOC Continuous ICI): Participants will continue current ICI therapy per standard of care (SOC). Standard infusion visits are maintained for the total of 2 years or until radiographic progression, unacceptable toxicity, other clinical indications for discontinuation or withdrawal of consent. Note: ICI therapy may be interrupted for toxicity and/or radiographic progression per SOC.

Arm B (MRD-Guided Intermittent ICI): Participants will interrupt ICI therapy upon randomization; reinitiate with the same ICI therapy (monotherapy or combination as documented at enrollment) if ctDNA(+) without evidence of radiographic progression per RECIST 1.1. Following reinitiation, ICI therapy may again be interrupted after achievement of ≥ 2 consecutive ctDNA-negative results (at least 6 weeks apart), and subsequently initiated upon recurrence of ctDNA positivity without evidence of radiographic progression. This cycle of MRD-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.

Response assessments include imaging (CT/ MRI) (BICR review) and ctDNA testing performed at 12 weeks and then continued q12 weeks; PRO (QLQ-C30, FACT-ICM, PRO-CTCAE & EQ-5D-5L) data collection (q12 weeks); and continued AE assessment reviewed per CTCAE v6.0 at each visit and unscheduled contacts. Concomitant medications / new therapies data will be reviewed at each visit and updated continuously. Biospecimens (optional) will be banked at enrollment and at confirmed progression for future immune and molecular studies. Survival status will be assessed every 3 months until death, withdrawal of consent, or study discontinuation whichever comes first, for a maximum period of 5 years.

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 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.

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: MRD-Guided Intermittent ICI
Participants will interrupt ICI therapy upon randomization; reinitiate with the same ICI therapy (monotherapy or combination as documented at enrollment) if ctDNA(+) without evidence of radiographic progression. ICI therapy may again be interrupted after achievement of ≥ 2 consecutive ctDNA-negative results and subsequently 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, or a maximum of 2 interruptions. 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 MRD-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 MRD-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 MRD-guided intermittent ICI therapy to SOC continuous ICI therapy as measured by 36 month PFS (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 MRD-guided intermittent ICI therapy and SOC continuous ICI therapy using 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)

July 8, 2026

Last Update Submitted That Met QC Criteria

July 1, 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.

Clinical Trials on NSCLC

Clinical Trials on Signatera Genome ultra-sensitive ctDNA blood test

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Bahrain

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

3
Subscribe