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NSCLC (Advanced Non-small Cell Lung Cancer)SIGNAL-IO 301NCT07689812

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.

A study testing Signatera Genome ultra-sensitive ctDNA blood test in people with NSCLC (Advanced Non-small Cell Lung Cancer) and NSCLC (Non-small Cell Lung Cancer), run by Natera, Inc..

Not yet recruiting

Opening soon. The study is approved but enrolment has not started yet. Sites may already take enquiries.

Sites and contacts
Official record
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Trial summary

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… Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Signatera Genome ultra-sensitive ctDNA blood test
Could I receive a placebo?
No, everyone receives an active treatment
How many people
920 participants
Where
No sites listed yet
Study dates
Dec 2026to Mar 2034
Phase
Interventional
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
Show all 27Show fewer
  • 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.

Who cannot join

  • 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.
Show all 14Show fewer
  • 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.

Trial locations and contacts

No sites are listed yet. Contact the study team or a site near you to ask about taking part.

Amanda L Andersen contact

844-778-4700

aandersen@natera.com

Brooke Cormane contact

844-778-4700

bcormane@natera.com

About this study

Official title: 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.

Being tested
Signatera Genome ultra-sensitive ctDNA blood test
Keywords
ctDNA, Circulating tumor DNA, Immune checkpoint inhibitor, ICI, Non-small cell lung cancer, NSCLC, Melanoma, Microsatellite Instability-High/deficient Mismatch Repair, MSI-High/dMMR, Colorectal Cancer, CRC, Renal cell carcinoma, RCC, Metastatic solid tumors, Signatera, Molecular residual disease, MRD, Biomarker-guided therapy, Adjuvant therapy, Tumor-informed assay
Medical subject headings
Carcinoma, Non-Small-Cell Lung, Melanoma, Carcinoma, Renal Cell, Colorectal Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Signatera Genome ultra-sensitive ctDNA blood testDevice

    The test is used to monitor for disease recurrence.

Study groups in NCT07689812
Study groupRoleWhat they receive
SOC Continuous ICIExperimentalParticipants 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.
Receives: Device: Signatera Genome ultra-sensitive ctDNA blood test
ctDNA-Guided Intermittent ICIExperimentalParticipants 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.
Receives: Device: Signatera Genome ultra-sensitive ctDNA blood test

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: 6 months from randomization

  2. 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.

    Measured: 3 years from randomization to death from any cause

Secondary outcomes (2)

  1. 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.

    Measured: 3 years from randomization to the first occurrence of disease progression measured by RECIST 1.1 or death from any cause, whichever occurs first

  2. 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.

    Measured: From randomization to Year 3

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted8 Jul 2026
  2. Study startDec 2026 (estimated)
  3. Primary completionDec 2033 (estimated)
  4. Study completionMar 2034 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase N/A
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
920 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT07689812
Sponsor's protocol ID
26-107-NCP
Acronym
SIGNAL-IO 301
Status last verified
Jun 2026
First submitted
1 Jul 2026
Last updated
4 Aug 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
Yes
Individual data sharing
No

Publications

  • Zalcman G, Madroszyk A, Guenzi E, Dayen C, Molinier O, Egenod T, Pote N, Debieuvre D, Beaucaire-Danel S, Dixmier A, Pichon E, Galland-Girodet S, Giroux-Leprieur E, Cloarec N, Cadranel J, Otto J, Romand P, Favier L, Martinez S, Mascaux C, Odier L, Cortot A, Audigier-Valette C, Langlais A, Amour E, Morin F, Antoine M, Gounant V, Westeel V, Toffart AC. Four-Year Outcomes of First-Line Nivolumab Plus Ipilimumab for 6 Months Versus Continuation in Patients With Advanced NSCLC: Results of the Randomized IFCT-1701 "DICIPLE" Phase III Trial. J Thorac Oncol. 2026 Jun;21(6):103609. doi: 10.1016/j.jtho.2026.103609. Epub 2026 Feb 12.

    PubMed 41690366

  • Vokes NI, Pan K, Le X. Efficacy of immunotherapy in oncogene-driven non-small-cell lung cancer. Ther Adv Med Oncol. 2023 Mar 18;15:17588359231161409. doi: 10.1177/17588359231161409. eCollection 2023.

    PubMed 36950275

  • Vokes N, Gandara D, Sezer A, Kilickap S, Gümüş M, Bondarenko I, Özgüroğlu M, Gogishvili M, Turk HM, Cicin I, Bentsion D. Circulating tumor DNA (ctDNA) dynamics and survival outcomes in patients with advanced NSCLC and high (> 50%) PD-L1 expression, randomized to cemiplimab vs chemotherapy. In ASCO Annual Meeting, Chicago, IL 2023 Jun.

  • Sun L, Bleiberg B, Hwang WT, Marmarelis ME, Langer CJ, Singh A, Cohen RB, Mamtani R, Aggarwal C. Association Between Duration of Immunotherapy and Overall Survival in Advanced Non-Small Cell Lung Cancer. JAMA Oncol. 2023 Aug 1;9(8):1075-1082. doi: 10.1001/jamaoncol.2023.1891.

    PubMed 37270700

  • Nakamura Y, Watanabe J, Akazawa N, Hirata K, Kataoka K, Yokota M, Kato K, Kotaka M, Kagawa Y, Yeh KH, Mishima S, Yukami H, Ando K, Miyo M, Misumi T, Yamazaki K, Ebi H, Okita K, Hamabe A, Sokuoka H, Kobayashi S, Laliotis G, Aushev VN, Sharma S, Jurdi A, Liu MC, Aleshin A, Rabinowitz M, Bando H, Taniguchi H, Takemasa I, Kato T, Kotani D, Mori M, Yoshino T, Oki E. ctDNA-based molecular residual disease and survival in resectable colorectal cancer. Nat Med. 2024 Nov;30(11):3272-3283. doi: 10.1038/s41591-024-03254-6. Epub 2024 Sep 16.

    PubMed 39284954

  • Martinez-Vila C, Teixido C, Martin R, Aya F, Sudhaman S, Budde GL, Gonzalez-Navarro EA, Alos L, Castrejon N, Ortiz JB, Krainock M, Liu MC, Arance A. Personalized Circulating Tumor DNA Assay to Assess Long-Term Clinical Benefit in Patients with Advanced Melanoma. Cancers (Basel). 2025 Nov 27;17(23):3804. doi: 10.3390/cancers17233804.

    PubMed 41375005

  • Larkin J, Sileni VC, Marqueste CG, Rutkowski P, Medina TM, Lao CD, Cowey CL, Schadendorf D, Wagstaff J, Dummer R, Queirolo P. LBA43 10-y survival outcomes from the phase III CheckMate 067 trial of nivolumab plus ipilimumab in advanced melanoma. Annals of Oncology. 2024 Sep 1;35:S1234-5.

  • Eroglu Z, Krinshpun S, Kalashnikova E, Sudhaman S, Ozturk Topcu T, Nichols M, Martin J, Bui KM, Palsuledesai CC, Malhotra M, Olshan P, Markowitz J, Khushalani NI, Tarhini AA, Messina JL, Aleshin A. Circulating tumor DNA-based molecular residual disease detection for treatment monitoring in advanced melanoma patients. Cancer. 2023 Jun 1;129(11):1723-1734. doi: 10.1002/cncr.34716. Epub 2023 Mar 4.

    PubMed 36869646

  • Botta GP, Abdelrahim M, Drengler RL, Aushev VN, Esmail A, Laliotis G, Brewer CM, George GV, Abbate SM, Chandana SR, Tejani MA, Malla M, Bansal D, Rivero-Hinojosa S, Spickard E, McCormick N, Cecchini M, Lacy J, Fei N, Kasi PM, Kasi A, Dayyani F, Hanna DL, Sharma S, Malhotra M, Aleshin A, Liu MC, Jurdi A. Association of personalized and tumor-informed ctDNA with patient survival outcomes in pancreatic adenocarcinoma. Oncologist. 2024 Oct 3;29(10):859-869. doi: 10.1093/oncolo/oyae155.

    PubMed 39022993

  • Bogani G, Cinquini M, Signorelli D, Pizzutilo EG, Romano R, Bersanelli M, Raggi D, Alfieri S, Buti S, Bertolini F, Bonomo P, Marandino L, Rizzo M, Monteforte M, Aiello M, Tralongo AC, Torri V, Di Donato V, Giannatempo P. A systematic review and meta-analysis on the optimal treatment duration of checkpoint inhibitoRS in solid tumors: The OTHERS study. Crit Rev Oncol Hematol. 2023 Jul;187:104016. doi: 10.1016/j.critrevonc.2023.104016. Epub 2023 May 6.

    PubMed 37156405

  • Ben-David R, Lidagoster S, Geduldig J, Kolanukuduru KP, Elkun Y, Tillu N, Mandel A, Almoflihi M, Kaufmann B, Attalla K, Mehrazin R, Wiklund P, Sfakianos JP. Undetectable pre-radical cystectomy circulating tumour DNA status predicts improved oncological outcomes. BJU Int. 2025 Mar;135(3):473-480. doi: 10.1111/bju.16556. Epub 2024 Oct 16.

    PubMed 39414578

  • Basu A, Au C, Kommalapati A, Kandala H, Sudhaman S, Mahmood T, Carson C, Pajak N, Dutta P, Calhoun M, Malhotra M, ElNaggar AC, Liu MC, Ferguson Iii J, Peyton C, Rais-Bahrami S, Tan A. Longitudinal Testing of Circulating Tumor DNA in Patients With Metastatic Renal Cell Carcinoma. JCO Precis Oncol. 2024 Dec;8:e2400667. doi: 10.1200/PO-24-00667. Epub 2024 Dec 18.

    PubMed 39693589

  • Andre T, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt C, Smith D, Garcia-Carbonero R, Benavides M, Gibbs P, de la Fouchardiere C, Rivera F, Elez E, Bendell J, Le DT, Yoshino T, Van Cutsem E, Yang P, Farooqui MZH, Marinello P, Diaz LA Jr; KEYNOTE-177 Investigators. Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer. N Engl J Med. 2020 Dec 3;383(23):2207-2218. doi: 10.1056/NEJMoa2017699.

    PubMed 33264544

  • Afzal MZ, Corea-Dilbert FE, Wankel B, Palmer JP, Pirruccello JP, Kale S, Sharma A, Lu Z, Ibrahim S, Cao Y, Sarwar T. Utility of circulating tumor DNA as a tool to detect minimal residual disease in patients with metastatic cancer and durable response following treatment with immune checkpoint inhibitors. American Society of Clinical Oncology Annual Meeting. 2023. e21563-e21563.

Questions about this trial

What is this clinical trial studying?

A study testing Signatera Genome ultra-sensitive ctDNA blood test in people with NSCLC (Advanced Non-small Cell Lung Cancer) and NSCLC (Non-small Cell Lung Cancer), run by Natera, Inc..

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 27 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: opening soon, as of the sponsor's last update on 4 Aug 2026. Status can change between updates, so confirm with the study contact before making plans.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Amanda L Andersen (844-778-4700, aandersen@natera.com), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT07689812, which also lists 14 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Aug 2026.

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