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.

NCT07689812 | Not Yet Recruiting DMC FDA Device

• 1 other identifier: 26-107-NCP
• Study Type: interventional
• Target: 920
• Locations: 0 countries
• Sites: N/A

Brief 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 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.

Conditions

DMMR Colorectal Cancer; Advanced Solid Tumors; NSCLC (Advanced Non-small Cell Lung Cancer); NSCLC (Non-small Cell Lung Carcinoma); Melanoma (Skin) Stage IV; CRC; RCC, Renal Cell Cancer; RCC; Metastatic Solid Tumors; NSCLC; Melanoma (Skin Cancer); MSI High Colorectal Cancer; NSCLC (Non-small Cell Lung Cancer); Solid Tumors; Advanced Solid Tumors Cancer

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; Advanced solid tumor

Outcome Measures

Primary Outcomes (2)

• 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.

  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.

  3 years from randomization to death from any cause

Secondary Outcomes (2)

• 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.

  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.

  From randomization to Year 3

Study Arms (2)

SOC Continuous ICI

EXPERIMENTAL

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

ctDNA-Guided Intermittent ICI

EXPERIMENTAL

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

Interventions

Signatera Genome ultra-sensitive ctDNA blood test DEVICE

The test is used to monitor for disease recurrence.

SOC Continuous ICI; ctDNA-Guided Intermittent ICI

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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.

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• Natera, Inc.: lead

Related Publications (14)

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  BACKGROUND

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung; Melanoma; Carcinoma, Renal Cell; Colorectal Neoplasms

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Skin Diseases; Skin and Connective Tissue Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Study Officials

• Caitlin Shonewolf, MD

  Natera, Inc.

  STUDY DIRECTOR

Central Study Contacts

Amanda L Andersen

CONTACT

844-778-4700; aandersen@natera.com

Brooke Cormane

CONTACT

844-778-4700; bcormane@natera.com

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: July 1, 2026
• First Posted: July 8, 2026
• Study Start (Estimated): December 1, 2026
• Primary Completion (Estimated): December 1, 2033
• Study Completion (Estimated): March 1, 2034
• Last Updated: July 23, 2026

Record last verified: 2026-06

Data Sharing

• IPD Sharing: Will not share