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
试验速览
- 阶段
- 不适用
- 状态
- 尚未招募
- 发起方
- Natera, Inc.
- 入组人数
- 920
- 主要终点
- 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.
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
- •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.
- •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.
排除标准
- •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.
研究组 & 干预措施
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.
干预措施: Signatera Genome ultra-sensitive ctDNA blood test (Device)
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.
干预措施: Signatera Genome ultra-sensitive ctDNA blood test (Device)
结局指标
主要结局
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.
时间窗: 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.
时间窗: 3 years from randomization to death from any cause
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.
时间窗: 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.
时间窗: 3 years from randomization to death from any cause
次要结局
- 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.(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.(From randomization to Year 3)
- 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)