ctDNA-MRD Guided Escalation of Ivonescimab and Docetaxel in Advanced NSCLC With Long-Term Responses to First-line Immunotherapy (CR1STAL-Adaptive)

NCT06951646 | Recruiting Phase 2

• 1 other identifier: LYG20240091
• Study Type: interventional
• Target: 70
• Locations: 1 country
• Sites: 20

Brief Summary

The CR1STAL-Adaptive study is a randomized, open-label, phase II multicenter interventional trial designed to evaluate the safety and efficacy of Ivonescimab (PD-1/VEGF bispecific antibody) combined with docetaxel versus standard treatment in patients with advanced NSCLC who have achieved long-term benefit from first-line immune checkpoint inhibitors (ICIs), but are ctDNA-MRD positive. Building upon insights from previous CR1STAL study (NCT05198154), the CR1STAL-Adaptive study supports the development of precision-guided, adaptive treatment strategies to delay progression and improve outcomes in NSCLC patients with a long-term response to immunotherapy. It represents a step forward in integrating dynamic molecular monitoring with individualized intervention strategies in the era of immunotherapy.

Conditions

Non Small Cell Lung Cancer; Immune Checkpoint Inhibitors (ICIs)

Keywords

Non Small Cell Lung Cancer (NSCLC); Immune Checkpoint Inhibitors (ICIs); Circulating-tumor DNA (ctDNA); Minimal Residual Disease (MRD); Ivonescimab (AK112); Adaptive Therapy; Bispecific Antibody; Escalation

Outcome Measures

Primary Outcomes (1)

• Progression-Free Survival (PFS) in ctDNA-Positive Population

  The duration from randomization to disease progression or death (whichever occurs first), as assessed by the investigator based on RECIST v1.1 criteria.

  3 years

Secondary Outcomes (10)

• Overall Survival (OS)

  5 years

• Adverse Event

  AEs must be collected from the start of treatment to 28days after discontinuation of study drug, up to 24months

• 18-Month PFS Rate

  3 years

• ctDNA Clearance Rate

  3 years

• Objective Response Rate (ORR)

  3 years

Other Outcomes (2)

• The correlation between biomarkers and efficacy prediction

  3 years

• Exploration of Multiparametric Imaging Biomarkers Predictive of Efficacy

  3 years

Study Arms (2)

Standard Treatment

OTHER

For ctDNA-positive patients, the original maintenance treatment (eg. immunotherapy or immunotherapy combined with chemotherapy) will be continued.

Other: Standard Treatment group

Escalation Treatment

EXPERIMENTAL

For ctDNA-positive patients, escalation treatment will be administrated

Drug: Ivonescimab; Drug: Docetaxel

Interventions

Ivonescimab DRUG

For ctDNA-positive patients, escalation treatment will be administrated Ivonescimab: Intravenous infusion (IV), 20 mg/kg, Day 1, every 3 weeks (Q3W); All enrolled participants will continue treatment until one of the following occurs, whichever comes first: * The investigator determines that there is no longer clinical benefit (based on imaging assessments and clinical status) * Unacceptable toxicity * Completion of 24 months of treatment * Other discontinuation criteria specified in the protocol are met.

Escalation Treatment

Docetaxel DRUG

For ctDNA-positive patients, escalation treatment will be administrated Docetaxel: IV, 75 mg/m², Day 1, Q3W (The investigator may adjust the chemotherapy dose and schedule based on the patient's tolerance during treatment.) All enrolled participants will continue treatment until one of the following occurs, whichever comes first: * The investigator determines that there is no longer clinical benefit (based on imaging assessments and clinical status) * Unacceptable toxicity * Completion of 24 months of treatment * Other discontinuation criteria specified in the protocol are met.

Also known as: AK112

Escalation Treatment

Standard Treatment group OTHER

For ctDNA-positive patients, continuing the original immunotherapy maintenance or immunotherapy combined with chemotherapy

Standard Treatment

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Sign written informed consent prior to any study-related procedures, be willing and able to complete the visits, treatment regimen, and laboratory tests specified in the schedule, and comply with other requirements of the study;
• Aged ≥18 and ≤75 years old;
• ECOG PS score 0-1;
• Expected survival time ≥ 12 weeks;
• Patients with stage IIIB-IIIC and IV non-small cell lung cancer confirmed by histology or cytology that cannot be treated locally (TNM lung cancer staging of the 9th edition of the International Association for the Study of Lung Cancer and the American Joint Committee on Cancer Classification);
• There must be no EGFR gene-sensitive mutation, ALK gene fusion or ROS1 gene fusion in non-squamous carcinoma
• Immunotherapy combined with platinum-containing doublet chemotherapy as a first-line standard treatment regimen;
• Non-PD with PFS at screening enrollment is 11 to 15 months;
• According to the Response Evaluation Criteria in Solid Tumors (RECIST version 1.1), it is recommended to have at least one measurable lesion, but patients without measurable lesions can still be included in the group (primary tumor recurrence or new metastatic lesions are considered PD).
• Participants with brain metastases who are asymptomatic or whose symptoms are stable after local treatment are allowed to enroll, as long as the participants meet the following conditions:
• There are measurable lesions outside the central nervous system
• No central nervous system symptoms or no worsening of symptoms for at least 2 weeks
• No need for glucocorticoid treatment, or glucocorticoid treatment was discontinued within 7 days before the first dose, or the glucocorticoid dosage was stable and reduced to less than 10mg/day prednisone (or equivalent dose) within 7 days before the first dose.
• \. Meet the following laboratory indicators (within 14 days before the first treatment):
• Routine blood test: absolute neutrophil count ≥1.5×109/L; platelet count ≥100×109/L; hemoglobin content ≥9.0 g/dL (no blood transfusion or erythropoietin-dependent administration within 7 days).

You may not qualify if:

• Concurrent participation in another interventional clinical study or receipt of another investigational drug, unless participating in an observational clinical study；
• Systemic therapy with proprietary Chinese medicines with anti-tumor indications or immunomodulatory drugs (including thiopeptides, interferons, interleukins, except those used locally for the control of hydrothorax or ascites) within 2 weeks prior to the first dose；
• No measurable lesions as defined by RECIST 1.1 due to prior radical treatment (e.g., surgery or radiotherapy)
• Subjects who have received systemic antiangiogenic therapy;
• Subjects who are enrolled in another clinical study at the same time, unless it is a non-interventional clinical study or the follow-up period of an interventional study (defined as the time between the first dose of this study and the last dose of the previous clinical study being more than 4 weeks or more than 5 half-lives of other study drugs, whichever is shorter);
• During the screening period, imaging shows that the tumor surrounds important blood vessels or there is significant necrosis or cavity, and the investigator determines that entering the study will cause a risk of bleeding;
• Imaging findings during the screening period show that the tumor invades important peripheral organs and blood vessels (such as the heart and pericardium, trachea, esophagus, aorta, superior vena cava, etc.) or there is a risk of developing esophagotracheal fistula or esophagopleural fistula;
• Active autoimmune diseases requiring systemic treatment (such as treatment with disease-modifying drugs, corticosteroids, and immunosuppressants) within 2 years before the first dose (excluding irAEs caused by the use of PD-1/L1 inhibitors). Replacement therapy (such as thyroxine, insulin, or physiological corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a systemic treatment;
• A history of major diseases within 1 year before the first dose, specifically:
• Unstable angina, myocardial infarction, congestive heart failure (NYHA classification ≥ Class 2) or vascular diseases (such as aortic aneurysm with a risk of rupture) that require hospitalization within 12 months before the first dose, or other cardiac damage that may affect the safety evaluation of the study drug (such as poorly controlled arrhythmia, myocardial ischemia, etc.);
• Hepatic encephalopathy, hepatorenal syndrome or Child-Pugh class B or more severe cirrhosis
• Current hypertension with systolic blood pressure ≥150 mmHg or diastolic blood pressure ≥100 mmHg after oral antihypertensive therapy;
• Hyperglycemia that cannot be controlled after treatment (fasting blood glucose \> 10 mmol/L);
• A history of esophageal and gastric varices, with severe ulcers and unresolved wounds, abdominal fistulas, intraabdominal abscesses, or acute gastrointestinal bleeding within 6 months before the first dose;
• Any arterial thromboembolic events, venous thromboembolic events of grade 3 orabove as specified in NCI CTCAE 5.0, transient ischemic attacks, cerebrovascular accidents, hypertensive crises, or hypertensive encephalopathy that occurred within 6 months before the first dose;

Sponsors & Collaborators

• Second Xiangya Hospital of Central South University: lead
• Nanjing Shihejiyin Technology, Inc.: collaborator
• Akeso: collaborator

Study Sites (20)

Hunan Cancer Hospital

Changsha, 410011, China

NOT YET RECRUITING

The Second Xiangya Hospital of Central South University

Changsha, 410011, China

RECRUITING

The Third Hospital of Changsha

Changsha, 410011, China

NOT YET RECRUITING

Xiangya Hospital of Central South University

Changsha, 410011, China

NOT YET RECRUITING

Changsha Central Hospital

Changsha, China

NOT YET RECRUITING

The First Hospital of Changsha

Changsha, China

NOT YET RECRUITING

The Third Xiangya Hospital of Central South University

Changsha, China

NOT YET RECRUITING

Army Medical Center (Daping Hospital)

Chongqing, China

NOT YET RECRUITING

Guiyang Public Health Clinical Center

Guiyang, China

NOT YET RECRUITING

Faculty of Medicine, The Chinese University of Hong Kong

Hong Kong, China

NOT YET RECRUITING

Kiang Wu Hospital, Macao

Macao, China

NOT YET RECRUITING

The First Affiliated Hospital of Nanchang University

Nanchang, China

NOT YET RECRUITING

The First Affiliated Hospital of Guangxi Medical University

Nanning, China

NOT YET RECRUITING

Liaoning Cancer Hospital and Institute

Shenyang, China

NOT YET RECRUITING

Shanxi Bethune Hospital

Taiyuan, China

NOT YET RECRUITING

Hubei Cancer Hospital

Wuhan, China

NOT YET RECRUITING

Renmin Hospital of Wuhan University

Wuhan, China

NOT YET RECRUITING

Union Hospital, Tongji Medical College, Huazhong University of Science and Technology

Wuhan, China

NOT YET RECRUITING

The First Affiliated Hospital of Xinxiang Medical University

Xinxiang, China

NOT YET RECRUITING

Zhuzhou Central Hospital

Zhuzhou, China

NOT YET RECRUITING

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung; Neoplasm, Residual

Interventions

Docetaxel

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes

Central Study Contacts

Fang Wu, MD, PhD

CONTACT

+86 13574858332; wufang4461@edu.csu.cn

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: Patients will be randomly assigned to the standard treatment group or the advanced treatment group. In the event of disease progression (PD), they are optional to receive the Ivonescimab plus docetaxel.

Study Record Dates

• First Submitted: April 23, 2025
• First Posted: April 30, 2025
• Study Start: March 10, 2026
• Primary Completion (Estimated): July 1, 2028
• Study Completion (Estimated): June 1, 2030
• Last Updated: March 9, 2026

Record last verified: 2026-03

Locations

CN (20)