Phase 1 Study of ATRA Plus a PD-1 Inhibitor in EGFR-Mutant NSCLC After Third-Generation EGFR-TKI Resistance

NCT07842887 | Not Yet Recruiting Phase 1 DMC

• 1 other identifier: NCC6532
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this Phase 1 clinical trial is to learn whether all-trans retinoic acid (ATRA) combined with tislelizumab is safe and tolerable in adults with EGFR-mutant non-small cell lung cancer (NSCLC). The study is for people whose cancer has worsened after treatment with a third-generation EGFR tyrosine kinase inhibitor and at least one standard systemic treatment, or who cannot tolerate or are not suitable for currently available standard treatments. The main questions this study aims to answer are:

• What side effects and dose-limiting toxicities occur with the combination of ATRA and tislelizumab?
• What is the highest dose of ATRA that can be given safely with tislelizumab, and what dose should be recommended for future studies? Researchers will also look for early signs that the combination can shrink or control the cancer and will assess how long participants live without their cancer getting worse and how long they live overall. Tumor tissue and blood samples will be studied to explore changes in the cancer and the immune system and to identify possible markers associated with treatment response or side effects. All participants will receive ATRA and tislelizumab; there is no comparison or placebo group. Participants will:
• Take ATRA by mouth twice daily, beginning 7 days before the first dose of tislelizumab. The ATRA dose will be assigned according to the dose level being studied.
• Receive tislelizumab by intravenous infusion once every 3 weeks.
• Undergo regular safety assessments, including physical examinations, blood tests, vital-sign measurements, and monitoring for side effects.
• Undergo imaging examinations approximately every 6 weeks during the first year to assess the cancer.
• Provide tumor tissue and blood samples for biomarker research.
• Attend an end-of-treatment visit, safety follow-up visits, and survival follow-up approximately every 3 months after treatment ends.

Conditions

EGFR-TKI-resistant Non-Small Cell Lung Cancer

Keywords

Third-Generation EGFR Tyrosine Kinase Inhibitor Resistance; Acquired Drug Resistance; Programmed Cell Death 1 Inhibitor; Dose Escalation; Tumor Immune Microenvironment; Predictive Biomarkers

Outcome Measures

Primary Outcomes (3)

• Incidence and Severity of Adverse Events

  The number and percentage of participants who experience adverse events, serious adverse events, and treatment-related adverse events will be summarized overall and by dose level. Safety will also be evaluated using clinically significant changes in laboratory test results, vital signs, physical examinations, and other safety assessments.

  From the first dose of ATRA through the safety follow-up visit, approximately 28 days after the last dose of study treatment

• Incidence of Dose-Limiting Toxicities

  The number and percentage of DLT-evaluable participants who experience a dose-limiting toxicity (DLT) will be summarized by ATRA dose level. DLTs will be assessed according to the protocol-defined criteria during the 28-day DLT evaluation period.

  From the start of the 7-day ATRA lead-in period through the end of the first 21-day combination-treatment cycle, a total of 28 days

• Maximum Tolerated Dose and/or Recommended Dose for Further Study

  The maximum tolerated dose (MTD) and/or recommended dose for further study will be determined using the prespecified 3+3 dose-escalation rules. The determination will be based primarily on the occurrence of DLTs at each ATRA dose level, together with the overall available safety and tolerability data for ATRA in combination with tislelizumab.

  At completion of dose escalation, based primarily on DLTs observed during each participant's 28-day DLT evaluation period

Secondary Outcomes (5)

• Objective Response Rate

  From the first dose of study treatment until disease progression, initiation of a new anticancer treatment, death, withdrawal of consent, loss to follow-up, or study completion, whichever occurs first, assessed for up to approximately 24 months

• Disease Control Rate

  From the first dose of study treatment until disease progression, initiation of a new anticancer treatment, death, withdrawal of consent, loss to follow-up, or study completion, whichever occurs first, assessed for up to approximately 24 months

• Progression-Free Survival

  From the first dose of study treatment until documented disease progression or death from any cause, whichever occurs first, assessed for up to approximately 24 months

• Overall Survival

  From the first dose of study treatment until death, withdrawal of consent, loss to follow-up, or study completion, assessed for up to approximately 24 months

• Changes in Tumor Molecular Characteristics

  At baseline and at documented disease progression, assessed for up to approximately 24 months

Other Outcomes (2)

• Changes in Peripheral Blood Immune-Cell Characteristics

  At baseline and at protocol-specified time points during treatment, assessed for up to approximately 24 months

• Association of Exploratory Biomarkers With Treatment Outcomes

  From baseline through disease progression, the end of study treatment, or study completion, assessed for up to approximately 24 months

Study Arms (1)

Experimental: All-Trans Retinoic Acid Plus Tislelizumab

EXPERIMENTAL

Participants will receive oral all-trans retinoic acid (ATRA) at the assigned dose level of 30 mg, 40 mg, or 50 mg twice daily in combination with tislelizumab 200 mg administered by intravenous infusion once every 3 weeks. ATRA will begin 7 days before the first tislelizumab infusion as an ATRA lead-in period and will then continue during the 21-day combination-treatment cycles. The dose-escalation phase will follow a conventional 3+3 design. After the recommended dose for further study has been determined, additional participants will receive the combination at that dose in a dose-expansion cohort. The dose-limiting toxicity evaluation period will include the 7-day ATRA lead-in period and the first 21-day combination-treatment cycle, for a total of 28 days. Treatment may continue until disease progression, unacceptable toxicity, withdrawal of consent, initiation of another anticancer treatment, investigator decision, or another protocol-defined discontinuation criterion.

Drug: All-trans retinoic acid; Drug: Tislelizumab

Interventions

All-trans retinoic acid DRUG

All-trans retinoic acid will be administered orally twice daily at an assigned dose level of 30 mg, 40 mg, or 50 mg. ATRA will begin 7 days before the first tislelizumab infusion and will continue during the subsequent 21-day combination-treatment cycles. Dose escalation will follow a conventional 3+3 design. After the recommended dose for further study has been determined, additional participants will receive ATRA at that dose in the dose-expansion cohort. ATRA may be interrupted, reduced, or permanently discontinued according to the type, severity, duration, and recovery of treatment-related toxicity.

Experimental: All-Trans Retinoic Acid Plus Tislelizumab

Tislelizumab DRUG

Tislelizumab, a programmed cell death protein 1 (PD-1) inhibitor, will be administered at a dose of 200 mg by intravenous infusion once every 3 weeks. The first dose will be administered after the 7-day ATRA lead-in period, and tislelizumab will then be given in combination with oral ATRA during each 21-day treatment cycle. Dose reduction of tislelizumab is not permitted. Treatment may be interrupted, resumed, or permanently discontinued for immune-related or other clinically significant adverse events according to applicable prescribing information, established toxicity-management guidance, and the investigator's clinical judgment.

Experimental: All-Trans Retinoic Acid Plus Tislelizumab

Eligibility Criteria

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

You may qualify if:

• Voluntarily provides written informed consent and agrees to comply with the study requirements.
• Aged 18 years or older, with no restriction based on sex.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Participants with an ECOG performance status of 2 may be enrolled at the investigator's discretion.
• Histologically or pathologically confirmed primary non-small cell lung cancer (NSCLC).
• Stage IV disease according to the eighth edition of the American Joint Committee on Cancer/Union for International Cancer Control TNM staging system, or recurrent or metastatic NSCLC that is not suitable for curative local treatment.
• A confirmed sensitizing EGFR mutation, including but not limited to an exon 19 deletion or an exon 21 L858R mutation.
• Previous treatment with a third-generation EGFR tyrosine kinase inhibitor, including but not limited to osimertinib, almonertinib, or furmonertinib, followed by radiographically confirmed disease progression according to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1).
• Disease progression after at least one standard systemic treatment following resistance to a third-generation EGFR tyrosine kinase inhibitor, or inability to tolerate or unsuitability for currently available standard treatment, as determined by the investigator.
• No clearly available and appropriate standard targeted therapy option, as determined by the investigator.
• At least one measurable lesion according to RECIST v1.1.
• Adequate major organ function to receive the study treatment, as determined by the investigator.
• Female participants of childbearing potential must have a negative pregnancy test and agree to use effective contraception during study treatment and for at least 1 month after the last dose of all-trans retinoic acid.
• Able to understand and comply with the study requirements, as determined by the investigator.

You may not qualify if:

• History of another malignancy, except for a malignancy that has been clinically cured and is considered by the investigator to have a low risk of recurrence.
• Uncontrolled brain metastases, leptomeningeal metastases, or a central nervous system lesion requiring urgent local treatment.
• Histologic transformation, such as transformation to small cell lung cancer.
• Uncontrolled acute or chronic infection, or an active infection requiring systemic anti-infective treatment.
• Active tuberculosis.
• Positive human immunodeficiency virus antibody test, active hepatitis B, or active hepatitis C.
• Active autoimmune disease, or a history of autoimmune disease requiring systemic immunosuppressive treatment.
• A history of a Grade 3 or higher immune-related adverse event following treatment with an immune checkpoint inhibitor, or permanent discontinuation of immunotherapy because of immune-related toxicity.
• Severe or uncontrolled cardiovascular or cerebrovascular disease.
• An unstable thrombotic or bleeding event requiring therapeutic intervention within 6 months before screening.
• Clinically significant uncontrolled hyperlipidemia, particularly markedly elevated triglycerides, that may increase the risks associated with all-trans retinoic acid treatment, as determined by the investigator.
• Uncontrolled Grade 2 or higher hepatic dysfunction, or underlying liver disease that may substantially increase the risk of ATRA-related hepatotoxicity, as determined by the investigator.
• History of a severe hypersensitivity reaction to all-trans retinoic acid, another retinoid, tislelizumab, or any component of these products.
• Pregnant or breastfeeding, or planning pregnancy or conception during the study.
• Previous or current benign intracranial hypertension or pseudotumor cerebri.

Sponsors & Collaborators

• Cancer Institute and Hospital, Chinese Academy of Medical Sciences: lead

Study Sites (1)

National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital

Beijing, Beijing Municipality, 100021, China

Location

MeSH Terms

Interventions

Tretinoin; tislelizumab

Intervention Hierarchy (Ancestors)

Vitamin A; Retinoids; Carotenoids; Polyenes; Alkenes; Hydrocarbons, Acyclic; Hydrocarbons; Organic Chemicals; Cyclohexenes; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Terpenes; Diterpenes; Pigments, Biological; Biological Factors

Central Study Contacts

Zhijie Wang Jiachen Xu, MD

CONTACT

+86 13466323860; jie_969@163.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Chief Physician

Study Record Dates

• First Submitted: September 21, 2026
• First Posted: September 25, 2026
• Study Start: October 1, 2026
• Primary Completion (Estimated): October 1, 2028
• Study Completion (Estimated): October 10, 2028
• Last Updated: September 25, 2026

Record last verified: 2026-09

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)