A Phase 1 Clinical Study of All-Trans Retinoic Acid in Combination With a PD-1 Inhibitor in Patients With EGFR-Mutant Non-Small Cell Lung Cancer After Acquired Resistance to a Third-Generation EGFR Tyrosine Kinase Inhibitor
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 入组人数
- 24
- 试验地点
- 1
- 主要终点
- Incidence and Severity of Adverse Events
研究概览
简要总结
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.
详细描述
This is a prospective, single-arm, open-label, Phase 1 dose-escalation and dose-expansion clinical trial evaluating all-trans retinoic acid (ATRA) in combination with tislelizumab in participants with advanced EGFR-mutant non-small cell lung cancer (NSCLC). The study population will include participants whose disease has progressed after a third-generation EGFR tyrosine kinase inhibitor (EGFR-TKI) and at least one standard systemic therapy, as well as participants who are unable to tolerate or are considered unsuitable for currently available standard treatment. Participants must have no clearly available and appropriate standard targeted therapy, as determined by the investigator.
The study is designed to characterize the safety and tolerability of the combination, identify the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D), and obtain preliminary evidence of antitumor activity. The study will also explore molecular and immune changes associated with treatment response and toxicity.
Dose Escalation and Dose Expansion
A conventional 3+3 dose-escalation design will be used. Three ATRA dose levels are planned:
- Dose Level 1: ATRA 30 mg orally twice daily
- Dose Level 2: ATRA 40 mg orally twice daily
- Dose Level 3: ATRA 50 mg orally twice daily
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 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
- •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
- •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.
- •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.
排除标准
- •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.
- •Current treatment with a tetracycline that cannot be discontinued.
- •Current treatment with another anticancer therapy or investigational product without completion of the protocol-required washout period.
- •Any other condition that, in the investigator's opinion, makes the individual unsuitable for participation in the clinical trial.
研究组 & 干预措施
Experimental: All-Trans Retinoic Acid Plus Tislelizumab
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.
干预措施: Tislelizumab (Drug)
Experimental: All-Trans Retinoic Acid Plus Tislelizumab
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.
干预措施: All-trans retinoic acid (Drug)
结局指标
主要结局
Incidence and Severity of Adverse Events
时间窗: From the first dose of ATRA through the safety follow-up visit, approximately 28 days after the last dose of study treatment
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.
Incidence of Dose-Limiting Toxicities
时间窗: 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
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.
Maximum Tolerated Dose and/or Recommended Dose for Further Study
时间窗: At completion of dose escalation, based primarily on DLTs observed during each participant's 28-day DLT evaluation period
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.
次要结局
- 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)
研究者
Zhijie Wang
Chief Physician
Cancer Institute and Hospital, Chinese Academy of Medical Sciences