Pembrolizumab + Platinum Doublets Without Radiation for Patients With PD-L1 ≥50% Locally Advanced Non-small Cell Lung Cancer: a Multicenter Prospective Single Arm Phase II Study
试验速览
- 阶段
- 2 期
- 发起方
- 入组人数
- 21
- 主要终点
- 2-year PFS rate
研究概览
简要总结
This is a phase II, multicenter, single-arm, non-blind study. To 21 patients with PD-L1 ≥50% locally advanced non-small cell lung cancer, the combination of Pembrolizumab and platinum-doublets will be intravenously administered without radiotherapy to evaluate the efficacy and safety of combination therapy with Pembrolizumab and platinum-doublets.
详细描述
Trial procedure:
As induction therapy, ≤4 courses of combination therapy with Pembrolizumab at 200 mg (day 1) and a platinum preparation will be performed at 3-week intervals until disease exacerbation or intolerable toxicity appearance. Concerning combination therapy with a platinum preparation, the combination of cisplatin (CDDP) at 75 mg/m2 (day 1) or carboplatin (CBDCA) at Area Under the Curve=6 (AUC=6) (day 1) + pemetrexed (PEM) at 500 mg/m2 (day 1) will be administered to patients with non-squamous cell carcinoma at 3-week intervals. To those with squamous cell carcinoma, carboplatin (CBDCA) at AUC=6 (day 1) + nanoparticle albumin-bound paclitaxel (nab-PTX) at 100 mg/m2 (days 1, 8, and 15) will be administered at 3-week intervals. If there is no exacerbation after the 4th course of induction therapy, it will be switched to maintenance therapy. For maintenance therapy, the combination of PEM at 500 mg/m2 (day 1) + Pembrolizumab at 200 mg (day 1) will be administered to patients with non-squamous cell carcinoma at 3-week intervals. To those with squamous cell carcinoma, Pembrolizumab at 200 mg (day 1) will be administered at 3-week intervals until disease exacerbation or intolerable toxicity appearance. Pembrolizumab administration should be continued for 2 years involving induction and maintenance therapies or until the 35th course.
In each patient, diagnostic imaging will be performed every 6 weeks (42 ± 7 days)(every 9 weeks after Week 18, every 12 weeks after Week 45) to evaluate tumor-reducing effects. Using images, the response rate (RR) and progression-free survival (PFS) will be evaluated based on the "Guidelines for evaluating the treatment response of solid cancer (RECIST 1.1)". It is possible to continue treatment until PD evaluated by the attending physician based on the RECIST 1.1, intolerable toxicity appearance, the appearance of concomitant diseases affecting the continuation of treatment, discontinuation based on the study investigator's evaluation, withdrawal, pregnancy, incompliance with investigational-drug administration or procedures described in the protocol, appearance of management-related reasons, or completion of Pembrolizumab administration for 2 years involving induction and maintenance therapies or the 35th course. Even after PD is definitively diagnosed by the study investigator based on the RECIST 1.1, it is possible to continue treatment if the patient's condition is stable and if treatment is considered to be advantageous for the patient by the study investigator. During the trial period, adverse events should be examined,and severity grading should be performed according to the CTCAE（NCI Common Terminology Criteria for Adverse Events）version 5.0.
In cases without any response at first radiographic evaluation (6 weeks), local salvage therapy using radiotherapy is recommended by a discretion of doctors in charge. At that timing, such cases are treated as a censored case.
After enrollment of 10 cases, the trial will be early terminated by confirmed PD according RECIST at their initial radiographic evaluation (6 weeks) more than 3 cases.
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
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histologically confirmed NSCLC
- •PD-L1 Total Proportion Score (TPS) ≥50%
- •Locally advanced NSCLC (unresectable stage III with indication of curative CRT based on Tumour, Node and Metastasis (TNM) classification of Union for International Cancer Control (UICC) version 8)
- •Treatment naïve for primary disease
- •Have at least measurable disease based on RECIST 1.
- •Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to
- •Have adequate organ function as defined in the following:
- •Adequate Organ Function and Laboratory Values
- •Hematological:
- •Absolute neutrophil count (ANC) ≥1500/μL Platelets ≥100 000/μL Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/L (a)
- •Creatinine OR Measured or calculated (b) creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≤1.5 × Upper Limit of Normal (ULN) OR ≥45 mL/min for participant with creatinine levels >1.5 × institutional ULN
- •Total bilirubin ≤1.5 ×ULN OR direct bilirubin ≤ULN for participants with total bilirubin levels >1.5 × ULN Aspartate aminotransferase (AST) (SGOT) and Alanine transaminase (ALT) (SGPT) ≤2.5 × ULN
- •Coagulation:
- •International normalized ratio (INR) OR prothrombin time (PT) Activated partial thromboplastin time (aPTT) ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants
- •Thyroid functions:
- •Thyroid-Stimulating Hormone (TSH) Within institutional ULN (If TSH is not within ULN at baseline, the participant may still be eligible if T3 and free T4 are within ULN.)
- •Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks.
- •Creatinine clearance (CrCl) should be calculated per institutional standard.
- •Male/female participants who are at least 20 years of age on the day of signing informed consent
- •Male participants:
- •A male participant must agree to use a contraception as detailed in of this protocol during the treatment period and for at least 120 days after the last dose of study treatment and refrain from donating sperm during this period.
- •Female participants:
- •A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: a.) Not a woman of childbearing potential (WOCBP) as defined in OR b.) A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 120 days after the last dose of study treatment.
- •The participant is discussed in a conference including radiation oncologists.
- •The participant (or legally acceptable representative if applicable) provides written informed consent for the trial.
排除标准
- •A WOCBP who has a positive urine pregnancy test within 72 hours prior to allocation. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
- •Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., Cytotoxic T Lymphocyte-associated Antigen 4 (CTLA-4), OX-40, CD137).
- •Has received any prior systemic anti-cancer therapy. Note: If participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment.
- •Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.
- •Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment.
- •Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.
- •Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
- •Has a known additional malignancy that is progressing or has required active treatment within the past 5 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, transitional cell carcinoma of urothelial cancer, or carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.
- •Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
- •Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 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.
- •Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
- •Has an active infection requiring systemic therapy.
- •Has a history of tissue/organ transplantation.
- •Has a known history of Human Immunodeficiency Virus (HIV).
- •Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (HCV) (defined as HCV RNA is detected) infection. Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.
- •Has a known history of active Tuberculosis (TB).
- •Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
- •Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
- •Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment.
研究组 & 干预措施
Immunotherapy plus chemotherapy
Combination of CDDP at 75 mg/m2 (day 1) or CBDCA at Area Under the Curve=6 (AUC=6) (day 1) + PEM at 500 mg/m2 (day 1) will be administered to patients with non-squamous cell carcinoma at 3-week intervals. To those with squamous cell carcinoma, CBDCA at AUC=6 (day 1) + nab-PTX at 100 mg/m2 (days 1, 8, and 15) will be administered at 3-week intervals. If there is no progression after the 4th course of induction therapy, it will be switched to maintenance therapy. For maintenance therapy, the combination of PEM at 500 mg/m2 (day 1) + Pembrolizumab at 200 mg (day 1) will be administered to patients with non-squamous cell carcinoma at 3-week intervals. To those with squamous cell carcinoma, Pembrolizumab at 200 mg (day 1) will be administered at 3-week intervals until disease progression or intolerable toxicity. Pembrolizumab administration should be continued for 2 years involving induction and maintenance therapies or until the 35th course.
干预措施: Pembrolizumab (Drug)
Immunotherapy plus chemotherapy
Combination of CDDP at 75 mg/m2 (day 1) or CBDCA at Area Under the Curve=6 (AUC=6) (day 1) + PEM at 500 mg/m2 (day 1) will be administered to patients with non-squamous cell carcinoma at 3-week intervals. To those with squamous cell carcinoma, CBDCA at AUC=6 (day 1) + nab-PTX at 100 mg/m2 (days 1, 8, and 15) will be administered at 3-week intervals. If there is no progression after the 4th course of induction therapy, it will be switched to maintenance therapy. For maintenance therapy, the combination of PEM at 500 mg/m2 (day 1) + Pembrolizumab at 200 mg (day 1) will be administered to patients with non-squamous cell carcinoma at 3-week intervals. To those with squamous cell carcinoma, Pembrolizumab at 200 mg (day 1) will be administered at 3-week intervals until disease progression or intolerable toxicity. Pembrolizumab administration should be continued for 2 years involving induction and maintenance therapies or until the 35th course.
干预措施: Cis Platinum (Drug)
Immunotherapy plus chemotherapy
Combination of CDDP at 75 mg/m2 (day 1) or CBDCA at Area Under the Curve=6 (AUC=6) (day 1) + PEM at 500 mg/m2 (day 1) will be administered to patients with non-squamous cell carcinoma at 3-week intervals. To those with squamous cell carcinoma, CBDCA at AUC=6 (day 1) + nab-PTX at 100 mg/m2 (days 1, 8, and 15) will be administered at 3-week intervals. If there is no progression after the 4th course of induction therapy, it will be switched to maintenance therapy. For maintenance therapy, the combination of PEM at 500 mg/m2 (day 1) + Pembrolizumab at 200 mg (day 1) will be administered to patients with non-squamous cell carcinoma at 3-week intervals. To those with squamous cell carcinoma, Pembrolizumab at 200 mg (day 1) will be administered at 3-week intervals until disease progression or intolerable toxicity. Pembrolizumab administration should be continued for 2 years involving induction and maintenance therapies or until the 35th course.
干预措施: Carboplatin (Drug)
Immunotherapy plus chemotherapy
Combination of CDDP at 75 mg/m2 (day 1) or CBDCA at Area Under the Curve=6 (AUC=6) (day 1) + PEM at 500 mg/m2 (day 1) will be administered to patients with non-squamous cell carcinoma at 3-week intervals. To those with squamous cell carcinoma, CBDCA at AUC=6 (day 1) + nab-PTX at 100 mg/m2 (days 1, 8, and 15) will be administered at 3-week intervals. If there is no progression after the 4th course of induction therapy, it will be switched to maintenance therapy. For maintenance therapy, the combination of PEM at 500 mg/m2 (day 1) + Pembrolizumab at 200 mg (day 1) will be administered to patients with non-squamous cell carcinoma at 3-week intervals. To those with squamous cell carcinoma, Pembrolizumab at 200 mg (day 1) will be administered at 3-week intervals until disease progression or intolerable toxicity. Pembrolizumab administration should be continued for 2 years involving induction and maintenance therapies or until the 35th course.
干预措施: Pemetrexed (Drug)
Immunotherapy plus chemotherapy
Combination of CDDP at 75 mg/m2 (day 1) or CBDCA at Area Under the Curve=6 (AUC=6) (day 1) + PEM at 500 mg/m2 (day 1) will be administered to patients with non-squamous cell carcinoma at 3-week intervals. To those with squamous cell carcinoma, CBDCA at AUC=6 (day 1) + nab-PTX at 100 mg/m2 (days 1, 8, and 15) will be administered at 3-week intervals. If there is no progression after the 4th course of induction therapy, it will be switched to maintenance therapy. For maintenance therapy, the combination of PEM at 500 mg/m2 (day 1) + Pembrolizumab at 200 mg (day 1) will be administered to patients with non-squamous cell carcinoma at 3-week intervals. To those with squamous cell carcinoma, Pembrolizumab at 200 mg (day 1) will be administered at 3-week intervals until disease progression or intolerable toxicity. Pembrolizumab administration should be continued for 2 years involving induction and maintenance therapies or until the 35th course.
干预措施: nab paclitaxel (Drug)
结局指标
主要结局
2-year PFS rate
时间窗: 2 years after enrollment of final patient
Number of non-progression cases/all enrolled cases at 2 years
次要结局
- OS(2 years after enrollment of final patient)
- Adverse events(6 months and 2 years after enrollment of final patient)
- Response rate(6 months after enrollment of final patient)
- PFS(2 years after enrollment of final patient)
研究者
Akito Hata
Akito Hata, Director of Division of Thoracic Oncology
Kobe Minimally Invasive Cancer Center