A Phase I Study of INCB024360 (Epacadostat) Alone, INCB024360 in Combination With Pembrolizumab (MK-3475), and INCB024360 and Pembrolizumab in Combination With Chemotherapy in Patients With Advanced Solid Tumors (KEYNOTE-434)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 34
- 主要终点
- Number of Participants Who Experienced At Least One Adverse Event (AE)
研究概览
简要总结
This is an open-label, non-randomized, Phase I study of epacadostat (INCB024360) alone and in combination with pembrolizumab with chemotherapy and pembrolizumab without chemotherapy in participants with advanced solid tumors. The primary objective of the trial is to evaluate the safety and tolerability of epacadostat administered alone and in combination with pembrolizumab with and without chemotherapy.
With protocol amendment 02 (26-April-2019), treatment with epacadostat was stopped in the "Epacad+Pembro+Cisplatin+Pemetrexed", "Epacad+Pembro+Carboplatin+Pemetrexed", and "Epacad+Pembro+Carboplatin+Paclitaxel" study arms.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 20 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •For Part A: Has a histologically-confirmed metastatic or locally advanced solid tumor that has failed to respond to standard therapy, progressed despite standard therapy, or for which standard therapy does not exist.
- •For Part B: Has a histologically-confirmed or cytologically confirmed diagnosis of non-small cell lung carcinoma (NSCLC) stage IIIB/IV, be naïve to systemic therapy, and have confirmation that epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK)-directed therapy is not indicated. Cohort 1 and 2 must have a histological or cytological diagnosis of non-squamous cancer.
- •Has at least one measurable lesion by computed tomography or magnetic resonance imaging per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1
- •Has Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
- •Has a life expectancy of ≥3 months
- •Females must not be pregnant (negative urine or serum human chorionic gonadotropin test within 72 hours of study start)
- •Women of childbearing potential and male participants must agree to use adequate contraception during the study through 120 days after the last dose of study medication
- •For Part A: Has provided tissue for programmed cell death ligand 1 (PD-L1)/ Indoleamine 2,3-dioxygenase 1 (IDO1) expression evaluation from an archival tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. For Part B submission of tissue is optional.
排除标准
- •Has received prior therapy with an anti-Programmed cell death protein (PD)-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) agents (including ipilimumab or any other antibody/drug specifically targeting T-cell co-stimulation or checkpoint pathways), or IDO1 inhibitor
- •Is currently participating or has participated in a study with an investigational compound or device within 4 weeks, or 5 times half-life of the investigational compound, whichever is longer, of initial dosing on this study
- •For Part A: Has had chemotherapy, targeted small molecule therapy, radiotherapy, major surgery, or biological cancer therapy (including monoclonal antibodies) within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to the first dose of study medication, or who has not recovered (≤ Grade 1 or baseline) from adverse events due to a previously administered treatment
- •For Part B: Has received radiotherapy within 7 days of the first dose of trial treatment or radiation therapy to the lung that is >30 Gray (Gy) within 6 months of the first dose of study medication
- •Is expected to require any other form of systemic or localized anti-neoplastic therapy while in study
- •Has active central nervous system (CNS) metastases and/or carcinomatous meningitis
- •Has symptomatic ascites or pleural effusion
- •Has an active autoimmune disease that has required systemic treatment
- •Is receiving systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 1 week prior to the first dose of study medication
- •Has an active infection requiring systemic therapy
- •Has history of (noninfectious) pneumonitis that required systemic steroids or current pneumonitis/interstitial lung disease
- •Has received a live vaccine within 4 weeks prior to the first dose of study medication
- •Has a known hypersensitivity to the components of the trial treatment or another monoclonal antibody
- •For Part B: Has a known sensitivity to any component of cisplatin, carboplatin, paclitaxel, or pemetrexed.
- •For Part B: Is on chronic systemic steroids with the exception of use of bronchodilators, inhaled steroids, or local steroid injections
- •For Part B cohort 1 and 2: Is unable to interrupt aspirin or other nonsteroidal ant-inflammatory drugs (NSAIDs), other than an aspirin dose ≤1.3 g per day, for a 5-day period (8-day period for long-acting agents, such as piroxicam).
- •For Part B cohort 1 and 2: Is unable or unwilling to take folic acid or vitamin B12 supplementation
- •Is Human Immunodeficiency Virus (HIV)-positive (HIV 1/2 antibodies)
- •Has known history of or is positive for active Hepatitis B (Hepatitis B surface antigen reactive) or has active Hepatitis C (Hepatitis C virus ribonucleic acid)
- •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 during the study through 120 days after the last dose of study medication
- •Has received monoamine oxidase inhibitors (MAOIs) within the 3 weeks before the first dose of study medication
- •Has any history of Serotonin Syndrome after receiving serotonergic drugs
- •Has presence of a gastrointestinal condition that may affect drug absorption
研究组 & 干预措施
Part A Cohort 1: epacadostat 25 mg
Participants received 25 mg of epacadostat orally twice daily (BID) alone on Days 1-5 of Cycle 1 (28-day cycle) with a washout on Days 6 and 7. On Day 8 participants received a one-time intravenous (IV) infusion of 200 mg pembrolizumab while continuing to receive 25 mg of epacadostat BID on Days 8-28. For each 21-day cycle thereafter, participants received a one-time IV infusion of 200 mg pembrolizumab on Day 1 and received 25 mg of epacadostat BID on Days 1-21 for up to 35 cycles (approximately 2 years).
干预措施: Epacadostat 25 mg (Drug)
Part A Cohort 1: epacadostat 25 mg
Participants received 25 mg of epacadostat orally twice daily (BID) alone on Days 1-5 of Cycle 1 (28-day cycle) with a washout on Days 6 and 7. On Day 8 participants received a one-time intravenous (IV) infusion of 200 mg pembrolizumab while continuing to receive 25 mg of epacadostat BID on Days 8-28. For each 21-day cycle thereafter, participants received a one-time IV infusion of 200 mg pembrolizumab on Day 1 and received 25 mg of epacadostat BID on Days 1-21 for up to 35 cycles (approximately 2 years).
干预措施: pembrolizumab 200 mg (Biological)
Part A Cohort 1: epacadostat 100 mg
Participants received 100 mg of epacadostat orally BID alone on Days 1-5 of Cycle 1 (28-day cycle) with a washout on Days 6 and 7. On Day 8 participants received a one-time IV infusion of 200 mg pembrolizumab while continuing to receive 100 mg of epacadostat BID on Days 8-28. For each 21-day cycle thereafter, participants received a one-time IV infusion of 200 mg pembrolizumab on Day 1 and received 100 mg of epacadostat BID on Days 1-21 for up to 35 cycles (approximately 2 years).
干预措施: Epacadostat 100 mg (Drug)
Part A Cohort 1: epacadostat 100 mg
Participants received 100 mg of epacadostat orally BID alone on Days 1-5 of Cycle 1 (28-day cycle) with a washout on Days 6 and 7. On Day 8 participants received a one-time IV infusion of 200 mg pembrolizumab while continuing to receive 100 mg of epacadostat BID on Days 8-28. For each 21-day cycle thereafter, participants received a one-time IV infusion of 200 mg pembrolizumab on Day 1 and received 100 mg of epacadostat BID on Days 1-21 for up to 35 cycles (approximately 2 years).
干预措施: pembrolizumab 200 mg (Biological)
Part A Cohort 2: epacadostat 25 mg+pembrolizumab
For each 21-day cycle, participants received a one-time IV infusion of 200 mg pembrolizumab on Day 1 and received 25 mg of epacadostat orally BID on Days 1-21 for up to 35 cycles (approximately 2 years).
干预措施: Epacadostat 25 mg (Drug)
Part A Cohort 2: epacadostat 25 mg+pembrolizumab
For each 21-day cycle, participants received a one-time IV infusion of 200 mg pembrolizumab on Day 1 and received 25 mg of epacadostat orally BID on Days 1-21 for up to 35 cycles (approximately 2 years).
干预措施: pembrolizumab 200 mg (Biological)
Part A Cohort 2: epacadostat 100 mg+pembrolizumab
For each 21-day cycle, participants received a one-time IV infusion of 200 mg pembrolizumab on Day 1 and received 100 mg of epacadostat orally BID on Days 1-21 for up to 35 cycles (approximately 2 years).
干预措施: Epacadostat 100 mg (Drug)
Part A Cohort 2: epacadostat 100 mg+pembrolizumab
For each 21-day cycle, participants received a one-time IV infusion of 200 mg pembrolizumab on Day 1 and received 100 mg of epacadostat orally BID on Days 1-21 for up to 35 cycles (approximately 2 years).
干预措施: pembrolizumab 200 mg (Biological)
Part B Cohort 1: pembrolizumab+cisplatin+pemetrexed
For each 21-day cycle, participants received a one-time IV infusion of 200 mg pembrolizumab on Day 1 and 100 mg of epacadostat orally BID on Days 1-21 for up to 35 cycles (approximately 2 years). For the first 4 cycles, participants also received a one-time IV infusion of 75 mg/m^2 cisplatin and 500 mg/m^2 pemetrexed on Day 1. Treatment with epacadostat was stopped with protocol amendment 02.
干预措施: Epacadostat 100 mg (Drug)
Part B Cohort 1: pembrolizumab+cisplatin+pemetrexed
For each 21-day cycle, participants received a one-time IV infusion of 200 mg pembrolizumab on Day 1 and 100 mg of epacadostat orally BID on Days 1-21 for up to 35 cycles (approximately 2 years). For the first 4 cycles, participants also received a one-time IV infusion of 75 mg/m^2 cisplatin and 500 mg/m^2 pemetrexed on Day 1. Treatment with epacadostat was stopped with protocol amendment 02.
干预措施: pembrolizumab 200 mg (Biological)
Part B Cohort 1: pembrolizumab+cisplatin+pemetrexed
For each 21-day cycle, participants received a one-time IV infusion of 200 mg pembrolizumab on Day 1 and 100 mg of epacadostat orally BID on Days 1-21 for up to 35 cycles (approximately 2 years). For the first 4 cycles, participants also received a one-time IV infusion of 75 mg/m^2 cisplatin and 500 mg/m^2 pemetrexed on Day 1. Treatment with epacadostat was stopped with protocol amendment 02.
干预措施: Cisplatin 75 mg/m^2 (Drug)
Part B Cohort 1: pembrolizumab+cisplatin+pemetrexed
For each 21-day cycle, participants received a one-time IV infusion of 200 mg pembrolizumab on Day 1 and 100 mg of epacadostat orally BID on Days 1-21 for up to 35 cycles (approximately 2 years). For the first 4 cycles, participants also received a one-time IV infusion of 75 mg/m^2 cisplatin and 500 mg/m^2 pemetrexed on Day 1. Treatment with epacadostat was stopped with protocol amendment 02.
干预措施: Pemetrexed 500 mg/m^2 (Drug)
Part B Cohort 2: pembrolizumab+carboplatin+pemetrexed
For each 21-day cycle, participants received a one-time IV infusion of 200 mg pembrolizumab on Day 1 and 100 mg of epacadostat orally BID on Days 1-21 for up to 35 cycles (approximately 2 years). For the first 4 cycles, participants also received a one-time IV infusion of Area Under the Curve (AUC) 5 carboplatin and 500 mg/m^2 pemetrexed on Day 1. Treatment with epacadostat was stopped with protocol amendment 02.
干预措施: Epacadostat 100 mg (Drug)
Part B Cohort 2: pembrolizumab+carboplatin+pemetrexed
For each 21-day cycle, participants received a one-time IV infusion of 200 mg pembrolizumab on Day 1 and 100 mg of epacadostat orally BID on Days 1-21 for up to 35 cycles (approximately 2 years). For the first 4 cycles, participants also received a one-time IV infusion of Area Under the Curve (AUC) 5 carboplatin and 500 mg/m^2 pemetrexed on Day 1. Treatment with epacadostat was stopped with protocol amendment 02.
干预措施: pembrolizumab 200 mg (Biological)
Part B Cohort 2: pembrolizumab+carboplatin+pemetrexed
For each 21-day cycle, participants received a one-time IV infusion of 200 mg pembrolizumab on Day 1 and 100 mg of epacadostat orally BID on Days 1-21 for up to 35 cycles (approximately 2 years). For the first 4 cycles, participants also received a one-time IV infusion of Area Under the Curve (AUC) 5 carboplatin and 500 mg/m^2 pemetrexed on Day 1. Treatment with epacadostat was stopped with protocol amendment 02.
干预措施: Carboplatin Area Under the Curve (AUC) 5 (Drug)
Part B Cohort 2: pembrolizumab+carboplatin+pemetrexed
For each 21-day cycle, participants received a one-time IV infusion of 200 mg pembrolizumab on Day 1 and 100 mg of epacadostat orally BID on Days 1-21 for up to 35 cycles (approximately 2 years). For the first 4 cycles, participants also received a one-time IV infusion of Area Under the Curve (AUC) 5 carboplatin and 500 mg/m^2 pemetrexed on Day 1. Treatment with epacadostat was stopped with protocol amendment 02.
干预措施: Pemetrexed 500 mg/m^2 (Drug)
Part B Cohort 3: pembrolizumab+carboplatin+paclitaxel
For each 21-day cycle, participants received a one-time IV infusion of 200 mg pembrolizumab on Day 1 and 100 mg of epacadostat orally BID on Days 1-21 for up to 35 cycles (approximately 2 years). For the first 4 cycles, participants also received a one-time IV infusion of AUC 6 carboplatin and 200 mg/m^2 paclitaxel on Day 1. Treatment with epacadostat was stopped with protocol amendment 02.
干预措施: Epacadostat 100 mg (Drug)
Part B Cohort 3: pembrolizumab+carboplatin+paclitaxel
For each 21-day cycle, participants received a one-time IV infusion of 200 mg pembrolizumab on Day 1 and 100 mg of epacadostat orally BID on Days 1-21 for up to 35 cycles (approximately 2 years). For the first 4 cycles, participants also received a one-time IV infusion of AUC 6 carboplatin and 200 mg/m^2 paclitaxel on Day 1. Treatment with epacadostat was stopped with protocol amendment 02.
干预措施: pembrolizumab 200 mg (Biological)
Part B Cohort 3: pembrolizumab+carboplatin+paclitaxel
For each 21-day cycle, participants received a one-time IV infusion of 200 mg pembrolizumab on Day 1 and 100 mg of epacadostat orally BID on Days 1-21 for up to 35 cycles (approximately 2 years). For the first 4 cycles, participants also received a one-time IV infusion of AUC 6 carboplatin and 200 mg/m^2 paclitaxel on Day 1. Treatment with epacadostat was stopped with protocol amendment 02.
干预措施: Paclitaxel 200 mg/m^2 (Drug)
Part B Cohort 3: pembrolizumab+carboplatin+paclitaxel
For each 21-day cycle, participants received a one-time IV infusion of 200 mg pembrolizumab on Day 1 and 100 mg of epacadostat orally BID on Days 1-21 for up to 35 cycles (approximately 2 years). For the first 4 cycles, participants also received a one-time IV infusion of AUC 6 carboplatin and 200 mg/m^2 paclitaxel on Day 1. Treatment with epacadostat was stopped with protocol amendment 02.
干预措施: Carboplatin AUC 6 (Drug)
结局指标
主要结局
Number of Participants Who Experienced At Least One Adverse Event (AE)
时间窗: Up to approximately 39.7 months
An adverse event is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An adverse event can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an adverse event. The number of participants who experienced an AE was reported for each arm.
Number of Participants Experiencing Dose-Limiting Toxicities (DLTs) According to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v.4.0)
时间窗: Up to Day 7 for Part A Cohort 1; up to Day 21 for Part A Cohort 2 and Part B
A DLT was defined as the occurrence of any treatment-emergent adverse event occurring up to and including Study Day 7 for Part A Cohort 1 or Day 21 for Part A Cohort 2 and Part B. The following criteria defined DLTs: Grade (G) 4 thrombocytopenia; G4 neutropenia (despite optimal supportive care in Part B) lasting \>1 week; febrile neutropenia (only if considered clinically significant in Part B); G4 toxicity; G3 laboratory abnormality lasting \>1 week: G3 toxicity excluding nausea or vomiting controlled within 72 hours, rash in the absence of desquamation, no mucosal involvement, does not require systemic steroids, and resolves to G1 by the next scheduled dose of pembrolizumab or 14 days; G2 or higher episcleritis, uveitis, or iritis; unable to receive 75% of epacadostat or 1 dose of pembrolizumab during the DLT observation period because of toxicity, even if the toxicity does not meet DLT criteria; or \>2 week delay in initiating Cycle 2 due to toxicity.
Number of Participants Who Discontinued Study Treatment Due to An Adverse Event (AE)
时间窗: Up to approximately 38.5 months
An adverse event is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An adverse event can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an adverse event. The number of participants who discontinued due to an AE was reported for each arm.
次要结局
- Terminal Half-Life (t1/2) of Epacadostat in Part A(Cycle 1 (28-day cycle): Days 1, 5, and 12 at predose and 0.5, 1, 2, 4, 6, 8 and 10 hours postdose)
- Maximum Concentration (Cmax) of Pembrolizumab in Part A Cycle 1(Cycle 1 (21-day pembrolizumab treatment cycle starting at Day 8 of Cycle 1): Day 1 predose and postdose within 30 minutes after the end of pembrolizumab infusion)
- Maximum Concentration (Cmax) of Pembrolizumab in Part B Cycle 1(Cycle 1 (21-day pembrolizumab treatment cycle starting at Day 8 of Cycle 1): Day 1 predose and postdose within 30 minutes after the end of pembrolizumab infusion)
- Trough Concentration (Ctrough) of Pembrolizumab in Part A Cycles 1, 2, 4, 6, and 8(Predose prior to the Cycles 1, 2, 4, 6, and 8 infusion)
- Maximum Concentration (Cmax) of Epacadostat in Part A(Cycle 1 (28-day cycle): Days 1, 5, and 12 at predose and 0.5, 1, 2, 4, 6, 8 and 10 hours postdose)
- Time to Maximum Concentration (Tmax) of Epacadostat in Part A(Cycle 1 (28-day cycle): Days 1, 5, and 12 at predose and 0.5, 1, 2, 4, 6, 8 and 10 hours postdose)
- Area Under the Concentration-Time Curve From Zero to the Time of the Last Measurable Concentration (AUC0-t) of Epacadostat in Part A(Cycle 1 (28-day cycle): Days 1, 5, and 12 at predose and 0.5, 1, 2, 4, 6, 8 and 10 hours postdose)
- Trough Concentration (Ctrough) of Epacadostat in Part A(Cycle 1 (28-day cycle): Days 1, 5, and 12 at predose)
- Trough Concentration (Ctrough) of Pembrolizumab in Part B Cycles 1, 2, 4, 6, and 8(Predose prior to the Cycles 1, 2, 4, 6, and 8 infusion)