NCT03599518终止1 期
A Multicenter, Open-Label Phase 1 Study of DS-1205c in Combination With Gefitinib in Subjects With Metastatic or Unresectable EGFR-Mutant Non-Small Cell Lung Cancer
适应症
干预措施
相关药物
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 20
- 试验地点
- 8
- 主要终点
- Number of Participants With Dose-limiting Toxicities (DLTs) Following Administration With DS-1205c in Combination With Gefitinib
研究概览
简要总结
This study has two parts: dose escalation and dose expansion.
The primary objectives are:
- For Dose Escalation, to assess the safety and tolerability of DS-1205c when combined with gefitinib in the study population and to determine the recommended dose for expansion of DS-1205c when combined with gefitinib in the study population
- For Dose Expansion, to assess the safety and tolerability of DS-1205c when combined with gefitinib in the study population.
In Dose Escalation, after a 7-day run in period (Cycle 0), there will be 21-day cycles (Cycle 1 onward). In Dose Expansion, there will be 21-day cycles.
The number of treatment cycles is not fixed in this study. Participants will continue study treatment for 36 months unless they decide not to (withdraw consent), their disease gets worse [progressive disease (PD)], or side effects become unacceptable (unacceptable toxicity).
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
- 20 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Has histologically or cytologically documented adenocarcinoma NSCLC
- •Has locally advanced or metastatic NSCLC, not amenable to curative surgery or radiation
- •Has acquired resistance to EGFR tyrosine kinase inhibitor (TKI) according to the Jackman criteria (PMID: 19949011):
- •Historical confirmation that the tumor harbors an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q) OR
- •Has experienced clinical benefit from an EGFR TKI, followed by systemic progression [Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) or World Health Organization (WHO)] while on continuous treatment with an EGFR TKI
- •Is currently receiving and able to interrupt gefitinib or discontinue erlotinib, afatinib, or osimertinib
- •Has been receiving gefitinib, erlotinib, afatinib, or osimertinib for at least 6 weeks with well-controlled related toxicities less than Grade 3 in severity at the time of screening period; participants who have been receiving gefitinib must be taking gefitinib at a dose of 250 mg/day
- •Has radiological documentation of disease progression while receiving continuous treatment with gefitinib, erlotinib, afatinib, or osimertinib
- •Has at least one measurable lesion per RECIST version 1.1
- •Is willing to provide archival tumor tissue from a biopsy performed after progression during treatment with gefitinib, erlotinib, afatinib, or osimertinib OR has at least one lesion, not previously irradiated, amenable to core biopsy and is willing to undergo screening tumor biopsy
- •Demonstrates absence of EGFR T790M mutation in tumor tissue since progression during gefitinib, erlotinib, afatinib, or osimertinib treatment
- •Has Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1, with no deterioration over the previous 2 weeks
排除标准
- •Has any evidence of small cell histology, or combined small cell and non-small cell histology, in original tumor biopsy or in screening biopsy performed since progression
- •Has previously documented evidence of anaplastic lymphoma kinase (ALK) fusion, ROS proto-oncogene 1 (ROS1) fusion, BRAF V600E mutation, rearranged during transfection (RET) rearrangement, human epidermal growth factor receptor 2 (HER2) mutation, or MET exon 14 skipping mutation - no new testing for these genomic alterations is required for Screening
- •Has received treatment with any of the following:
- •Any cytotoxic chemotherapy, immune checkpoint inhibitor therapy, investigational agent or other anticancer drug(s) from a previous cancer treatment regimen or clinical study (other than EGFR TKI), within 14 days of the first dose of study treatment
- •Immune checkpoint inhibitor therapy within 30 days of first dose of study treatment
- •Major surgery (excluding placement of vascular access) within 4 weeks of the first dose of study treatment
- •Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks, or palliative radiation therapy within 2 weeks of the first dose of study drug treatment
- •Has history of other active malignancy within 3 years prior to enrollment, except:
- •Adequately treated non-melanoma skin cancer OR
- •Superficial bladder tumors (Tumor stage "a" [Ta], Tumor stage "is" [Tis], Tumor stage "1" [T1]) OR
- •Curatively treated in situ disease OR
- •Low-risk non-metastatic prostate cancer (with Gleason score < 7 on antiandrogen therapy)
- •Has spinal cord compression or clinically active brain metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms - Subjects with clinically inactive brain metastases may be included in the study. Subjects with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of whole brain radiotherapy and study enrollment (1 week for stereotactic radiotherapy).
- •Has retinal disease in the eye that is not due to neovascular age-related macular degeneration (nAMD; eg, significant diabetic retinopathy, glaucomatous retinal atrophy, retinal detachment)
- •Has history of myocardial infarction within the past 6 months
- •Has symptomatic congestive heart failure [New York Heart Association (NYHA) Classes II-IV], unstable angina, or cardiac arrhythmia requiring antiarrhythmic treatment
- •Has left ventricular ejection fraction (LVEF) < 45% by either echocardiogram (ECHO) or multigated acquisition (MUGA) scan
- •Has any clinically important abnormalities in rhythm, conduction or morphology of resting ECG, eg, complete left bundle branch block, third-degree heart block, second-degree heart block, or PR interval > 250 milliseconds (ms)
- •Has a mean corrected QT interval using Fridericia's correction (QTcF) prolongation >470 ms for females and >450 ms for males in three successive Screening measurements
- •Unable or unwilling to discontinue concomitant use of drugs that are known to prolong the QT interval
- •Has any factors that increase the risk of QTc prolongation or risk of arrhythmic events, such as congenital long QT. syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives
- •Has a history of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required corticosteroid treatment, has current ILD/pneumonitis, or has suspected ILD/pneumonitis which cannot be ruled out by imaging at screening
- •Has history of pancreatitis within the past 6 months
研究组 & 干预措施
DS-1205c with Gefitinib
Experimental
Participants receive DS-1205c (at planned doses given orally twice daily: 200 mg, 400 mg, 800 mg, 1000 mg, 1200 mg) in combination with daily 250 mg oral dose of gefitinib
干预措施: DS-1205c (Drug)
DS-1205c with Gefitinib
Experimental
Participants receive DS-1205c (at planned doses given orally twice daily: 200 mg, 400 mg, 800 mg, 1000 mg, 1200 mg) in combination with daily 250 mg oral dose of gefitinib
干预措施: Gefitinib (Drug)
结局指标
主要结局
Number of Participants With Dose-limiting Toxicities (DLTs) Following Administration With DS-1205c in Combination With Gefitinib
时间窗: Cycle 0 Day 1 (7-day cycle) to Cycle 1 Day 21 (each cycle is 21 days)
A dose-limiting toxicity (DLT) was defined as any treatment-emergent adverse event (TEAE) not attributable to disease or disease-related processes that occurs during the DLT-evaluation period (Cycle 0 Day 1 to Cycle 1 Day 21 of Dose Escalation) and is Grade 3 or above, according to NCI-CTCAE version 5.0.
Number of Participants With Treatment-emergent Adverse Events Occurring in Participants Following Administration With DS-1205c in Combination With Gefitinib
时间窗: Screening, Cycle 0 (7-day cycle), Days -1, 1, 2, 4, 6, and 7; Cycle 1 (21-day cycle), Days 1, 4, 8, and 15; Cycle 2 (21-day cycle), Days 1, 2, and 8; Cycle 3 and beyond (21-day cycles), Day 1; and end-of-treatment, 30 days after last dose, up to 1 year
An adverse event (AE) was defined as any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A treatment-emergent adverse event (TEAE) was defined as an AE that occurs, having been absent before the first dose of study drug, or has worsened in severity after the initiating the study drug until 37 days after last dose of the study drug.
次要结局
- Progression-free Survival Assessed by Investigator Following Administration of DS-1205c in Combination With Gefitinib(Screening; Cycle 0 (7-day cycle); Cycle 1 and beyond (21-day cycles), Every 6 weeks (± 7 days) in the first 24 weeks after Day 1 of Cycle 1, and every 12 weeks (± 7 days) thereafter; and end-of-treatment, 30 days after last dose, up to 1 year)
- Pharmacokinetic Parameter Area Under the Plasma Concentration Curve of DS-1205a Following Administration of DS-1205c in Combination With Gefitinib(Predose, 1, 2, 4, 6, 8, and 10 hours of Cycle 0 (7-day cycle; DS-1205c alone), Days 1 and 7; Predose of Cycle 1 (21-day cycle), Day 1 (DS-1205c + gefitinib); Predose, 1, 2, 4, 6, 8, and 10 hours of Cycle 2 (21-day cycle; DS-1205c + gefitinib), Day 1)
- Number of Participants With Best Overall Response With Confirmation as Assessed by Investigator Following Administration of DS-1205c in Combination With Gefitinib(Screening; Cycle 0 (7-day cycle); Cycle 1 and beyond (21-day cycles), Every 6 weeks (± 7 days) in the first 24 weeks after Day 1 of Cycle 1, and every 12 weeks (± 7 days) thereafter; and end-of-treatment, 30 days after last dose, up to 1 year)
- Overall Survival in Participants Following Administration of DS-1205c in Combination With Gefitinib(Screening; Cycle 0 (7-day cycle); Cycle 1 and beyond (21-day cycles), Every 6 weeks (± 7 days) in the first 24 weeks after Day 1 of Cycle 1, and every 12 weeks (± 7 days) thereafter; and end-of-treatment, 30 days after last dose, up to 1 year)
- Pharmacokinetic Parameter Time to Maximum Concentration (Tmax) of DS-1205a Following Administration of DS-1205c in Combination With Gefitinib(Predose, 1, 2, 4, 6, 8, and 10 hours of Cycle 0 (7-day cycle; DS-1205c alone), Days 1 and 7; Predose of Cycle 1 (21-day cycle), Day 1 (DS-1205c + gefitinib); Predose, 1, 2, 4, 6, 8, and 10 hours of Cycle 2 (21-day cycle; DS-1205c + gefitinib), Day 1)
- Pharmacokinetic Parameter of Maximum Concentration (Cmax) of DS-1205a Following Administration of DS-1205c in Combination With Gefitinib(Predose, 1, 2, 4, 6, 8, and 10 hours of Cycle 0 (7-day cycle; DS-1205c alone), Days 1 and 7; Predose of Cycle 1 (21-day cycle), Day 1 (DS-1205c + gefitinib); Predose, 1, 2, 4, 6, 8, and 10 hours of Cycle 2 (21-day cycle; DS-1205c + gefitinib), Day 1)
- Disease Control Rate Assessed by Investigator Following Administration of DS-1205c in Combination With Gefitinib(Screening; Cycle 0 (7-day cycle); Cycle 1 and beyond (21-day cycles), Every 6 weeks (± 7 days) in the first 24 weeks after Day 1 of Cycle 1, and every 12 weeks (± 7 days) thereafter; and end-of-treatment, 30 days after last dose, up to 1 year)
- Pharmacokinetic Parameter Trough Plasma Concentration (Ctrough) of DS-1205a Following Administration of DS-1205c in Combination With Gefitinib(Predose, 1, 2, 4, 6, 8, and 10 hours of Cycle 0 (7-day cycle; DS-1205c alone), Days 1 and 7; Predose of Cycle 1 (21-day cycle), Day 1 (DS-1205c + gefitinib); Predose, 1, 2, 4, 6, 8, and 10 hours of Cycle 2 (21-day cycle; DS-1205c + gefitinib), Day 1)
研究者
研究点 (8)
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