A Phase I Open-label, Dose Escalation Study to Investigate The Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of GSK2879552 Given Orally in Subjects With Relapsed/Refractory Small Cell Lung Carcinoma
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 29
- 试验地点
- 1
- 主要终点
- Part 1: Number of Participants Withdrawn Due to Toxicities
研究概览
简要总结
GSK2879552 is a potent, selective, mechanism-based inactivator of Lysine Specific Demethylase 1 (LSD1)/ CoRepressor for Element-1-Silencing Transcription factor (CoREST) activity. This is a phase I, open-label, multi-center, non-randomized, 2-part first time in human (FTIH) study for GSK2879552. Part 1 is a dose escalation phase to determine the recommended phase 2 dose (RP2D) for GSK2879552 based on the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) profiles observed after oral administration of GSK2879552. Any dose level(s) may be expanded up to 12 subjects in order to collect additional data on PK and PD.The safety and PK/PD data will be reviewed prior to the dose decision, and the dose escalation will be guided by the Neuenschwander -continuous reassessment method (N-CRM). Built-in safety constraints are in place to prevent exposing subjects to undue risk of toxicity. Once RP2D is identified, an expansion cohort (Part 2) of up to 30 subjects will be enrolled to further evaluate the clinical activity and tolerability of GSK2879552 in subjects with relapsed/refractory SCLC.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 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
- •Provided signed written informed consent
- •Males and females >=18 years of age (at the time consent is obtained).
- •Histologically or cytologically confirmed diagnosis of small cell lung carcinoma. Subjects must have measurable disease per RECIST 1.1 (for Part 2 only).
- •Recurrent or refractory disease after receiving at least one prior standard/approved platinum-containing chemotherapy regimen, or where standard therapy is refused. Part 2 only: Subjects must have recurrent disease after receiving a maximum of two prior chemotherapy regimens including at least one platinum containing regimen.
- •Eastern Cooperative Oncology Group (ECOG) performance status of <=
- •(ECOG performance status of 0 or 1).
- •Tumor tissue requirements: Availability of archival tissue, or willingness to undergo fresh biopsy at baseline; Enrollment in PK/PD cohort may be limited to subjects with disease amenable to pre- and post-dose biopsies, and willingness to undergo biopsy.
- •All prior treatment-related toxicities must be National Cancer Institute- Common Toxicity Criteria for Adverse Events (NCI-CTCAE), version 4.0 <=Grade 1 at the time of enrollment (except for alopecia)
- •Adequate baseline organ function
- •Women of childbearing potential must have a negative serum pregnancy test within 7 days of first dose of study treatment and agree to use effective contraception, as defined in protocol, during the study and for 7 days following the last dose of study treatment.
- •Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception as described in protocol from the administration of the first dose of study treatment until 3 months after the last dose of study treatment to allow for clearance of any altered sperm.
- •Able to swallow and retain orally administered study treatment and does not have any clinically significant gastrointestinal (GI) abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach and/or bowels.
- •French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.
排除标准
- •Concurrent malignancy other than SCLC. History of other malignancy is allowed as long as there is no evidence of active disease or need for treatment.
- •Currently receiving anti-cancer therapy. Exceptions: Zoledronic acid and denosumab to treat bone metastasis are allowed.
- •Prior treatment with temozolomide, dacarbazine or procarbazine.
- •Prior treatment with poly ADP ribose polymerase (PARP) inhibitors (e.g., olaparib, ABT-888).
- •Baseline Montreal Cognitive Assessment (MOCA) score of 22 or lower.
- •Received major surgery, radiotherapy, or immunotherapy within 4 weeks of GSK2879552 administration. Chemotherapy regimens with delayed toxicity within the last four weeks (six weeks for prior nitrosourea or mitomycin C). Chemotherapy regimens given continuously or on a weekly basis with limited potential for delayed toxicity or palliative radiation to a limited area within the last two weeks.
- •Administration of an investigational drug within 28 days or 5 half-lives, whichever is shorter preceding the first dose of study treatment(s) in this study.
- •French subjects: The French subject has participated in any study using an investigational study treatment(s) during the previous 28 days.
- •Subjects with current/a history of bleeding disorder or coagulopathy or who are at particularly high risk for bleeding complications.
- •Requiring anticoagulants at therapeutic doses or platelet inhibitor.
- •Current use of a prohibited medication or expected to require any of these medications during treatment with the investigational drug
- •Evidence of severe or uncontrolled systemic diseases. Any serious and/or unstable pre-existing medical, psychiatric disorder, or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures, in the opinion of the investigator
- •Known active Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) infections. Subjects with laboratory evidence of HBV clearance may be enrolled
- •Leptomeningeal metastases or spinal cord compression due to disease.
- •Subjects with previously untreated or uncontrolled brain metastases.
- •Cardiac abnormalities
- •Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to GSK2879552 or LSD1 inhibitors that contraindicates their participation.
- •Lactating female
- •Consumption of Seville oranges, grapefruit, grapefruit hybrids, grapefruit juice, pommelos, or exotic citrus fruits, from 1 day prior to the first dose of study treatment(s) until the last dose of study drug.
研究组 & 干预措施
Dose Escalation Cohort
The safety and PK/PD data will be reviewed prior to the dose decision, and the dose escalation will be guided by the Neuenschwander -continuous reassessment method (N-CRM).The dose escalation will complete when RP2D is determined. The RP2D will be the MTD or a lower dose that provides adequate PK exposure and biologic activity with superior tolerability.
干预措施: GSK2879552 (Drug)
Dose Expansion Cohort
Once the RP2D has been determined, an expansion cohort of up to 30 subjects will be enrolled in order to better characterize the clinical activity and safety profile of the RP2D
干预措施: GSK2879552 (Drug)
结局指标
主要结局
Part 1: Number of Participants Withdrawn Due to Toxicities
时间窗: Median of 7.286 weeks of drug exposure
Participants were monitored from start of the study till the development of toxicity. The data for number of participants withdrawn due to toxicities has been presented.
Part 1: Number of Participants With Serious Adverse Events (SAEs) and Non-SAEs
时间窗: Median of 7.286 weeks of drug exposure
An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability, is a congenital anomaly/ birth defect, other situations and is associated with liver injury or impaired liver function. The analysis was performed on All Treated Population which included all participants who received at least one dose of study treatment.
Part 1: Number of Participants With Dose Limiting Toxicities (DLT)
时间窗: Median of 7.286 weeks of drug exposure
An event was considered a DLT if it occurs within the first 28 days of treatment, and meets one of the following criteria unless it can be clearly established that the event is unrelated to treatment: recurrent Grade 3 anemia after initial transfusion or Grade 3 anemia lasting \> 7 days in participants who are not transfused, Grade 4 neutropenia, Grade 3 neutropenia \> 7 days duration, febrile neutropenia as defined by Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, Grade 3 thrombocytopenia requiring dose reduction, Grade 4 thrombocytopenia lasting \> 3 days or of any duration if associated with clinically significant bleeding, drug related Grade 3 or 4 non-hematologic toxicity, drug related Grade 2 toxicity (at any time during treatment) and treatment delay of 14 days or greater due to unresolved drug-related toxicity.
Part 1: Number of Participants With Dose Reduction or Delays
时间窗: Median of 7.286 weeks of drug exposure
The number of participants who had any dose reduction or delay have been presented. All dose reductions were due to AEs.
Part 1: Number of Participants With Abnormal Findings for Electrocardiogram (ECG) Parameters
时间窗: Median of 7.286 weeks of drug exposure
Single measurements of 12-lead ECGs were obtained in a semi-recumbent or supine position after at least a 5 minutes rest using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and corrected QT (QTc) intervals. The number of participants with abnormal - not clinically significant and abnormal - clinically significant "worst-case on-therapy" value have been presented.
Part 1: Number of Participants With Change in Clinical Chemistry Toxicity Grade From Baseline
时间窗: Baseline and median of 7.286 weeks of drug exposure
Blood samples were collected for evaluation of clinical chemistry parameters including potassium, aspartate aminotransferase (AST), total bilirubin, creatinine, alanine aminotransferase (ALT), uric acid, glucose, gamma glutamyl transferase (GGT), albumin, sodium, calcium, alkaline phosphatase, and phosphorus, inorganic. Baseline value was defined as the most recent, non-missing value from a central laboratory prior to or on the first dose of study treatment. Change from Baseline was defined as any visit value minus Baseline value. The number of participants with any grade increase in clinical chemistry parameters have been presented. The clinical chemistry parameters for which any grade increase worst-case on-therapy value was reported have been only summarized. NA represents data was not available. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Part 1:Number of Participants With Critical Changes in Values of Vital Signs in Response to Drug
时间窗: Median of 7.286 weeks of drug exposure
Vital sign measurements includes systolic blood pressure (SBP), diastolic blood pressure (DBP), temperature, respiration rate and heart rate. Vital signs were measured after resting for at least 5 minutes in a semi-supine position. The number of participants with critical changes in values of vital signs in response to drug have been presented.
Part 1: Number of Participants With Change in Hematology Toxicity Grade From Baseline
时间窗: Baseline and median of 7.286 weeks of drug exposure
Blood samples were collected for the analysis of hematology parameters including hemoglobin, lymphocytes, total neutrophils, platelet count and white blood cell (WBC) count. Baseline value was defined as the most recent, non-missing value from a central laboratory prior to or on the first dose of study treatment. Change from Baseline was defined as any visit value minus Baseline value. The number of participants with any grade increase in hematology parameters have been presented. The hematology parameters for which any grade increase worst-case on-therapy value was reported have been only summarized.
Part 1: Number of Participants With Abnormal Findings Undergoing Physical Examinations
时间窗: Median of 7.286 weeks of drug exposure
The complete physical examination included assessments of the head, eyes, ears, nose, throat, skin, thyroid, neurological, lungs, cardiovascular, abdomen (liver and spleen), lymph nodes and extremities. A brief physical examination included assessments of the skin, lungs, cardiovascular system, and abdomen (liver and spleen). All abnormal physical examination findings were reported as AEs within the AE specific case report form (CRF) page. Hence, data was not captured separately for this outcome as number of participants with abnormal findings with respect to physical examinations. NA indicates data was not available as all abnormal physical examination findings were reported as AEs.
Part 2: Number of Participants Achieving Disease Control Rate at Week 16
时间窗: Week 16
Clinical response was planned to be assessed by the investigator using computer tomography or magnetic resonance imaging scans. Clinical response was defined as disease control rate based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 at Week 16. Disease control rate was defined as number of participants achieving complete response (CR), partial response (PR) and stable disease (SD) per RECIST version 1.1. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.
次要结局
- Part 1: Area Under the Concentration-time Curve From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration (AUC [0-t]) Following Single and Repeat Dose Administration of GSK2879552(Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 1 and Day 15)
- Part 1: Area Under the Concentration-time Curve From Time Zero (Pre-dose) Extrapolated to Infinite Time (AUC [0-infinity]) Following Single Dose Administration of GSK2879552(Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 1)
- Part 1: Area Under the Concentration-time Curve Over the Dosing Interval (AUC [0-tau]) Following Repeat Dose Administration of GSK2879552(Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose on Day 15)
- Part 1: Apparent Terminal Phase Half-life (T1/2) Following Single and Repeat Dose Administration of GSK2879552(Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 1 and Day 15)
- Part 2: Number of Participants Withdrawn Due to Toxicities(Up to 2 years)
- Part 1: Maximum Observed Plasma Concentration (Cmax) Following Single and Repeat Dose Administration of GSK2879552(Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 1 and Day 15)
- Part 1: Apparent Terminal Phase Elimination Rate Constant (Lambda z) Following Single and Repeat Dose Administration of GSK2879552(Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 1 and Day 15)
- Part 2: Number of Participants With Change in Hematology Toxicity Grade From Baseline(Baseline and up to 2 years)
- Part 2: Volume of Distribution Following Administration of GSK2879552(Pre-dose, 0.5, and 3 hours post-dose on Day 1; Pre-dose on Day 8; Pre-dose, 0.5 to 1 hour, and 4 to 6 hours on Day 15; Pre-dose at Day 22 and up to every 4 weeks until Week 48)
- Part 1: Time to Reach Cmax (Tmax) Following Single and Repeat Dose Administration of GSK2879552(Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 1 and Day 15)
- Part 1: Accumulation Ratio Following Administration of GSK2879552(Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 1 and Day 15)
- Part 1: Number of Participants Achieving Disease Control Rate at Week 16(Week 16)
- Part 1 :Median Effective Dose (ED50) of GSK2879552 With Respect to Platelet Nadir as Percent Change From Baseline and Dose(Baseline and median of 7.286 weeks of drug exposure)
- Part 1: ED50 of GSK2879552 With Respect to Platelet Nadir as Percent Change From Baseline and Cmax(Baseline and median of 7.286 weeks of drug exposure)
- Part 1: ED50 of GSK2879552 With Respect to Platelet Nadir as Percent Change From Baseline and AUC (0 to Infinity)(Baseline and median of 7.286 weeks of drug exposure)
- Part 1: Time Invariance Ratio Following Administration of GSK2879552(Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 1 and Day 15)
- Part 2: Number of Participants With SAEs and Non-SAEs(Up to 2 years)
- Part 2: Number of Participants With DLTs(Up to 2 years)
- Part 2: Number of Participants With Dose Reduction or Delays(Up to 2 years)
- Part 2: Number of Participants With Change in Clinical Chemistry Toxicity Grade From Baseline(Baseline and up to 2 years)
- Part 2:Number of Participants With Critical Changes in Values of Vital Signs in Response to Drug(Up to 2 years)
- Part 2: Clearance Following Administration of GSK2879552(Pre-dose, 0.5, and 3 hours post-dose on Day 1; Pre-dose on Day 8; Pre-dose, 0.5 to 1 hour, and 4 to 6 hours on Day 15; Pre-dose at Day 22 and up to every 4 weeks until Week 48)
- Part 2: ED50 of GSK2879552 With Respect to Platelet Nadir as Percent Change From Baseline and AUC (0 to Infinity)(Baseline and Up to 2 years)
- Part 2: Number of Participants With Abnormal Findings for ECG Parameters(Up to 2 years)
- Part 2: Number of Participants With Abnormal Findings Undergoing Physical Examinations(Up to 2 years)
- Part 2: Duration of Response(Up to 2 years)
- Part 2: ED50 of GSK2879552 With Respect to Platelet Nadir as Percent Change From Baseline and Dose(Baseline and up to 2 years)
- Part 2: ED50 of GSK2879552 With Respect to Platelet Nadir as Percent Change From Baseline and Cmax(Baseline and up to 2 years)
- Part 2: Progression Free Survival (PFS)(Up to 2 years)
- Part 2: Percentage of Participants Achieving CR and PR(Up to 2 years)