A Phase IB Dose Exploration Trial With MK-8628, a Small Molecule Inhibitor of the Bromodomain and Extra-Terminal (BET) Proteins, in Subjects With Selected Advanced Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 13
- 主要终点
- Number of Participants Who Experienced a Dose Limiting Toxicity (DLT) During Cycle 1
研究概览
简要总结
This is a study to determine the recommended dose of birabresib (MK-8628)(formerly known as OTX015) for further studies in participants with advanced nuclear protein in testis (NUT) midline carcinoma (NMC), triple negative breast cancer (TNBC), non-small cell lung cancer (NSCLC), or castration-resistant prostate cancer (CRPC). This is a two-part parallel study: Part A will establish the recommended dose by evaluating dose limiting toxicity (DLT), safety, discontinuation, and early efficacy and Part B will enroll participants with NMC only and will evaluate safety and efficacy in this population.
详细描述
The sponsor decided to terminate the program after evaluation of safety and efficacy data at the dose levels tested (Part A). The decision to discontinue the birabresib program was based on limited efficacy signals and was not due to safety-related concerns. No participants entered or were treated in Part B of the study.
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
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Males and females ≥18 years of age for NSCLC, TNBC, and CRPC
- •Males and females ≥16 years of age for NMC
- •Diagnosis of one of the following advanced solid tumors for which standard therapy either does not exist or has proven ineffective, intolerable or inacceptable for the participant: NMC;TNBC; NSCLC; or CRPC
- •Have at least 1 measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) 1.
- •CRPC participants may be enrolled with objective evidence of disease as per Prostate Cancer Working Group (PCWG2) criteria
- •Life expectancy ≥3 months
- •Eastern Cooperative Oncology Group (ECOG) Performance Status ≤1
- •Have an interval of ≥3 weeks (or ≥2 weeks for NMC participants) since chemotherapy (≥6 weeks for nitrosoureas or mitomycin C), immunotherapy, hormone therapy or any other anticancer therapy or surgical intervention resection, or ≥3 half-lives for monoclonal antibodies, or ≥5 half-lives for other non-cytotoxic agents (whichever is longer)
- •CRPC participants must maintain ongoing androgen deprivation therapy with a gonadotropin releasing hormone (GnRH) analogue, antagonist or orchiectomy providing serum testosterone is <50 ng/dL (<1.7 nmol/L)
- •Participants receiving bisphosphonate or denosumab therapy must be on stable doses for at least 4 weeks before start of study therapy
- •Females must not be pregnant (negative urine or serum human chorionic gonadotropin test within 72 hours of study start)
- •Females of childbearing potential and male participants must agree to use adequate contraception starting with the first dose of trial treatment through 90 days after the last dose of study medication
排除标准
- •Has inability to swallow oral medications or presence of a gastrointestinal disorder (e.g. malabsorption) deemed to jeopardize intestinal absorption of birabresib
- •Has persistent grade >1 clinically significant toxicities related to prior antineoplastic therapies (except for alopecia). Stable sensory neuropathy ≤ grade 2 National Cancer Institute (NCI) - Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 is accepted
- •Known primary central nervous system (CNS) malignancy or symptomatic or untreated CNS metastases. Treated and stable CNS metastases are allowed.
- •History of prior or concomitant malignancies within 3 years of study start
- •Have other serious illness or medical condition, such as active infection, unresolved bowel obstruction, psychiatric disorders, or cerebrovascular accident within 1 year of study start
- •Known human immunodeficiency virus (HIV) and/or active Hepatitis B or C infections
- •Have one of the following cardiac-related conditions: Congestive heart failure or angina pectoris (except if medically controlled); myocardial infarction (within 1 year of study start); uncontrolled hypertension; or uncontrolled arrhythmias
- •Other concomitant anticancer treatment
- •Participation in another clinical trial or treatment with any investigational drug (excluding anticancer treatments) within 30 days of study start
- •Concomitant therapy with strong CYP3A4 inhibitors or inducers
- •Therapeutic anticoagulation (e.g. warfarin, heparin, etc.) must be stopped at least 7 days prior to the first dose of birabresib. Low-dose low molecular weight heparin (LMWH) is permitted
- •Is pregnant or breast-feeding
研究组 & 干预措施
Birabresib 20 mg CRPC Cohort-Part A
Participants in the CRPC cohort in Part A of the study received birabresib 20 mg orally (PO), twice a day (BID), in a fasted state for 21 consecutive days per cycle. Participants received birabresib in continuous cycles up to 24 months.
干预措施: Birabresib (Drug)
Birabresib 20 mg NMC Cohort-Part A
Participants in the NMC cohort in Part A of the study received birabresib 20 mg PO, BID, in a fasted state for 21 consecutive days per cycle. Participants received birabresib in continuous cycles up to 24 months.
干预措施: Birabresib (Drug)
Birabresib 20 mg TNBC Cohort-Part A
Participants in the TNBC cohort in Part A of the study received birabresib 20 mg PO, BID, in a fasted state for 21 consecutive days per cycle. Participants received birabresib in continuous cycles up to 24 months.
干预措施: Birabresib (Drug)
NMC Cohort-Part B
Participants (up to 30) in Part B will receive birabresib at one dose level below the dose currently being administered in Part A of the study. Once the recommended Phase 2 dose (RP2D) from Part A is established, participants in Part B will receive birabresib at the RP2D. Participants will continue receiving birabresib at an assigned/adjusted dose level for continuous cycles up to 24 months.
干预措施: Birabresib (Drug)
结局指标
主要结局
Number of Participants Who Experienced a Dose Limiting Toxicity (DLT) During Cycle 1
时间窗: From time of first dose up to the end of the first cycle (up to 21 days)
A DLT was any of the following deemed drug related (DR) by investigator: Grade (G)4 hematologic toxicity lasting ≥7 days except thrombocytopenia; G4 thrombocytopenia; G3 thrombocytopenia with bleeding; G3 or 4 febrile neutropenia. G4 non-hematologic (NH) toxicity (not laboratory); G3 NH toxicity (not laboratory), nausea, vomiting, or diarrhea lasting \>3 days despite supportive care; G3 or 4 NH laboratory abnormality requiring medical intervention, hospitalization, or persisting \>1 week; alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \>8X Upper Limit of Normal(ULN); ALT or AST \>5XULN for \>2 weeks; ALT or AST \>3XULN and total bilirubin \>2XULN or international normalization ratio \>1.5; ALT or AST \>3XULN with fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash and/or eosinophilia (\>5%); DR adverse event leading to discontinuation or \>20% missed planned doses in Cycle 1; DR toxicity causing \>2 week delay in starting Cycle 2; or G5 toxicity.
次要结局
- Number of Participants Who Discontinued Study Treatment Due to an AE(From time of first dose until the end of treatment (up to 24 months))
- Observed Minimum Concentration (Cmin) of MK-8628(Cycle1/Day 1: predose, 20 minutes, 1 hour, 2.25 hours (hrs), 3.25 hrs, 8 hrs, and 12 hrs postdose)
- Time to Maximum Concentration (Tmax) of MK-8628(Cycle1/Day 1: predose, 20 minutes, 1 hour, 2.25 hours (hrs), 3.25 hrs, 8 hrs, and 12 hrs postdose)
- Number of Participants Who Experienced at Least One Adverse Event (AE)(From time of first dose until the end of the 30-day follow-up (up to 25 months))
- Objective Response Rate (ORR)(Assessed every 6 weeks from time of first dose until disease progression (up to 24 months))
- Duration of Response (DOR)(Assessed every 6 weeks from time of first dose until disease progression (up to 24 months))
- Observed Maximum Concentration (Cmax) of MK-8628(Cycle1/Day 1: predose, 20 minutes, 1 hour, 2.25 hours (hrs), 3.25 hrs, 8 hrs, and 12 hrs postdose)
- Apparent Terminal Half-Life (t1/2) of MK-8628(Cycle1/Day 1: predose, 20 minutes, 1 hour, 2.25 hours (hrs), 3.25 hrs, 8 hrs, and 12 hrs postdose)
- Area Under the Concentration-time Curve of MK-8628 From Time 0 to Infinity (AUC 0-∞)(Cycle1/Day 1: predose, 20 minutes, 1 hour, 2.25 hours (hrs), 3.25 hrs, 8 hrs, and 12 hrs postdose)
- Disease Control Rate (DCR)(Assessed every 6 weeks from time of first dose until disease progression (up to 24 months))
- Apparent Total Body Clearance (CL/F) of MK-8628(Cycle1/Day 1: predose, 20 minutes, 1 hour, 2.25 hours (hrs), 3.25 hrs, 8 hrs, and 12 hrs postdose)
- Apparent Volume of Distribution During the Terminal Phase (Vz/F) of MK-8628(Cycle1/Day 1: predose, 20 minutes, 1 hour, 2.25 hours (hrs), 3.25 hrs, 8 hrs, and 12 hrs postdose)