A Phase 1 Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Alobresib (Formerly GS-5829) as a Monotherapy in Subjects With Advanced Solid Tumors and Lymphomas and in Combination With Exemestane or Fulvestrant in Subjects With Estrogen Receptor Positive Breast Cancer
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 33
- 主要终点
- Number of Participants Experiencing Dose Limiting Toxicities (DLTs)
研究概览
简要总结
The primary objectives of this study are to characterize the safety and tolerability and determine the maximum tolerated dose (MTD) or recommended dose for phase 2 study (RDP2) of alobresib as a monotherapy in participants with advanced solid tumors and lymphomas, and in combination with exemestane or fulvestrant in participants with advanced estrogen receptor positive breast cancer.
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
- •Group 1: Histologically or cytologically confirmed advanced malignant solid tumor or lymphoma (any subtype) that is refractory to or intolerant of standard therapy or for which no standard therapy is available
- •Group 2: Post-menopausal women with advanced stage estrogen receptor positive breast cancer who are candidates for exemestane or fulvestrant
- •Group 3: Individuals with lymphoma are limited to diffuse large B-cell lymphoma and peripheral T-cell lymphoma that are refractory to or intolerant of standard therapy or for which no standard therapy is available
- •Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 1
- •Adequate organ function defined as follows:
- •Hematologic: Platelets ≥ 100 x 10^9/L; Hemoglobin ≥ 9.0 g/ dL; Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L (without platelet transfusion or any growth factors within previous 7 days of the hematologic laboratory values obtained at screening visit). Participants in the Group 3 lymphoma expansion may be enrolled with an ANC of ≥ 1.0 x 10^9 /L; Platelets ≥ 75 x 10^9 /L.
- •Hepatic: Aspartate transaminase (AST) / Alanine transaminase (ALT) ≤ 2.5 x upper limit of normal (ULN) (if liver metastases are present, ≤ 5 x ULN); Total or conjugated bilirubin ≤ 1.5 x ULN
- •Renal: Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 60 ml/min as calculated by the cockcroft-gault method
- •Coagulation: International Normalized Ratio (INR) ≤ 1.2
排除标准
- •Known brain metastasis or leptomeningeal disease
- •Myocardial infarction, symptomatic congestive heart failure (New York Heart Association Classification > Class II), unstable angina, or serious uncontrolled cardiac arrhythmia within the last 6 months of study Day 1
- •Major surgery, defined as any surgical procedure that involves general anesthesia and a significant incision (ie, larger than what is required for placement of central venous access, percutaneous feeding tube, or biopsy) within 28 days of first dose of study drug
- •History of long QT syndrome or whose corrected QT interval (QTc) measured (Fridericia method) at screening is prolonged (> 450 ms for males and > 470 ms for females). Individuals who screen-fail due to this criterion are not eligible to be re-screened
- •Clinically significant bleeding within 28 days of study Day 1
- •Known human immunodeficiency virus (HIV) infection
- •Hepatitis B surface antigen positive
- •Hepatitis C virus (HCV) antibody positive
- •No active anticoagulation within 7 days of study Day 1; including acetylsalicylic acid, low molecular weight heparin, or warfarin.
- •Note: Other protocol defined Inclusion/Exclusion criteria may apply.
研究组 & 干预措施
Monotherapy: Alobresib 0.6 mg
Participants with advanced solid tumors and lymphomas who have failed or are intolerant to standard therapy or for whom no standard therapy exists, will receive alobresib at a dose of 0.6 mg to determine the MTD.
干预措施: Alobresib (Drug)
Monotherapy: Alobresib 1.4 mg
Participants with advanced solid tumors and lymphomas who have failed or are intolerant to standard therapy or for whom no standard therapy exists, will receive alobresib at a dose of 1.4 mg to determine the MTD.
干预措施: Alobresib (Drug)
Monotherapy: Alobresib 2 mg
Participants with advanced solid tumors and lymphomas who have failed or are intolerant to standard therapy or for whom no standard therapy exists, will receive alobresib at a dose of 2 mg to determine the MTD.
干预措施: Alobresib (Drug)
Monotherapy: Alobresib 3 mg
Participants with advanced solid tumors and lymphomas who have failed or are intolerant to standard therapy or for whom no standard therapy exists, will receive alobresib at a dose of 3 mg to determine the MTD.
干预措施: Alobresib (Drug)
Monotherapy: Alobresib 4 mg
Participants with advanced solid tumors and lymphomas who have failed or are intolerant to standard therapy or for whom no standard therapy exists, will receive alobresib at a dose of 4 mg to determine the MTD.
干预措施: Alobresib (Drug)
Monotherapy: Alobresib 6 mg
Participants with advanced solid tumors and lymphomas who have failed or are intolerant to standard therapy or for whom no standard therapy exists, will receive alobresib at a dose of 6 mg to determine the MTD.
干预措施: Alobresib (Drug)
Combination Therapy: Alobresib 2 mg + Exemestane
Participants with advanced stage estrogen receptor positive breast cancer for whom no standard curative therapy exists, will receive alobresib at a dose of 2 mg in combination with exemestane 25 mg.
干预措施: Alobresib (Drug)
Combination Therapy: Alobresib 2 mg + Exemestane
Participants with advanced stage estrogen receptor positive breast cancer for whom no standard curative therapy exists, will receive alobresib at a dose of 2 mg in combination with exemestane 25 mg.
干预措施: Exemestane (Drug)
Combination Therapy: Alobresib 2 mg + Fulvestrant
Participants with advanced stage estrogen receptor positive breast cancer for whom no standard curative therapy exists, will receive alobresib at a dose of 2 mg in combination with fulvestrant 500 mg.
干预措施: Alobresib (Drug)
Combination Therapy: Alobresib 2 mg + Fulvestrant
Participants with advanced stage estrogen receptor positive breast cancer for whom no standard curative therapy exists, will receive alobresib at a dose of 2 mg in combination with fulvestrant 500 mg.
干预措施: Fulvestrant (Drug)
Combination Therapy: Alobresib 3 mg + Fulvestrant
Participants with advanced stage estrogen receptor positive breast cancer for whom no standard curative therapy exists, will receive alobresib at a dose of 3 mg in combination with fulvestrant 500 mg.
干预措施: Alobresib (Drug)
Combination Therapy: Alobresib 3 mg + Fulvestrant
Participants with advanced stage estrogen receptor positive breast cancer for whom no standard curative therapy exists, will receive alobresib at a dose of 3 mg in combination with fulvestrant 500 mg.
干预措施: Fulvestrant (Drug)
结局指标
主要结局
Number of Participants Experiencing Dose Limiting Toxicities (DLTs)
时间窗: Baseline (Day 1) up to 28 days
A DLT was a toxicity, considered possibly related to alobresib, and which occurred during DLT assessment window (Day 1 through Cycle 1 Day 28) in each cohort: Grade ≥ 4 neutropenia (absolute neutrophil count \[ANC\] \< 500/mm\^3); Grade ≥3 neutropenia (ANC\< 1000/mm\^3) with fever (a single temperature of \> 38.3°C or a sustained temperature of ≥ 38°C for more than 1 hour \[hr\]); Grade ≥ 3 thrombocytopenia; Grade ≥ 2 bleeding; Grade ≥ 3 non hematologic toxicity, except Grade 3 nausea or emesis with maximum duration of 48 hrs on adequate medical therapy and Grade 3 diarrhea which persists for \< 72 hrs in absence of maximal medical therapy; Grade ≥ 2 non hematologic treatment-emergent adverse event (TEAE) of potential clinical significance; treatment interruption ≥ 7 days due to unresolved toxicity; and any Grade 3 or 4 elevation in aspartate aminotransferase (AST) or alanine aminotransferase (ALT) associated with a Grade 2 elevation in bilirubin that is at least possibly related to alobresib.
次要结局
- Pharmacokinetic (PK) Parameter: Cmax of Alobresib(Cycle 1: Predose (0 hr), 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hrs postdose on Days 1 and 8 (1 Cycle = 28 days))
- PK Parameter: Ctau of Alobresib(Cycle 1: Predose (0 hr), 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hrs postdose on Day 8 (1 Cycle = 28 days))
- PK Parameter: AUCtau of Alobresib(Cycle 1: Predose (0 hr), 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hrs postdose on Day 8 (1 Cycle = 28 days))
- PK Parameter: t1/2 of Alobresib(Cycle 1: Predose (0 hr), 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hrs postdose on Days 1 and 8 (1 Cycle = 28 days))
- PK Parameter: AUC0-24 of Alobresib(Cycle 1: Predose (0 hr), 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hrs postdose on Days 1 and 8 (1 Cycle = 28 days))
- PK Parameter: Tmax of Alobresib(Cycle 1: Predose (0 hr), 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hrs postdose on Days 1 and 8 (1 Cycle = 28 days))