A Phase I, Open-label, Dose-finding Study of GSK2636771 Administered in Combination With Enzalutamide (Xtandi^TM ) in Male Subjects With Metastatic Castration-Resistant Prostate Cancer (mCRPC)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 37
- 试验地点
- 1
- 主要终点
- Number of Participants With Non-serious Adverse Events (Non-SAEs) and Serious Adverse Events (SAEs) During run-in Period
研究概览
简要总结
This Phase I, open-label, dose-finding, multicenter study is designed to determine the recommended Phase II dose (RP2D) for the combination of an orally administered Phosphatidylinositol-4,5-bisphosphate 3-kinase beta (PI3K-beta) inhibitor (GSK2636771) with enzalutamide. Subjects with phosphatase and tensin homolog (PTEN)-deficient metastatic castration-resistant prostate cancer (mCRPC) who are receiving a stable dose of enzalutamide with a recently demonstrated progression (either by RECIST [Response Evaluation Criteria In Solid Tumors] version 1.1, prostate-specific antigen [PSA] progression, and/or progression in bone) per the Prostate Cancer Working Group 2 (PCWG2) criteria will be enrolled. Eligible subjects will be enrolled in the Dose-Escalation Phase to determine the maximum tolerated dose (MTD) of the combination therapy using a modified 3+3 dose escalation procedure. The safety, pharmacokinetics (PK) and clinical efficacy will also be assessed to guide the selection of the RP2D. The starting dose will be GSK2636771 300 mg once daily in combination with the recommended dose (160 milligram [mg] once daily) of oral enzalutamide. Once the RP2D has been established, additional subjects will be enrolled in the Dose Expansion Phase to further evaluate the safety, PK and preliminary clinical activity. Safety assessments will be performed throughout the study including physical examinations, vital signs, clinical laboratory tests, 12 lead electrocardiograms and monitoring of adverse events. Blood samples will be collected for pharmacokinetic analysis. Subjects will continue treatment until an unacceptable toxicity, disease progression, withdrawal of consent or death occurs. A post-treatment follow-up visit will be performed within 30 days of the last dose of study treatment. Xtandi is a registered trademark of Astellas Pharma Inc
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
- Male
- 接受健康志愿者
- 否
入选标准
- •Signed written informed consent provided
- •Males >=18 years of age (at the time consent is obtained)
- •Histologically or cytologically confirmed diagnosis of prostate adenocarcinoma, surgically castrated or continuous medical castration (for >=8 weeks prior to Screening)
- •Serum testosterone <50 nanogram per deciliter (ng/dL) (1.7 nanomole per liter [nM/L])
- •PTEN deficient tumor as documented from archival or fresh (from biopsy) tumor tissue analyzed by GlaxoSmithKline selected laboratory
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- •Completed at least 12 weeks of prior continuous therapy with enzalutamide. A 2 week or less treatment (enzalutamide) holiday will be permitted prior to initiating study treatment.
- •Most recent enzalutamide dose received is 160 mg once daily with no change in dose for at least 2 weeks prior to Screening.
- •Has progressive disease at time of enrollment defined as one or more of the following criteria: PSA progression defined by PCWG2 criteria or soft tissue disease progression defined by RECIST 1.1 or bone disease progression defined by PCWG2 criteria Able to swallow and retain orally administered medication.
- •Adequate baseline organ function.
- •Must have a QT interval corrected for heart rate according to Fridericia's formula (QTcF) <470 milli seconds (msec) or <480 msec with bundle branch block.
- •Male subject with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception from time of Screening until 3 months after the last dose of study treatment.
排除标准
- •Prior treatment with: anti-cancer therapy (e.g., chemotherapy with delayed toxicity, immunotherapy, biologic therapy or chemoradiation) within 21 days (or within 42 days if prior nitrosourea or mitomycin C containing therapy) prior to enrollment and/or daily or weekly chemotherapy without the potential for delayed toxicity within 14 days prior to enrolment. Subjects may remain on luteinizing hormone releasing hormone (LHRH) agonists (i.e., leuprolide, goserelin, triptorelin or histrelin). Subjects must have prior enzalutamide treatment; Any PI3K, AKT or mammalian target of rapamycin (mTOR) inhibitors; Investigational drug(s) within 30 days or 5 half-lives, whichever is longer, prior to enrollment
- •Prior malignancy other than CRPC. Subjects who have been disease-free for 5 years, or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible.
- •Current use of or anticipated requirement during the study of prohibited medication(s) (any investigational drug(s), Other anti-cancer therapy (chemotherapy, radiation therapy, immunotherapy, biologic therapy, or hormone therapy other than for replacement), AR antagonists (e.g., bicalutamide, flutamide, nilutamide), 5-alpha reductase inhibitors (e.g., finasteride, dutasteride), Androgens (e.g., testosterone, dihydroepiandrosterone), Herbal medication(s) that may affect PSA levels (e.g., saw palmetto), Other herbal medications including, but not limited to: St. John's wort, kava, ephedra (ma huang), gingko biloba, yohimbe and ginseng)
- •Any unresolved >=Grade 2 (per CTCAE v 4.0) toxicity from previous anti-cancer therapy at the time of enrollment, except alopecia or Grade 2 anemia (if hemoglobin is >9.0 g/dL)
- •Any >=Grade 2 hypophosphatemia (per CTCAE v4.0) at the time of enrolment
- •Serum calcium >=Grade 1 (per CTCAE v4.0) at time of enrolment, unless ionized calcium is within normal range
- •Presence of any clinically significant gastrointestinal (GI) abnormality or other condition(s) that may alter absorption such as malabsorption syndrome or major resection of the stomach or substantial portion of the small intestine
- •Active peptic ulcer disease or history of abdominal fistula, GI perforation, or intra abdominal abscess within 28 days prior to enrolment
- •Previous major surgery within 28 days prior to enrolment
- •Known active infection requiring intravenous (IV) or oral anti-infective treatment
- •Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment.
- •A positive pre-study drug/alcohol screening (testing at time of screening is not required).
- •A positive test for human immunodeficiency virus (HIV) antibody (testing at time of screening is not required).
- •Evidence of severe or uncontrolled systemic diseases (e.g., unstable or uncompensated respiratory, hepatic, renal or cardiac disease)
- •History of seizure or any condition that may predispose subject to seizure (e.g., prior cortical stroke or significant brain trauma). History of loss of consciousness or transient ischemic attack within 12 months of randomization
- •History or evidence of cardiovascular risk including any of the following: Clinically significant electrocardiogram abnormalities including second degree (Type II) or third degree atrioventricular block; history of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty, stenting, or bypass grafting within the past 6 months prior to enrolment, Class III or IV heart failure as defined by the New York Heart Association functional classification system, LVEF below 50%; known cardiac metastases
- •Poorly controlled hypertension (defined as systolic blood pressure of>=150 millimeter of mercury (mmHg) or diastolic blood pressure of >100 mmHg based on a mean of three measurements at approximately 2-minute intervals)
- •History of congenital platelet function defect (e.g., Bernard-Soulier syndrome, Chediak-Higashi syndrome, Glanzmann thrombasthenia, storage pool defect)
- •Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to GSK2636771or enzalutamide or excipients.
- •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.
- •Exposure to more than 4 investigational medicinal products within 12 months prior to the first dose of study treatment
研究组 & 干预措施
Phase 1-Dose Escalation
Subject receiving a stable dose of enzalutamide 160 mg once daily will receive GSK2636771 following a modified 3+3 dose escalation procedure (Cohort -1: 200 mg, Cohort 1: 300 mg and Cohort 2: 400 mg) to evaluate the safety and PK for each combination dose level and to guide selection of the RP2D of the combination. If the combination doses in Cohort 1 are not tolerable, lower doses as defined in the de-escalation cohort (Cohort -1) will be evaluated. If the de-escalation cohort (Cohort -1) is not tolerable, further dose-escalation using a continuous daily dosing schedule for both compounds simultaneously will be terminated. Additional dose levels of GSK2636771 or alternative dosing schedules may be explored based upon ongoing assessment of safety and PK. Dose modification decisions will be made utilizing all available data at the end of each DLT determination period (28 days).
干预措施: GSK2636771 (Drug)
Phase 1-Dose Escalation
Subject receiving a stable dose of enzalutamide 160 mg once daily will receive GSK2636771 following a modified 3+3 dose escalation procedure (Cohort -1: 200 mg, Cohort 1: 300 mg and Cohort 2: 400 mg) to evaluate the safety and PK for each combination dose level and to guide selection of the RP2D of the combination. If the combination doses in Cohort 1 are not tolerable, lower doses as defined in the de-escalation cohort (Cohort -1) will be evaluated. If the de-escalation cohort (Cohort -1) is not tolerable, further dose-escalation using a continuous daily dosing schedule for both compounds simultaneously will be terminated. Additional dose levels of GSK2636771 or alternative dosing schedules may be explored based upon ongoing assessment of safety and PK. Dose modification decisions will be made utilizing all available data at the end of each DLT determination period (28 days).
干预措施: Enzalutamide (Drug)
Phase 2- Dose Expansion
Additional 20 subjects will be assigned to receive GSK2636771 at the MTD or RP2D determined in the Dose-Escalation Phase while continuing treatment with enzalutamide to evaluate the long-term safety of the combination as well as the 12-week non-PD rate
干预措施: GSK2636771 (Drug)
Phase 2- Dose Expansion
Additional 20 subjects will be assigned to receive GSK2636771 at the MTD or RP2D determined in the Dose-Escalation Phase while continuing treatment with enzalutamide to evaluate the long-term safety of the combination as well as the 12-week non-PD rate
干预措施: Enzalutamide (Drug)
结局指标
主要结局
Number of Participants With Non-serious Adverse Events (Non-SAEs) and Serious Adverse Events (SAEs) During run-in Period
时间窗: Up to Week 2
An adverse event (AE) is any untoward medical occurrence in a participant or clinical investigation participants, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is any untoward medical occurrence that, at any dose: results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, protocol-specific SAEs: All events of possible study treatment-induced liver injury with hyperbilirubinemia defined as alanine aminotransferase (ALT) \>=3 times upper limit of normal (ULN), and bilirubin \>=2 times ULN (\>35 percent \[%\] direct) (or ALT \>=3 times ULN and international normalized ratio (INR) \>1.5 if INR is measured) or termed 'Hy's Law' events (INR measurement is not required and the threshold value stated did not apply to participants receiving anticoagulants) or any new primary cancer.
Number of Participants With Non-SAEs and SAEs During Combination Treatment Period
时间窗: Up to maximum 675 days
An AE is any untoward medical occurrence in a participant or clinical investigation participants, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is any untoward medical occurrence that, at any dose: results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, protocol-specific SAEs: All events of possible study treatment-induced liver injury with hyperbilirubinemia defined as ALT \>=3 times ULN, and bilirubin \>=2 times ULN (\>35% direct) (or ALT \>=3 times ULN and INR \>1.5 if INR is measured) or termed 'Hy's Law' events (INR measurement is not required and the threshold value stated did not apply to participants receiving anticoagulants) or any new primary cancer.
Number of Participant With Dose-limiting Toxicities (DLT) During Combination Treatment Period
时间窗: Up to Day 28
An event was considered as DLT if the event was attributed (definitely, probably or possibly) to study treatment, occured within the first 28 days of combination treatment (DLT reporting period), and met one of the following criteria: Febrile neutropenia of any grade or duration as per Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, Grade 4 neutropenia lasting \>5 days, Grade 3 or greater non-hematologic toxicity that cannot be controlled with routine supportive measures, Grade 4 thrombocytopenia, ALT \>3 times ULN with bilirubin \>2 times ULN or ALT \>=3 times ULN and \>=1.5 times Baseline ALT value, if enrolled with liver metastases/tumor infiltration at Baseline), together with bilirubin \>=2 times ULN.
Percent Change From Baseline in Hematology Parameters During Combination Treatment Period: Basophils, Eosinophils, Hematocrit, Hemoglobin, Lymphocytes, MCH, MCV, Monocytes, Total Neutrophils, Platelet Count, WBC Count
时间窗: Baseline (Day 1), Weeks 2,3,4,5,8,12,16,20,24,28,32,36,40,44,48,52,56,60,64,68,72,76,80,84 and 88
Blood samples were collected to analyze the hematology parameters: basophils, eosinophils, hematocrit, hemoglobin, lymphocytes, mean corpuscular hemoglobin (MCH), mean corpuscular volume (MCV), monocytes, total neutrophils, platelet count and white blood cells (WBCs) count. Baseline value is the latest GSK2636771 pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value. Percent change from Baseline was calculated as 100 multiplied by (post-Baseline visit value minus Baseline divided by Baseline).
Percent Change From Baseline in Hematology Parameters During Combination Treatment Period: International Normalized Ratio (INR), Prothrombin Time (PT), Partial Thromboplastin Time (PTT)
时间窗: Baseline (Day 1), Week 4
Blood samples were collected to analyze the hematology parameters: INR, PT and PTT. Baseline value is the latest GSK2636771 pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value. Percent change from Baseline was calculated as 100 multiplied by (post-Baseline visit value minus Baseline divided by Baseline).
Percent Change From Baseline in Chemistry Parameters in Combination Treatment Period:ALT, Albumin, ALP, AST, Calcium, CO2, Chloride, Creatinine, Direct Bilirubin, Glucose, Lactate Dehydrogenase, Magnesium, Potassium, Sodium, Total Bilirubin, Total Protein
时间窗: Baseline (Day 1), Weeks 1,2,3,4,5,8,12,16,20,24,28,32,36,40,44,48,52,56,60,64,68,72,76,80,84 and 88
Blood samples were collected to analyze the chemistry parameters: ALT, Albumin, Alkaline phosphatase (ALP), Aspartate amino transferase (AST), Calcium, Carbon dioxide (CO2), Chloride, Creatinine, Direct bilirubin, Glucose, Lactate dehydrogenase, Magnesium, Potassium, Sodium, Total bilirubin and Total protein. Baseline value is the latest GSK2636771 pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value. Percent change from Baseline was calculated as 100 multiplied by (post-Baseline visit value minus Baseline divided by Baseline).
Percent Change From Baseline in Chemistry Parameters During Combination Treatment Period: Blood Urea Nitrogen (BUN), Uric Acid
时间窗: Baseline (Day 1), Weeks 1, 2,3,4,5,8,12,16,20,24,28,32,36,40,44,48,52,56,60,64,68,72,76,80,84 and 88
Blood samples were collected to analyze the chemistry parameters: BUN and uric acid. Baseline value is the latest GSK2636771 pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value. Percent change from Baseline was calculated as 100 multiplied by (post-Baseline visit value minus Baseline divided by Baseline).
Percent Change From Baseline in Urine Concentration of Calcium, Creatinine Concentration, Magnesium, Phosphate, Protein During Combination Treatment Period
时间窗: Baseline (Day 1), Weeks 1, 3, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 48, 56 and 64
Urine samples were collected to analyze the urinalysis parameters: Calcium, Creatinine concentration (conc), Magnesium, Phosphate and Protein. Baseline value is the latest GSK2636771 pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value. Percent change from Baseline was calculated as 100 multiplied by (post-Baseline visit value minus Baseline divided by Baseline).
Number of Participants With Abnormal Clinically Significant Electrocardiogram (ECG) Findings During Combination Treatment Period
时间窗: Weeks 4, 8, 16, 24, 32, 40, 48, 56, 64, 72, 80 and 88
A 12-lead ECG was obtained after the participant had rested at least 5 minutes in a semi-recumbent or supine position at each time point during the study using ECG machine that automatically measured PR, QRS, QT and Corrected QT interval (QT duration corrected for heart rate by Bazett's formula \[QTcB\] and Fridericia's formula \[QTcF\]). Clinically significant abnormal findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition. Number of participants with abnormal clinical significant ECG findings are presented.
Number of Participants With Worst Case Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Results by Maximum Grade Increase Post-Baseline Relative to Baseline During Combination Treatment Period
时间窗: Up to maximum 654 days
SBP and DBP were measured after resting for 5 minutes in semi-supine position. SBP and DBP were graded according to Common Toxicity Criteria for Adverse Events (CTCAE) version 4. 'Any grade increase' is defined as an increase in CTCAE grade relative to Baseline grade. For SBP, Grade 0: \<120 millimeters of mercury \[mmHg\]), Grade 1: 120-139 mmHg, Grade 2: 140-159 mmHg, Grade 3:\>=160 mmHg. For DBP, Grade 0: \<80 mmHg, Grade 1: 80-89 mmHg, Grade 2: 90-99 mmHg, Grade 3: \>=100 mmHg. Higher grade indicate worst outcome. Data for worst-case post-Baseline is reported.
Number of Participants With Worst Case Post-Baseline Results for Heart Rate During Combination Treatment Period
时间窗: Up to maximum 654 days
Heart rate was measured after resting for 5 minutes in semi-supine position. The clinical concern range for heart rate was: low: decrease to \<60 beats per minute (bpm) and high: increase to \>100 bpm. Participants were counted in the worst case category that their value changed to (low, within range or no change, or high) unless there was no change in their category. Participants whose value category was unchanged (e.g., High to High), or whose value became within range, were recorded in the 'Change to normal or No Change' category. Participants were counted twice if the participant had both values 'decrease to \<60 bpm' and 'increase to \>100 bpm' during post-Baseline visits. Data for worst case post-Baseline is reported.
Number of Participants With Worst Case Post-Baseline Results for Body Temperature During Combination Treatment Period
时间窗: Up to maximum 654 days
Temperature was measured after resting for 5 minutes in semi-supine position. The clinical concern range for body temperature was: low: decrease to \<=35 degrees celsius, high: increase to \>=38 degrees celsius. Participants were counted in the worst case category that their value changed to (low, within range or no change, or high) unless there was no change in their category. Participants whose value category was unchanged (e.g., High to High), or whose value became within range, were recorded in the 'Change to normal or No Change' category. Participants were counted twice if the participant had both values 'decreased to \<=35 degree celsius' and 'increased to \>=38 degrees celsius' during post-Baseline visits. Data for worst-case post-Baseline is presented.
Non-progressive Disease (Non-PD) Rate at Week 12 According to Prostate Cancer Working Group 2 (PCWG2) Criteria in GSK2636771 200mg/Enzalutamide 160mg - Overall Arm
时间窗: At Week 12
The 12-week non-PD rate was defined as percentage of participants without progression(non-PD) at Week12 as determined from Prostate-specific antigen(PSA) results, radiographic assessment per Response Evaluation Criteria In Solid Tumors(RECIST)1.1 and bone scan.Disease progression was defined by 1 or more of the following:PSA progression alone; PSA progression according to the PCWG2 criteria with accompanying progression by RECIST1.1 or bone scan for participants with soft tissue Baseline disease; Bone progression on bone scan according to PCWG2 criteria; or Radiographic progression in soft tissue or bone by RECIST1.1 for participants with Baseline disease.Modified All Treated Clinical Activity Population consisted of all participants who received at least 1 dose of GSK2636771 and who were treated at the same dose as dose expansion cohort and have been on study drug for at least 12weeks or have discontinued study treatment due to disease progression, died or withdrawn for any reason.
次要结局
- Prostate-specific Antigen Decrease From Baseline >=50% (PSA50) Response Rate at 12 Weeks During Combination Treatment Period(At Week 12)
- Time to PSA Progression According to PCWG2 Criteria During Combination Treatment Period(Up to maximum 654 days)
- Time to Radiological Progression According to PCWG2 Criteria During Combination Treatment Period(Up to maximum 654 days)
- Plasma Concentration of GSK2636771 in GSK2636771/Enzalutamide Expansion Cohort in Combination Treatment Period(Week 5: Pre-dose, 1, 2, 3, 5-6, 6-7, 7-8 hours post-dose; Weeks 8 and 12: Pre-dose)
- Objective Response Rate (ORR) During Combination Treatment Period(Up to maximum 654 days)
- Radiological Progression Free Survival (rPFS) Per PCWG2 Criteria During Combination Treatment Period(Up to maximum 654 days)
- Plasma Concentration of GSK2636771 in GSK2636771/Enzalutamide Escalation Cohorts in Combination Treatment Period(Week 5: Pre-dose, 0.5, 1, 2, 3, 4, 6 hours post-dose; Weeks 8 and 12: Pre-dose)
- Plasma Concentration of N-desmethyl Enzalutamide in GSK2636771/Enzalutamide Expansion Cohort in Combination Treatment Period(Week 5: Pre-dose, 1, 2, 3, 5-6, 6-7, 7-8 hours post-dose; Weeks 8 and 12: Pre-dose)
- Plasma Concentration of Enzalutamide in GSK2636771/Enzalutamide Escalation Cohorts in Combination Treatment Period(Week 5: Pre-dose, 0.5, 1, 2, 3, 4, 6 hours post-dose; Weeks 8 and 12: Pre-dose)
- Plasma Concentration of Enzalutamide in GSK2636771/Enzalutamide Expansion Cohort in Combination Treatment Period(Week 5: Pre-dose, 1, 2, 3, 5-6, 6-7, 7-8 hours post-dose; Weeks 8 and 12: Pre-dose)
- Plasma Concentration of N-desmethyl Enzalutamide in GSK2636771/Enzalutamide Escalation Cohorts in Combination Treatment Period(Week 5: Pre-dose, 0.5, 1, 2, 3, 4, 6 hours post-dose; Weeks 8 and 12: Pre-dose)