Clinical trial NCT02215096: Dose-finding Study of GSK2636771 When Administered in Combination With Enzalutamide in Male Subjects With Metastatic Castration-Resistant Prostate Cancer
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Neoplasms
Keywords: enzalutamide
metastatic castration-resistant prostate cancer
GSK2636771
PI3K-beta
PTEN deficiency
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2014-08-13
Enrollment: 37
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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


Eligibility criteria: Inclusion Criteria:

* 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.

Exclusion Criteria:

* 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

Primary outcomes:
measure: Number of Participants With Non-serious Adverse Events (Non-SAEs) and Serious Adverse Events (SAEs) During run-in Period
timeFrame: Up to Week 2
measure: Number of Participants With Non-SAEs and SAEs During Combination Treatment Period
timeFrame: Up to maximum 675 days
measure: Number of Participant With Dose-limiting Toxicities (DLT) During Combination Treatment Period
timeFrame: Up to Day 28
measure: 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
timeFrame: 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
measure: Percent Change From Baseline in Hematology Parameters During Combination Treatment Period: International Normalized Ratio (INR), Prothrombin Time (PT), Partial Thromboplastin Time (PTT)
timeFrame: Baseline (Day 1), Week 4
measure: 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
timeFrame: 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
measure: Percent Change From Baseline in Chemistry Parameters During Combination Treatment Period: Blood Urea Nitrogen (BUN), Uric Acid
timeFrame: 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
measure: Percent Change From Baseline in Urine Concentration of Calcium, Creatinine Concentration, Magnesium, Phosphate, Protein During Combination Treatment Period
timeFrame: Baseline (Day 1), Weeks 1, 3, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 48, 56 and 64
measure: Number of Participants With Abnormal Clinically Significant Electrocardiogram (ECG) Findings During Combination Treatment Period
timeFrame: Weeks 4, 8, 16, 24, 32, 40, 48, 56, 64, 72, 80 and 88
measure: 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
timeFrame: Up to maximum 654 days
measure: Number of Participants With Worst Case Post-Baseline Results for Heart Rate During Combination Treatment Period
timeFrame: Up to maximum 654 days
measure: Number of Participants With Worst Case Post-Baseline Results for Body Temperature During Combination Treatment Period
timeFrame: Up to maximum 654 days
measure: 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
timeFrame: At Week 12
Secondary outcomes:
measure: Prostate-specific Antigen Decrease From Baseline >=50% (PSA50) Response Rate at 12 Weeks During Combination Treatment Period
timeFrame: At Week 12
measure: Objective Response Rate (ORR) During Combination Treatment Period
timeFrame: Up to maximum 654 days
measure: Time to PSA Progression According to PCWG2 Criteria During Combination Treatment Period
timeFrame: Up to maximum 654 days
measure: Time to Radiological Progression According to PCWG2 Criteria During Combination Treatment Period
timeFrame: Up to maximum 654 days
measure: Radiological Progression Free Survival (rPFS) Per PCWG2 Criteria During Combination Treatment Period
timeFrame: Up to maximum 654 days
measure: Plasma Concentration of GSK2636771 in GSK2636771/Enzalutamide Expansion Cohort in Combination Treatment Period
timeFrame: Week 5: Pre-dose, 1, 2, 3, 5-6, 6-7, 7-8 hours post-dose; Weeks 8 and 12: Pre-dose
measure: Plasma Concentration of GSK2636771 in GSK2636771/Enzalutamide Escalation Cohorts in Combination Treatment Period
timeFrame: Week 5: Pre-dose, 0.5, 1, 2, 3, 4, 6 hours post-dose; Weeks 8 and 12: Pre-dose
measure: Plasma Concentration of Enzalutamide in GSK2636771/Enzalutamide Escalation Cohorts in Combination Treatment Period
timeFrame: Week 5: Pre-dose, 0.5, 1, 2, 3, 4, 6 hours post-dose; Weeks 8 and 12: Pre-dose
measure: Plasma Concentration of Enzalutamide in GSK2636771/Enzalutamide Expansion Cohort in Combination Treatment Period
timeFrame: Week 5: Pre-dose, 1, 2, 3, 5-6, 6-7, 7-8 hours post-dose; Weeks 8 and 12: Pre-dose
measure: Plasma Concentration of N-desmethyl Enzalutamide in GSK2636771/Enzalutamide Escalation Cohorts in Combination Treatment Period
timeFrame: Week 5: Pre-dose, 0.5, 1, 2, 3, 4, 6 hours post-dose; Weeks 8 and 12: Pre-dose
measure: Plasma Concentration of N-desmethyl Enzalutamide in GSK2636771/Enzalutamide Expansion Cohort in Combination Treatment Period
timeFrame: Week 5: Pre-dose, 1, 2, 3, 5-6, 6-7, 7-8 hours post-dose; Weeks 8 and 12: Pre-dose
Other outcomes:
Locations:
city: Duarte
country: United States
facility: GSK Investigational Site
state: California
city: Los Angeles
country: United States
facility: GSK Investigational Site
state: California
city: Los Angeles
country: United States
facility: GSK Investigational Site
state: California
city: Washington
country: United States
facility: GSK Investigational Site
state: District of Columbia
city: Detroit
country: United States
facility: GSK Investigational Site
state: Michigan
city: New York
country: United States
facility: GSK Investigational Site
state: New York
city: Houston
country: United States
facility: GSK Investigational Site
state: Texas
city: London
country: United Kingdom
facility: GSK Investigational Site
city: Sutton
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Sarker D, Dawson NA, Aparicio AM, Dorff TB, Pantuck AJ, Vaishampayan UN, Henson L, Vasist L, Roy-Ghanta S, Gorczyca M, York W, Ganji G, Tolson J, de Bono JS. A Phase I, Open-Label, Dose-Finding Study of GSK2636771, a PI3Kbeta Inhibitor, Administered with Enzalutamide in Patients with Metastatic Castration-Resistant Prostate Cancer. Clin Cancer Res. 2021 Oct 1;27(19):5248-5257. doi: 10.1158/1078-0432.CCR-21-1115.