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Dose-finding Study of GSK2636771 When Administered in Combination With Enzalutamide in Male Subjects With Metastatic Castration-Resistant Prostate Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02215096
Recruitment Status : Completed
First Posted : August 13, 2014
Last Update Posted : December 16, 2019
Information provided by (Responsible Party):

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

Condition or disease Intervention/treatment Phase
Neoplasms Drug: GSK2636771 Drug: Enzalutamide Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 35 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : November 13, 2014
Actual Primary Completion Date : October 3, 2019
Actual Study Completion Date : October 3, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Prostate Cancer

Arm Intervention/treatment
Experimental: 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).
Drug: GSK2636771
GSK is available as 100 mg hard gelatin oral capsule to be taken once daily/continuous until treatment withdrawal under fasting conditions for at least 1hour (h) before and 2h after dosing with approximately 200 mL of water

Drug: Enzalutamide
Enzalutamide will be sourced locally from commercial stock for sites in countries where it is approved

Experimental: 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
Drug: GSK2636771
GSK is available as 100 mg hard gelatin oral capsule to be taken once daily/continuous until treatment withdrawal under fasting conditions for at least 1hour (h) before and 2h after dosing with approximately 200 mL of water

Drug: Enzalutamide
Enzalutamide will be sourced locally from commercial stock for sites in countries where it is approved

Primary Outcome Measures :
  1. Safety and tolerability as assessed by Adverse events (AEs) and serious adverse events (SAEs) [ Time Frame: Up to 3 years ]
    An AE is any untoward medical occurrence in a subject or clinical investigation subject, 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, or is a congenital anomaly/birth defect. Protocol-specific SAEs include all events of possible study treatment-induced liver injury with hyperbilirubinemia defined as alanine amino transferase (ALT) >=3 times upper limit of normal (ULN), and bilirubin >=2 times ULN (>35% direct) (or ALT >=3 times ULN and international normalization ratio (INR) >1.5 if INR is measured) or termed 'Hy's Law' events (INR measurement is not required and the threshold value stated will not apply to patients receiving anticoagulants), any new primary cancer(s)

  2. Safety and tolerability as assessed by dose-limiting toxicities (DLTs) [ Time Frame: Up to 3 years ]
    An event will be considered a DLT if the event is attributed (definitely, probably or possibly) to study treatment during the first 28 days of treatment, and meets one of the following criteria: Grade 3 or greater non-hematologic toxicity that cannot be controlled with routine supportive measures (e.g., antiemetics, antidiarrheals); Grade 4 neutropenia lasting >5 days; Febrile neutropenia, of any grade or duration as defined by Common Terminology Criteria for Adverse Events (CTCAE) 4.0; Grade 4 thrombocytopenia; ALT >3 times ULN with bilirubin >2 times ULN (or ALT >5 times ULN and 150% of baseline ALT, if enrolled with liver metastases/tumor infiltration at baseline); Any Grade 2 or greater toxicity per CTCAE 4.0 that would be considered dose-limiting

  3. Safety and tolerability as assessed changes in laboratory values [ Time Frame: Up to 3 years ]
    Laboratory assessment includes hematology, clinical chemistry and urinalysis

  4. Safety and tolerability as assessed by electrocardiograms (ECGs) [ Time Frame: Up to 3 years ]
  5. Safety and tolerability as assessed by vital signs [ Time Frame: Up to 3 years ]
    Vital sign assessment will include blood pressure, temperature and pulse rate

  6. Non-progressive disease (PD) rate for 12 weeks according to PCWG2 criteria [ Time Frame: Up to 3 years ]
    Non PD rate was assessed either by RECIST 1.1, PSA progression, and/or progression in bone

Secondary Outcome Measures :
  1. Plasma concentrations of enzalutamide and N desmethyl enzalutamide [ Time Frame: Day 29 ]
    Blood samples for analysis of enzalutamide and N-desmethyl enzalutamide will be collected pre-dose and 0.5, 1, 2, 3, 4, and 6, post-dose on the day prior to administration of GSK2636771 on Day -1 and at pre-dose and 0.5, 1, 2, 3, 4, and 6, hrs post-dose on Day 29

  2. Blood GSK2636771 concentrations [ Time Frame: Day 29 ]
    Blood samples for analysis of GSK2636771 will be collected at pre-dose and 0.5, 1, 2, 3, 4, and 6, hrs post-dose on Day 29

  3. Prostate specific antigen (PSA) as defined in PCWG2 guidelines and RECIST 1.1 response [ Time Frame: Up to 3 years ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02215096

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United States, California
GSK Investigational Site
Duarte, California, United States, 91010
GSK Investigational Site
Los Angeles, California, United States, 90089
GSK Investigational Site
Los Angeles, California, United States, 90095
United States, District of Columbia
GSK Investigational Site
Washington, District of Columbia, United States, 20007
United States, Michigan
GSK Investigational Site
Detroit, Michigan, United States, 48201
United States, New York
GSK Investigational Site
New York, New York, United States, 10016
United States, Texas
GSK Investigational Site
Houston, Texas, United States, 77030
United Kingdom
GSK Investigational Site
London, United Kingdom, SE1 9RT
GSK Investigational Site
Sutton, United Kingdom, SM2 5PT
Sponsors and Collaborators
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Study Director: GSK Clinical Trials GlaxoSmithKline

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Responsible Party: GlaxoSmithKline Identifier: NCT02215096    
Other Study ID Numbers: 200331
2013-005111-27 ( EudraCT Number )
First Posted: August 13, 2014    Key Record Dates
Last Update Posted: December 16, 2019
Last Verified: December 2019
Keywords provided by GlaxoSmithKline:
metastatic castration-resistant prostate cancer
PTEN deficiency
Additional relevant MeSH terms:
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Prostatic Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Genital Diseases, Male
Prostatic Diseases
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action