Dose-finding Study of GSK2636771 When Administered in Combination With Enzalutamide in Male Subjects With Metastatic Castration-Resistant Prostate Cancer
Condition: Neoplasms
MeSH terms: Prostatic Neoplasms
Intervention: GSK2636771; Enzalutamide
Intervention description: 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; Enzalutamide will be sourced locally from commercial stock for sites in countries where it is approved
Intervention MeSH terms: GSK2636771
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 37.0
Sex: Male
Minimum age: 18 Years
Healthy volunteers: No
Keywords: enzalutamide; metastatic castration-resistant prostate cancer; GSK2636771; PI3K-beta; PTEN deficiency

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