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

NCT02215096

Description:

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

Related Conditions:
  • Prostate Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: 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)

Clinical Trial IDs

  • ORG STUDY ID: 200331
  • NCT ID: NCT02215096

Conditions

  • Cancer

Interventions

DrugSynonymsArms
GSK2636771Phase 1-Dose Escalation
EnzalutamidePhase 1-Dose Escalation

Purpose

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

Trial Arms

NameTypeDescriptionInterventions
Phase 1-Dose EscalationExperimentalSubject 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).
  • GSK2636771
  • Enzalutamide
Phase 2- Dose ExpansionExperimentalAdditional 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
  • GSK2636771
  • Enzalutamide

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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety and tolerability as assessed by Adverse events (AEs) and serious adverse events (SAEs)
Time Frame:Up to 3 years
Safety Issue:
Description: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)

Secondary Outcome Measures

Measure:Plasma concentrations of enzalutamide and N desmethyl enzalutamide
Time Frame:Day 29
Safety Issue:
Description: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
Measure:Blood GSK2636771 concentrations
Time Frame:Day 29
Safety Issue:
Description: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
Measure:Prostate specific antigen (PSA) as defined in PCWG2 guidelines and RECIST 1.1 response
Time Frame:Up to 3 years
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:GlaxoSmithKline

Trial Keywords

  • enzalutamide
  • metastatic castration-resistant prostate cancer
  • GSK2636771
  • PI3K-beta
  • PTEN deficiency

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