Clinical Trials /

Dose Escalation and Dose Expansion Study of GSK525762 in Combination With Androgen Deprivation Therapy and Other Agents in Subjects With Castrate-resistant Prostate Cancer

NCT03150056

Description:

The study aims to evaluate the combination of GSK525762 with other agents that have been shown to be effective in the treatment of CRPC or metastatic CRPC, including approved agents (e.g., abiraterone, enzalutamide) as well as investigational agents for mCRPC that have proven to show efficacy and can be combined based on complimentary mechanism of action. As a first step, the combination of GSK525762 will be evaluated as a combination with abiraterone or enzalutamide in men with metastatic or advanced castrate-resistant prostate cancer who have progressed on at least one line of prior androgen receptor (AR)-targeted therapy. This study is designed to determine the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) based on safety, tolerability, pharmacokinetic, and efficacy profiles of GSK525762 in combination with either abiraterone (Arm A) or enzalutamide (Arm B). Arm A and Arm B will further have 2 cohorts: A1, A2 and B1, B2 respectively based on prior lines of therapy (L2 [chemo-naive subjects treated with a second androgen-deprivation therapy] and Lx [subjects treated with both prior androgen-deprivation therapy and chemotherapy]). During dose escalation, both the treatment arms (A and B) will follow a modified Toxicity Probability Interval (mTPI) design. Approximately 130 subjects will be enrolled worldwide in this study. Subjects from both dose escalation and dose expansion may be combined to reach 30 subjects. The total duration of study will be approximately 2 to 3 years. A subject will be considered to have completed the study if they are followed until death.

Related Conditions:
  • Prostate Adenocarcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Dose Escalation and Dose Expansion Study of GSK525762 in Combination With Androgen Deprivation Therapy and Other Agents in Subjects With Castrate-resistant Prostate Cancer
  • Official Title: A Phase IB Open-label, Dose Escalation and Expansion Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of GSK525762 in Combination With Androgen Deprivation Therapy and Other Agents in Subjects With Castrate-resistant Prostate Cancer (CRPC)

Clinical Trial IDs

  • ORG STUDY ID: 204697
  • SECONDARY ID: 2016-003416-13
  • NCT ID: NCT03150056

Conditions

  • Solid Tumours

Interventions

DrugSynonymsArms
GSK525762GSK525762 + Enzalutamide (Arm B)
AbirateroneGSK525762 + abiraterone (Arm A)
EnzalutamideGSK525762 + Enzalutamide (Arm B)
PrednisoneGSK525762 + abiraterone (Arm A)

Purpose

The study aims to evaluate the combination of GSK525762 with other agents that have been shown to be effective in the treatment of CRPC or metastatic CRPC, including approved agents (e.g., abiraterone, enzalutamide) as well as investigational agents for mCRPC that have proven to show efficacy and can be combined based on complimentary mechanism of action. As a first step, the combination of GSK525762 will be evaluated as a combination with abiraterone or enzalutamide in men with metastatic or advanced castrate-resistant prostate cancer who have progressed on at least one line of prior androgen receptor (AR)-targeted therapy. This study is designed to determine the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) based on safety, tolerability, pharmacokinetic, and efficacy profiles of GSK525762 in combination with either abiraterone (Arm A) or enzalutamide (Arm B). Arm A and Arm B will further have 2 cohorts: A1, A2 and B1, B2 respectively based on prior lines of therapy (L2 [chemo-naive subjects treated with a second androgen-deprivation therapy] and Lx [subjects treated with both prior androgen-deprivation therapy and chemotherapy]). During dose escalation, both the treatment arms (A and B) will follow a modified Toxicity Probability Interval (mTPI) design. Approximately 130 subjects will be enrolled worldwide in this study. Subjects from both dose escalation and dose expansion may be combined to reach 30 subjects. The total duration of study will be approximately 2 to 3 years. A subject will be considered to have completed the study if they are followed until death.

Trial Arms

NameTypeDescriptionInterventions
GSK525762 + abiraterone (Arm A)ExperimentalEligible subjects will receive treatment with GSK525762 in combination with abiraterone. Subjects will be abiraterone-refractory or resistant from L2 and Lx lines of therapy. Two dose combinations, 60 mg or 80 mg of GSK525762 will be administered once daily. There is also a possibility of dose reduction to 40 mg in case of toxicity. Dosing will continue until unacceptable toxicity, progression of disease, withdrawal of consent, death, or completion of study. Subjects may also receive prednisone in combination with abiraterone dosing.
  • GSK525762
  • Abiraterone
  • Prednisone
GSK525762 + Enzalutamide (Arm B)ExperimentalEligible subjects will receive treatment with GSK525762 in combination with enzalutamide. Subjects will be enzalutamide -refractory or resistant from L2 and Lx lines of therapy. Two to three dose combinations 80 mg, 100 mg and 120 mg of GSK525762 will be administered once daily based on the emerging data from the dose escalation part. There is also a possibility of dose reduction to 60 mg in case of toxicity. Dosing will continue until unacceptable toxicity, progression of disease, withdrawal of consent, death, or completion of study.
  • GSK525762
  • Enzalutamide

Eligibility Criteria

        Inclusion Criteria

          -  Written informed consent provided

          -  Males >=18 years of age (at the time written consent is obtained for screening)

          -  Histologically confirmed adenocarcinoma of the prostate: screening and on-treatment
             biopsy is mandatory. If adequate number of paired biopsy samples are collected (>=20
             paired samples for each dose level in each Arm, unless an Arm is closed early), then
             further biopsy sampling will be considered based on available data; screening biopsy
             can be waived if patient had a recent biopsy after failure of ADT therapy (within 30
             days) and the biopsy sample is secured to be sent as screening biopsy for this study.

          -  Surgically or medically castrated, with testosterone levels of <=50 nanograms per
             deciliter (ng/dL) (<2.0 nanometer [nM]). If the patient is being treated with
             luteinizing hormone-releasing hormone (LHRH) agonists/antagonists (patient who have
             not undergone orchiectomy) this therapy must have been initiated at least 4 weeks
             prior to Cycle 1 Day 1 and must be continued throughout the study.

          -  Subjects must have failed prior therapy with abiraterone, enzalutamide, or both: has
             completed at least 12 weeks of prior continuous therapy with abiraterone or
             enzalutamide; has not been without abiraterone or enzalutamide treatment for >30 days
             prior to initiation of study treatment; lead-in dosing period for enzalutamide only
             will be required under the following circumstance:

               1. If the subject has enzalutamide discontinuation for >7 days prior to dosing start
                  with GSK525762 plus enzalutamide on trial, then a enzalutamide only lead-in
                  dosing of 28 days is required

               2. If the subject has enzalutamide discontinuation for <=7 days prior to dosing
                  start with GSK525762 plus enzalutamide on trial, then a enzalutamide only lead-in
                  dosing of 14 days is required

               3. If the subject is on continuous dosing with enzalutamide prior to dosing start
                  with GSK525762 plus enzalutamide on trial, then subject can start on combined
                  dosing at end of screening period; Lead-in dosing period for abiraterone only
                  will be required: if the subject has abiraterone discontinuation for more than 3
                  days prior to dosing start with GSK525762 plus abiraterone on trial, then
                  abiraterone only lead-in dosing of 7 days is required.

          -  One to two line(s) of prior taxane-based chemotherapy allowed. If docetaxel
             chemotherapy is used more than once, this will be considered as one regimen.

          -  Documented prostate cancer progression as assessed by the investigator with one of the
             following: PSA progression defined by a minimum of 3 rising PSA levels with an
             interval of >=1 week between each determination. The PSA value at screening must be
             >=5 microgram (µg)/L (5 ng/mL) if PSA is the only indication of progression; subjects
             on systemic glucocorticoids for control of symptoms must have documented PSA
             progression by PCWG3 while on systemic glucocorticoids prior to commencing Cycle 1 Day
             1 treatment.

          -  Radiographic progression of soft tissue disease by PCWG3-modified RECIST 1.1 criteria
             or bone metastasis with 2 or more documented new bone lesions on a bone scan with or
             without PSA progression

          -  Eastern Cooperative Oncology Group performance status of 0 or 1

          -  Life expectancy >12 weeks

          -  Able to swallow and retain orally administered medication

          -  Must have adequate organ function as defined by the following values: white blood
             cells >3 x 10^9/liter(L); absolute neutrophil count (ANC) >= 1.5 x 10^9/L; hemoglobin
             >= 9 grams per decilitre (g/dL) subjects that required transfusion or growth factor
             need to demonstrate stable hemoglobin for 7 days of 9 g/dL; platelets >=100 x 10^9/L;
             prothrombin time (PT)/International normalized ration (INR) and partial thromboplastin
             time (PTT) <= 1.5 x upper limit of normal (ULN); albumin >=2.5 g/dL; total bilirubin
             <=1.5 x ULN; aspartate transaminase (AST) <=2.5 x ULN; alanine transaminase (ALT)
             <=2.5 x ULN OR <5 x ULN; creatinine <=1.5 x ULN is acceptable for subjects with
             documented liver metastases/tumor infiltration; creatinine clearance >= 50 mL/min;
             ejection fraction>= lower limit of normal (LLN) by echocardiogram or multigated
             acquisition (MUGA) and minimum of 50% left ventricular ejection fraction (LVEF);
             testosterone <=50 nanograms per deciliter (ng/dL)

          -  Male subject with a female partner of childbearing potential or pregnant must agree to
             use two acceptable methods of contraception from time of first dose of study treatment
             until 4 months after the last dose of study treatments

        Exclusion Criteria

          -  Surgery or local prostatic intervention (excluding a prostatic biopsy) less than 28
             days of Cycle 1 Day 1.

          -  Subjects with neuroendocrine and/or small cell CRPC

          -  Recent prior therapy, defined as: Any investigational or approved non-biologic
             anti-cancer drug (see exception below) within 14 days prior to the first dose of
             GSK525762 and abiraterone/enzalutamide. Exception: For allowed androgen deprivation
             therapy (hormonal, abiraterone, enzalutamide. Concomitant prednisone (or equivalent)
             allowed in combination with abiraterone dosing, any nitrosoureas or mitomycin C within
             42 days prior to the first dose of GSK525762 and abiraterone/enzalutamide, any
             anti-cancer biologic agents within five half-lives prior to the first dose of
             GSK525762 and abiraterone/enzalutamide, if the subject received radiotherapy <90 days
             prior to study treatment, the irradiated lesion cannot be the only lesion used for
             evaluating response. Exception: Any radiotherapy within 14 days prior to the first
             dose of GSK525762 and abiraterone/enzalutamide must be limited to a single fraction of
             radiotherapy for the purpose of palliation (confined to one field) is permitted, any
             major surgery within 28 days prior to the first dose of GSK525762 and
             abiraterone/enzalutamide

          -  Evidence of severe or uncontrolled systemic diseases (e.g., unstable or uncompensated
             respiratory, hepatic, renal, cardiac disease, or clinically significant bleeding
             episodes). Any serious and/or unstable pre-existing medical (aside from malignancy),
             psychiatric disorder, or other conditions that could interfere with subject's safety,
             obtaining informed consent or compliance to the study procedures, in the opinion of
             the Investigator; systolic blood pressure higher than 150 millimeter of mercury (mmHg)
             or diastolic blood pressure higher than 90 mmHg found on 2 separate occasions
             separated by 1 week, despite adequate therapy, will be defined as uncontrolled
             hypertension; uncontrolled diabetes mellitus (despite therapeutic, compliance
             intervention) as defined by a hemoglobin A1c (HbA1c) level more than 8% and/or
             occurrence of more than 2 episodes of ketoacidosis in the 12 months prior to the first
             dose of study drug.

          -  Cardiac abnormalities as evidenced by any of the following: Baseline QT interval
             corrected for heart rate by Fridericia's formula (QTcF) interval >=450 milliseconds
             (msec), clinically significant conduction abnormalities or arrhythmias, such as
             subjects with second degree (Type II) or third degree atrio-ventricular block, history
             or evidence of current ≥Class II congestive heart failure as defined by New York Heart
             Association (NYHA), history of acute coronary syndromes (including unstable angina and
             myocardial infarction), coronary angioplasty, or stenting within the past 3 months.
             Subjects with a history of stent placement requiring ongoing anti-coagulant therapy
             (e.g., clopidogrel, prasugrel) will not be permitted to enroll, known cardiac
             metastasis.

          -  Subjects with history of known bleeding disorder(s) or history of clinically
             significant hemorrhage (e.g., gastrointestinal , neurologic), within the past 6
             months.

          -  Therapeutic-dose anticoagulation (e.g., warfarin, low-molecular weight heparin [LMWH],
             or novel oral anticoagulants) must be discontinued and coagulation parameters must be
             normalized prior to the first dose of abiraterone/enzalutimide. Prophylactic
             anticoagulation, with low doses (per standard practice) of agents such as low
             molecular weight heparin (LMWH), direct thrombin inhibitors, or factor Xa inhibitors
             is permitted.

          -  Concurrent use of high dose aspirin (doses up to 81 mg oral dose daily allowed) and
             non-steroidal anti-inflammatory drugs (NSAIDS), except for where NSAIDs provide
             documented benefit over other analgesics, and then to be used with caution including
             concomitant use of proton pump inhibitors).

          -  Any acute toxicities due to prior chemotherapy and / or radiotherapy that have not
             resolved to a Common Terminology Criteria for Adverse Events version 4.0 grade <=1
             with the exception of chemotherapy induced alopecia and grade 2 peripheral neuropathy.

          -  The patient has an active second malignancy other than curatively resected basal cell
             or squamous cell carcinoma of the skin, in situ carcinoma of the bladder, or other
             cancers for which they are treated with curative intent with no active disease in the
             3 years prior to enrollment.

          -  Subjects with known symptomatic brain metastasis are not suitable for enrolment.
             Subjects with asymptomatic, stable, treated brain metastases are eligible for study
             entry.

          -  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 prior
             to enrollment

          -  Subjects with symptomatic or impending cord compression unless appropriately treated
             beforehand and clinically stable and asymptomatic.

          -  Subjects who have experienced a seizure or seizures within 6 months of study treatment
             or who are currently being treated with cytochrome P450 enzyme inducing anti-epileptic
             drugs for seizures (use of anti-epileptic drugs to control pain is allowed in subjects
             not suffering from seizures unless drug is excluded due to Cytochrome P450 3A4
             induction - phenytoin, carbamazepine, Phenobarbital.

          -  Current use of a prohibited medication or planned use of any forbidden medications
             during treatment with GSK525762 and abiraterone/enzalutamide. This includes
             medications with significant risk of Torsades de pointes as well as those that are
             potent inducers or inhibitors of CYP3A4 enzymes or strong inhibitors of CYP2C8.

          -  Subjects with gastrointestinal disorders likely to interfere with absorption of the
             study medication.

          -  Subjects with known bleeding diathesis will be excluded from the study.

          -  Current active liver or biliary disease (with the exception of Gilbert's syndrome or
             asymptomatic gallstones, liver metastases or otherwise stable chronic liver disease
             per investigator assessment).

          -  Initiating bisphosphonate or denosumab therapy or adjusting dose/regimen within 3
             months prior to Cycle 1 Day 1. Subjects on a stable bisphosphonate or denosumab
             therapy are eligible and may continue.

          -  Any serious known immediate or delayed hypersensitivity reaction to GSK525762 or
             idiosyncrasy to drugs chemically related to the investigational drugs. Additionally,
             any known hypersensitivity to either enzalutamide, abiraterone or any excipients would
             be excluded.

          -  Known history of human immunodeficiency virus (HIV)

          -  Presence of hepatitis B surface antigen (HBsAg) or positive hepatitis C antibody test
             result at screening. Subjects with positive hepatitis C antibody due to prior resolved
             disease can be enrolled only if a confirmatory negative hepatitis C ribonucleic acid
             polymerase chain reaction is obtained.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of subjects with adverse events (AE) and serious adverse events (SAE)
Time Frame:Approximately up to 3 years
Safety Issue:
Description:Any AE is any untoward medical occurrence in a subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment will be categorized as SAE.

Secondary Outcome Measures

Measure:Plasma concentration of GSK525762 and selected metabolites
Time Frame:Day 1 of Week (W) 1 and W3 (Pre-dose, 30 minutes (m)±5m, 1h±10m, 3h±30m, 6 to 12 hours (h) and 24 h±2h prior to dosing); Day 1 of W5 (pre-dose, 0.5-1h post-dose, [optional] 4-12h post-dose); and every 8W from W9 to W49 (pre-dose and 0.5-1 h post-dose)
Safety Issue:
Description:Concentration of GSK525762 will be determined following repeat-dose oral administration in combination with abiraterone or enzalutamide
Measure:Plasma concentration of abiraterone or enzalutamide
Time Frame:Day 1 of Week (W) 1 and W3 (Pre-dose, 30 minutes (m)±5m, 1h±10m, 3h±30m, 6 to 12 hours (h) and 24 h±2h prior to dosing); Day 1 of W5 (pre-dose, 0.5-1h post-dose, [optional] 4-12h post-dose); and every 8W from W9 to W49 (pre-dose and 0.5-1 h post-dose)
Safety Issue:
Description:Concentration of abiraterone or enzalutamide will be determined following repeat-dose oral administration in combination with GSK525762
Measure:Overall response rate (ORR) based on Prostate Cancer Working Group (PCWG3)-modified Response Evaluation Criteria In Solid Tumors (RECIST) 1.1
Time Frame:Approximately up to 3 years
Safety Issue:
Description:The overall response rate is defined as complete response (CR) plus partial response (PR)
Measure:Circulating Tumor Cell (CTC) response
Time Frame:Approximately up to 3 years
Safety Issue:
Description:CTC response rate is defined as reduction from ≤5 cells/7.5 milliliter (mL) blood to ≥5 cells/7.5 mL blood
Measure:Percentage of subjects with PSA response at Week 4
Time Frame:Week 4
Safety Issue:
Description:PSA response is defined as percent of subjects achieving ≥30% decrease from baseline PSA at 4 weeks
Measure:Time to disease progression
Time Frame:Approximately up to 3 years
Safety Issue:
Description:Time to disease progression will be evaluated either by PCWG3-modified RECIST 1.1, PSA progression, and/or progression in bone
Measure:Radiographic Progression-free survival (rPFS) based on PCWG3-modified RECIST 1.1
Time Frame:Approximately up to 3 years
Safety Issue:
Description:rPFS is defined as the time from study treatment start until the first date of either disease progression or death due to any cause
Measure:Composite Response Rate defined as any one of the following: a) Response based on PCWG3-modified RECIST1.1, b) PSA decrease of ≥50% at Week 12 and thereafter, or c) Circulating Tumor-cell Count Conversion
Time Frame:Approximately up to 3 years
Safety Issue:
Description:CRR will be assessed.
Measure:The performance status as measured by Eastern Cooperative Oncology Group (ECOG) scale
Time Frame:Approximately up to 3 years
Safety Issue:
Description:Performance status assessments are based on 5-point ECOG scale where 0 is fully active, able to carry on all pre-disease performance without restriction. 1 is restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, example, light house work, office work. 2 is ambulatory and capable of all selfcare, but unable to carry out any work activities; up and about more than 50 percent of waking hrs. 3 is capable of only limited selfcare; confined to bed or chair more than 50% of waking hours. 4 is completely disabled; cannot carry on any selfcare; totally confined to bed or chair. 5 is dead.
Measure:The change in the quality of life as measured by European Organization for Research and Treatment of Cancer Quality of Life (QOL) Questionnaire (EORTC QLQ-C30)
Time Frame:Approximately up to 3 years
Safety Issue:
Description:EORTC-QLQ-C30 is a 30-item subject self-report questionnaire composed of both multi-item and single scales, including a global health status/quality of life (GHS/QoL) scale. Participants rate items on a four-point scale, with 1 as "not at all" and 4 as "very much." A change of 5 - 10 points is considered a small. A change of 10 - 20 points is considered a moderate change.
Measure:Pain as assessed with The Brief Pain Inventory-Short Form (BPI-SF)
Time Frame:Approximately up to 3 years
Safety Issue:
Description:BPI-SF questionnaire is used to assess how pain interferes with patient's functioning in addition to measuring the intensity and location of pain.

Details

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

Trial Keywords

  • abiraterone
  • castrate-resistant prostate cancer
  • androgen receptor targeted therapy
  • RP2D
  • enzalutamide
  • GSK525762

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