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

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ClinicalTrials.gov Identifier: NCT03150056
Recruitment Status : Recruiting
First Posted : May 11, 2017
Last Update Posted : August 24, 2018
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Solid Tumours Drug: GSK525762 Drug: Abiraterone Drug: Enzalutamide Drug: Prednisone Phase 1

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 130 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : May 31, 2017
Estimated Primary Completion Date : September 28, 2018
Estimated Study Completion Date : July 29, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Prostate Cancer

Arm Intervention/treatment
Experimental: GSK525762 + abiraterone (Arm A)
Eligible 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.
Drug: GSK525762
GSK525762 will be available as 5 milligram (mg) and 25 mg white to slightly colored, round, biconvex with no markings, film-coated tablet and will be administered with 240 milliliter (mL) water. The 20 mg tablet formulation is in development and will be used when available.

Drug: Abiraterone
Abiraterone will be available as 250 mg white to off-white, oval tablets debossed with AA250 on one side. It will be administered with 240 mL water.

Drug: Prednisone
5 mg prednisone will be administered as a concomitant medication in combination with abiraterone

Experimental: GSK525762 + Enzalutamide (Arm B)
Eligible 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.
Drug: GSK525762
GSK525762 will be available as 5 milligram (mg) and 25 mg white to slightly colored, round, biconvex with no markings, film-coated tablet and will be administered with 240 milliliter (mL) water. The 20 mg tablet formulation is in development and will be used when available.

Drug: Enzalutamide
Enzalutamide will be available as 40 mg white to off-white oblong soft gelatin capsules imprinted in black ink with ENZ. It will be administered with 240 mL water.




Primary Outcome Measures :
  1. Number of subjects with adverse events (AE) and serious adverse events (SAE) [ Time Frame: Approximately up to 3 years ]
    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.

  2. Number of subjects with dose reductions or delays [ Time Frame: Approximately up to 3 years ]
    Dose reductions or delays will be evaluated during the treatment period.

  3. Number of subjects withdrawn due to toxicity [ Time Frame: Approximately up to 3 years ]
    Withdrawals will be collected during the study period until the end of study.

  4. Number of subjects with abnormality in laboratory parameters [ Time Frame: Approximately up to 3 years ]
    Laboratory parameters includes clinical chemistry, hematology parameters, liver function tests, routine urinalysis and cardiac studies

  5. Number of subjects with abnormality in vital signs [ Time Frame: Approximately up to 3 years ]
    Vital signs to be measured in semi-supine position after 5 minutes rest will include temperature, systolic and diastolic blood pressure, pulse rate, and respiratory rate.

  6. Number of subjects with abnormality in electrocardiogram (ECG) [ Time Frame: Approximately up to 3 years ]
    Triplicate 12-lead ECGs will be obtained, prior to dosing at specific time periods

  7. Number of subjects with abnormality in any cardiotoxicity parameters [ Time Frame: Approximately up to 3 years ]
    Echocardiography (ECHO) or multigated acquisition (MUGA) scan will be performed to assess cardiotoxicity

  8. Number of subjects with abnormality in gastrointestinal parameters [ Time Frame: Approximately up to 3 years ]
    Gastrointestinal effects will be assessed during the treatment period.

  9. Percentage of subjects with Prostate Specific Antigen 50 (PSA50) [ Time Frame: At 12 weeks and there after (assessed up to maximum of 3 years) ]
    PSA50 is ≥50% decrease in PSA from baseline. It will be analyzed after 12 weeks of treatment


Secondary Outcome Measures :
  1. 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) ]
    Concentration of GSK525762 will be determined following repeat-dose oral administration in combination with abiraterone or enzalutamide

  2. 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) ]
    Concentration of abiraterone or enzalutamide will be determined following repeat-dose oral administration in combination with GSK525762

  3. 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 ]
    The overall response rate is defined as complete response (CR) plus partial response (PR)

  4. Circulating Tumor Cell (CTC) response [ Time Frame: Approximately up to 3 years ]
    CTC response rate is defined as reduction from ≤5 cells/7.5 milliliter (mL) blood to ≥5 cells/7.5 mL blood

  5. Percentage of subjects with PSA response at Week 4 [ Time Frame: Week 4 ]
    PSA response is defined as percent of subjects achieving ≥30% decrease from baseline PSA at 4 weeks

  6. Time to disease progression [ Time Frame: Approximately up to 3 years ]
    Time to disease progression will be evaluated either by PCWG3-modified RECIST 1.1, PSA progression, and/or progression in bone

  7. Radiographic Progression-free survival (rPFS) based on PCWG3-modified RECIST 1.1 [ Time Frame: Approximately up to 3 years ]
    rPFS is defined as the time from study treatment start until the first date of either disease progression or death due to any cause

  8. 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 ]
    CRR will be assessed.

  9. The performance status as measured by Eastern Cooperative Oncology Group (ECOG) scale [ Time Frame: Approximately up to 3 years ]
    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.

  10. 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 ]
    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.

  11. Pain as assessed with The Brief Pain Inventory-Short Form (BPI-SF) [ Time Frame: Approximately up to 3 years ]
    BPI-SF questionnaire is used to assess how pain interferes with patient's functioning in addition to measuring the intensity and location of pain.



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

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 ClinicalTrials.gov identifier (NCT number): NCT03150056


Contacts
Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com

  Show 22 Study Locations
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT03150056     History of Changes
Other Study ID Numbers: 204697
First Posted: May 11, 2017    Key Record Dates
Last Update Posted: August 24, 2018
Last Verified: August 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by GlaxoSmithKline:
abiraterone
castrate-resistant prostate cancer
androgen receptor targeted therapy
RP2D
enzalutamide
GSK525762

Additional relevant MeSH terms:
Prostatic Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Genital Diseases, Male
Prostatic Diseases
Prednisone
Androgens
Anti-Inflammatory Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents