Clinical Trials /

Apalutamide Plus Intermittent Hormone Therapy Versus Intermittent Hormone Therapy Alone in Prostate Cancer

NCT02811809

Description:

This study is open to men who have biochemical recurrence (BCR, increased PSA) following local treatment of their prostate cancer. Androgen deprivation therapy (ADT) is a standard treatment option, but is only effective for 16-24 months and has a number of side effects that impact quality of life. These side effects may include fatigue, hot flushing, loss of sex drive, brain fog, decreased bone mineral density, loss of muscle mass, mild anemia (low levels of red blood cells that can make people feel tired and weak), diabetes (low blood sugar), heart disease, metabolic syndromes (sometimes called "pre-diabetes" and includes obesity, increased blood pressure, high levels of cholesterol and triglycerides in blood), and risk of fractures. An alternative to continuous ADT is intermittent administration, where patients are given "breaks" from ADT to let their testosterone levels return to baseline. There are a number of potential benefits to intermittent hormone therapy (IHT): (1) longer time to the development of resistance; (2) improved patient quality of life owing to recovery from adverse effects, particularly sexual function; and (3) substantial cost savings owing to less time spent receiving medication. Leuprolide is the name of the ADT / IHT drug. Apalutamide is an investigational drug, which means it has not been approved by the Food and Drug Administration (FDA). It is an antitumor drug, taken by mouth. The purpose of this study is to determine the ability of Apalutamide to extend the time between the first two injections of leuprolide and improve quality of life. This study will also look at the safety of Apalutamide and the effects that Apalutamide has on prostate cancer. Men will be randomized (like flipping a coin) to receive: - Group A: Leuprolide + Apalutamide or - Group B: Leuprolide only (until second leuprolide injection), then leuprolide + Apalutamide 45 men will be in Group A and 21 men will be in Group B. Leuprolide is given as an intramuscular shot that lasts for 3 months intermittently and Apalutamide is taken by mouth (4 tablets) daily. Each cycle is 4 weeks long. Intermittent treatment with Apalutamide + leuprolide will continue until continuous leuprolide is needed to maintain undetectable PSA levels (i.e., PSA levels rise above undetectable level unless leuprolide is given without pause, every 3 months).

Related Conditions:
  • Prostate Adenocarcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Apalutamide Plus Intermittent Hormone Therapy Versus Intermittent Hormone Therapy Alone in Prostate Cancer
  • Official Title: Apalutamide Plus Intermittent Hormone Therapy (IHT) Versus IHT Alone in Prostate Cancer Patients With Biochemical Recurrence

Clinical Trial IDs

  • ORG STUDY ID: GU-15-105
  • SECONDARY ID: HSC-MS-16-0477
  • NCT ID: NCT02811809

Conditions

  • Prostate Cancer

Interventions

DrugSynonymsArms
ApalutamideARN-509, JNJ-56021927Apalutamide + IHT
IHTLeuprolide, Lupron DepotApalutamide + IHT

Purpose

This study is open to men who have biochemical recurrence (BCR, increased PSA) following local treatment of their prostate cancer. Androgen deprivation therapy (ADT) is a standard treatment option, but is only effective for 16-24 months and has a number of side effects that impact quality of life. These side effects may include fatigue, hot flushing, loss of sex drive, brain fog, decreased bone mineral density, loss of muscle mass, mild anemia (low levels of red blood cells that can make people feel tired and weak), diabetes (low blood sugar), heart disease, metabolic syndromes (sometimes called "pre-diabetes" and includes obesity, increased blood pressure, high levels of cholesterol and triglycerides in blood), and risk of fractures. An alternative to continuous ADT is intermittent administration, where patients are given "breaks" from ADT to let their testosterone levels return to baseline. There are a number of potential benefits to intermittent hormone therapy (IHT): (1) longer time to the development of resistance; (2) improved patient quality of life owing to recovery from adverse effects, particularly sexual function; and (3) substantial cost savings owing to less time spent receiving medication. Leuprolide is the name of the ADT / IHT drug. Apalutamide is an investigational drug, which means it has not been approved by the Food and Drug Administration (FDA). It is an antitumor drug, taken by mouth. The purpose of this study is to determine the ability of Apalutamide to extend the time between the first two injections of leuprolide and improve quality of life. This study will also look at the safety of Apalutamide and the effects that Apalutamide has on prostate cancer. Men will be randomized (like flipping a coin) to receive: - Group A: Leuprolide + Apalutamide or - Group B: Leuprolide only (until second leuprolide injection), then leuprolide + Apalutamide 45 men will be in Group A and 21 men will be in Group B. Leuprolide is given as an intramuscular shot that lasts for 3 months intermittently and Apalutamide is taken by mouth (4 tablets) daily. Each cycle is 4 weeks long. Intermittent treatment with Apalutamide + leuprolide will continue until continuous leuprolide is needed to maintain undetectable PSA levels (i.e., PSA levels rise above undetectable level unless leuprolide is given without pause, every 3 months).

Detailed Description

      Prostate-specific antigen (PSA) is a sensitive and specific biomarker of prostate tissue.
      Monitoring of PSA after local treatment for prostate cancer can assist in identifying
      patients who have only increased PSA (biochemical recurrence [BCR]) despite no symptoms,
      signs, or evidence of radiographic metastatic disease. This subpopulation of patients are
      referred to as having "biochemical failure." Androgen deprivation therapy (ADT) is a standard
      treatment option, but is only effective for 16-24 months and has a number of side effects
      that impact quality of life. These side effects may include fatigue, hot flushing, loss of
      sex drive, brain fog, decreased bone mineral density, loss of muscle mass, mild anemia,
      diabetes, heart disease, metabolic syndromes and risk of fractures. An alternative to
      continuous ADT is intermittent administration, where patients are given "breaks" from ADT to
      let their testosterone levels return to baseline. There are a number of potential benefits to
      intermittent hormone therapy (IHT): (1) longer time to the development of resistance, owing
      to the removal of constant pressure causing faster mutation of resistant cells; (2) improved
      patient quality of life owing to recovery from adverse effects, particularly sexual function;
      and (3) substantial cost savings owing to less time spent receiving medication. Leuprolide is
      the name of the ADT / IHT drug.

      Apalutamide is an investigational antitumor drug, taken by mouth. It is a synthetic compound
      rationally designed to bind the androgen receptor (with higher affinity than enzalutamide or
      bicalutamide), prevent both nuclear translocation and DNA binding, and induce apoptosis. It
      has greater antitumor activity at a lower dose, achieves steady-state levels at a lower dose,
      and accumulates more into tumor tissue without building up in the brain, which both increases
      effectiveness and decreases the risk of seizure.

      Apalutamide's mechanism of action gives it the potential to extend the time to PSA increase
      during intermittent ADT, delaying the necessity for continuous ADT. Investigators will assess
      the potential applications of intermittent ADT plus Apalutamide for participants with BCR.
      This study will elucidate the potential of this regimen to reduce the burden of adverse
      events of continuous ADT and delay the development of hormone resistance.

      This is a randomized crossover study intended to determine the interval of ADT administration
      achievable with supportive Apalutamide treatment. Investigators will assess the significance
      of time to PSA recurrence, time to next leuprolide injection, time to testosterone recovery,
      duration of testosterone recovery, time to biochemical recurrence, percentage of men
      developing biochemical recurrence, number of detectable CTCs, and quality of life measures.

      Treatment will be 66 participants in 2:1 randomized crossover - 45 IHT + apalutamide:21 IHT
      only until second leuprolide injection, then IHT + apalutamide

      Apalutamide + IHT Participants will be treated with 240 mg (4 60 mg tablets) oral Apalutamide
      daily plus 22.5 mg 3-month depot intramuscular leuprolide intermittently.

      IHT Participants will receive 22.5 mg 3-month depot intramuscular leuprolide until PSA
      progression, when they will receive 240 mg oral Apalutamide daily plus 22.5 mg 3-month depot
      intramuscular leuprolide intermittently.

      Participants remain on study until continuous ADT is required to maintain castrate PSA levels
      (i.e., leuprolide is needed every 3 months to maintain PSA <1 ng/dL).
    

Trial Arms

NameTypeDescriptionInterventions
Apalutamide + IHTExperimentalParticipants will be treated with 240 mg (4-60 mg tablets) oral Apalutamide daily plus 22.5 mg 3-month depot intramuscular leuprolide intermittently.
  • Apalutamide
  • IHT
IHT onlyActive ComparatorParticipants will receive 22.5 mg 3-month depot intramuscular leuprolide until PSA progression, then they will crossover to Apalutamide + IHT
  • IHT

Eligibility Criteria

        Inclusion Criteria:

          -  Age ≥ 18 years

          -  Patients with a diagnosis of adenocarcinoma of the prostate

          -  Patients with BCR (PSA becomes detectable, with absolute value ≥1) following
             prostatectomy who have no evidence of metastatic disease based on radiographic
             assessment.

          -  Patients with BCR following radiation therapy who have no radiographic involvement per
             mpMRI and CT (RTOG-ASTRO Phoenix criteria), size of pelvic nodes ≤1 cm, and whose
             MRI-directed prostate biopsies are negative.

          -  Patients must be free of serious comorbidity as determined by investigator.

          -  Clinical laboratory values at screening:

          -  Serum testosterone level ≥150 ng/dL

          -  Hemoglobin ≥9.0 g/dL, independent of transfusion and/or growth factors within 3 months
             prior to randomization

          -  Platelet count ≥100,000 /µL independent of transfusion and/or growth factors within 3
             months prior to randomization

          -  Serum albumin ≥3.0 g/dL

          -  GFR >45 mL/min

          -  Serum potassium ≥3.5 mmol/L

          -  Serum total bilirubin ≤1.5 × ULN (Note: In subjects with Gilbert's syndrome, if total
             bilirubin is >1.5 × ULN, measure direct and indirect bilirubin and if direct bilirubin
             is ≤1.5 × ULN, subject may be eligible)

          -  Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) <2.5 × ULN

          -  Medications known to lower the seizure threshold (see list under prohibited meds,
             Appendix 3) must be discontinued or substituted at least 4 weeks prior to study entry.

          -  Agrees to use a condom (even men with vasectomies) and another effective method of
             birth control if he is having sex with a woman of childbearing potential or agrees to
             use a condom if he is having sex with a woman who is pregnant while on study drug and
             for 3 months following the last dose of study drug. Must also agree not to donate
             sperm during the study and for 3 months after receiving the last dose of study drug.

          -  Written, informed consent to participate in this study.

        Exclusion Criteria:

          -  PSA doubling time >12 months

          -  Positive for HIV or chronic hepatitis B or hepatitis C infection

          -  Another primary malignancy that has not been in remission for at least 2 years.
             Non-melanoma skin cancer allowed.

          -  Use of herbal products that may decrease PSA levels (e.g., saw palmetto) or systemic
             corticosteroids greater than the equivalent of 10 mg of prednisone per day within 4
             weeks of screening laboratory studies.

          -  Any other condition, including concurrent medical condition, social circumstance or
             drug dependency, which in the opinion of the investigator could compromise patient
             safety and/or compliance with study requirements

          -  History of any of the following:

               -  Seizure or known condition that may pre-dispose to seizure (e.g. prior stroke
                  within 1year to randomization, brain arteriovenous malformation, Schwannoma,
                  meningioma, or other benign CNS or meningeal disease which may require treatment
                  with surgery or radiation therapy)

               -  Severe or unstable angina, myocardial infarction, symptomatic congestive heart
                  failure, arterial or venous thromboembolic events (eg, pulmonary embolism,
                  cerebrovascular accident including transient ischemic attacks), or clinically
                  significant ventricular arrhythmias within 6 months prior to randomization Any
                  condition that in the opinion of the investigator, would preclude participation
                  in this study

          -  Current evidence of any of the following:

               -  Uncontrolled hypertension

               -  Gastrointestinal disorder affecting absorption

               -  Active infection (eg, human immunodeficiency virus [HIV] or viral hepatitis) Any
                  condition that in the opinion of the investigator, would preclude participation
                  in this study
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:Time to second injection
Time Frame:48 months
Safety Issue:
Description:Time to second injection

Secondary Outcome Measures

Measure:Time to prostate-specific antigen (PSA) nadir
Time Frame:48 months
Safety Issue:
Description:Time to prostate-specific antigen (PSA) nadir
Measure:Duration of PSA nadir
Time Frame:48 months
Safety Issue:
Description:Duration of PSA nadir
Measure:Time to testosterone recovery to >50 ng/dl
Time Frame:48 months
Safety Issue:
Description:Time to testosterone recovery to >50 ng/dl
Measure:Duration of testosterone recovery
Time Frame:48 months
Safety Issue:
Description:Duration of testosterone recovery
Measure:Circulating tumor cell (CTC) enumeration
Time Frame:48 months
Safety Issue:
Description:Circulating tumor cell (CTC) enumeration
Measure:Time until BCR after discontinuation of Apalutamide and ADT
Time Frame:48 months
Safety Issue:
Description:Time until BCR after discontinuation of Apalutamide and ADT
Measure:Quality of life as determined by FACT-P survey
Time Frame:48 months
Safety Issue:
Description:Quality of life as determined by FACT-P survey
Measure:Number of Adverse Events
Time Frame:48 months
Safety Issue:
Description:Number of Adverse Events

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Robert J Amato

Trial Keywords

  • Prostate cancer
  • Apalutamide
  • IHT
  • BCR
  • Biochemical recurrence
  • intermittent hormone therapy

Last Updated

June 3, 2019