Clinical Trials /

Androgen Deprivation Therapy and Apalutamide With or Without Radiation Therapy for the Treatment of Biochemically Recurrent Prostate Cancer, RESTART Study

NCT04585932

Description:

This phase II trial studies how well androgen deprivation therapy and apalutamide with or without radiation therapy works for the treatment of prostate cancer that has a rise in the blood level of prostate-specific antigen (PSA) and has come back after treatment with surgery or radiation (biochemically recurrent). Androgens can cause the growth of prostate tumor cells. Apalutamide may help fight prostate cancer by blocking the use of androgens by the tumor cells. Androgen deprivation therapy drugs, leuprolide or degarelix, work to lower the amount of androgen in the body, also preventing the tumor cells from growing. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving radiation therapy with apalutamide and androgen deprivation therapy may help to control prostate cancer that has come back in only a few (up to 5) spots in the body.

Related Conditions:
  • Prostate Carcinoma
Recruiting Status:

Withdrawn

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Androgen Deprivation Therapy and Apalutamide With or Without Radiation Therapy for the Treatment of Biochemically Recurrent Prostate Cancer, RESTART Study
  • Official Title: Phase 2 Response Evaluation of Finite Systemic Therapy With Advanced Androgen Signaling Inhibition and Radiation Therapy for Oligorecurrent Prostate Cancer (RESTART)

Clinical Trial IDs

  • ORG STUDY ID: 2019-1093
  • SECONDARY ID: NCI-2020-02553
  • SECONDARY ID: 2019-1093
  • NCT ID: NCT04585932

Conditions

  • Biochemically Recurrent Prostate Carcinoma
  • Metastatic Prostate Carcinoma
  • Oligometastatic Prostate Carcinoma
  • Stage IV Prostate Cancer AJCC v8
  • Stage IVA Prostate Cancer AJCC v8
  • Stage IVB Prostate Cancer AJCC v8

Interventions

DrugSynonymsArms
ApalutamideARN 509, ARN-509, ARN509, Erleada, JNJ 56021927, JNJ-56021927Group I (apalutamide, leuprolide, degarelix)
DegarelixFE200486, FirmagonGroup I (apalutamide, leuprolide, degarelix)
Leuprolide AcetateA-43818, Abbott 43818, Abbott-43818, Carcinil, Depo-Eligard, Eligard, Enanton, Enantone, Enantone-Gyn, Ginecrin, LEUP, Leuplin, Leuprorelin Acetate, Lucrin, Lucrin Depot, Lupron, Lupron Depot, Lupron Depot-3 Month, Lupron Depot-4 Month, Lupron Depot-Ped, Lutrate, Procren, Procrin, Prostap, TAP-144, Trenantone, Uno-Enantone, ViadurGroup I (apalutamide, leuprolide, degarelix)

Purpose

This phase II trial studies how well androgen deprivation therapy and apalutamide with or without radiation therapy works for the treatment of prostate cancer that has a rise in the blood level of prostate-specific antigen (PSA) and has come back after treatment with surgery or radiation (biochemically recurrent). Androgens can cause the growth of prostate tumor cells. Apalutamide may help fight prostate cancer by blocking the use of androgens by the tumor cells. Androgen deprivation therapy drugs, leuprolide or degarelix, work to lower the amount of androgen in the body, also preventing the tumor cells from growing. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving radiation therapy with apalutamide and androgen deprivation therapy may help to control prostate cancer that has come back in only a few (up to 5) spots in the body.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To assess PSA progression-free survival in both treatment arms.

      SECONDARY OBJECTIVES:

      I. To assess time of recovery of serum testosterone in both treatment arms. II. To assess PSA
      progression-free survival and overall survival following testosterone recovery in both
      treatment arms.

      III. To assess safety of androgen deprivation therapy (ADT) + apalutamide as well as ADT +
      apalutamide in combination radiation therapy.

      IV. To assess the time to first new metastasis or local / pelvic recurrence in both treatment
      arms.

      V. To assess the impact of both treatment arms on quality of life. VI. To assess the impact
      of both treatment arms on metabolic syndrome parameters.

      VII. To assess the impact of both treatment arms on bone density. VIII. To investigate the
      association of changes in repeat advanced imaging with outcome.

      IX. To compare fluciclovine and prostate specific membrane antigen (PSMA) positron emission
      tomography (PET)/computed tomography (CT).

      EXPLORATORY OBJECTIVE:

      I. To identify potential markers of response or resistance to the administered therapies.

      OUTLINE: Patients are randomized to 1 of 2 groups.

      GROUP I: Patients receive apalutamide orally (PO) once daily (QD) on days 1-28 and ADT
      consisting of leuprolide intramuscularly (IM) every 12 weeks or degarelix subcutaneously (SC)
      every 4 weeks. Treatment repeats every 28 days for 12 cycles in the absence of disease
      progression or unacceptable toxicity.

      GROUP II: Patients receive apalutamide PO QD on days 1-28 and ADT consisting of leuprolide IM
      every 12 weeks or degarelix SC every 4 weeks. Treatment repeats every 28 days for 12 cycles
      in the absence of disease progression or unacceptable toxicity. Patients also undergo
      radiation therapy (RT) between cycles 4-7 in the absence of disease progression or
      unacceptable toxicity.

      After completion of study treatment, patients are followed up every 3 and 4 months.
    

Trial Arms

NameTypeDescriptionInterventions
Group I (apalutamide, leuprolide, degarelix)Active ComparatorPatients receive apalutamide PO QD on days 1-28 and ADT consisting of leuprolide IM every 12 weeks or degarelix SC every 4 weeks. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity.
  • Apalutamide
  • Degarelix
  • Leuprolide Acetate
Group II (apalutamide, leuprolide, degarelix, RT)ExperimentalPatients receive apalutamide PO QD on days 1-28 and ADT consisting of leuprolide IM every 12 weeks or degarelix SC every 4 weeks. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo RT between cycles 4-7 in the absence of disease progression or unacceptable toxicity.
  • Apalutamide
  • Degarelix
  • Leuprolide Acetate

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically confirmed prostate cancer

          -  Signed informed consent form (ICF) indicating that the subject understands the purpose
             of, and procedures required for, the study and is willing to participate in the study

          -  Consent to MD Anderson laboratory protocol Lab02-152

          -  Available tumor tissue sample (recently collected +/- archival)

          -  Biochemically recurrent prostate cancer following definitive treatment with radical
             prostatectomy or / and external beam radiation therapy. Patient may have received
             prior androgen deprivation with or without other treatments in the neoadjuvant,
             adjuvant or salvage setting as long as >= 6 months from discontinuation have elapsed
             at the time of randomization

          -  Progression based on the following criteria:

               -  PSA progression: For patients with prior radical prostatectomy (+/- radiation),
                  PSA progression defined by a minimum of two rising PSA levels with an interval of
                  at least 1 week between each determination and a PSA of >= 0.5 ng/ml at
                  screening. For patients with only prior definitive radiation of the prostate, PSA
                  recurrence is defined as PSA >= nadir+2 ng/mL

               -  PSA doubling time of =< 12 months at the time of study entry. Calculation of PSA
                  doubling time should include the use of all available PSA values obtained within
                  past 12 months prior to randomization, with a minimum of 3 values >= 0.1 ng/mL
                  PSA values obtained prior to localized therapy will be excluded. PSA doubling
                  time to be estimated using Memorial Sloan Kettering Cancer Center online
                  calculator

               -  Identification of up to 5 metastatic lesions or/and pelvic node recurrent sites
                  by advanced imaging technology (PSMA PET/CT or fluciclovine PET/CT). In case of
                  inconsistency between the two imaging modalities, up to 5 lesions in the PSMA/PET
                  will be accepted. All sites should be eligible to be treated with definitive
                  intent. At least one of these lesions will be histologically confirmed.
                  Symptomatic metastatic disease or disease impending symptoms (e.g. brain
                  metastasis, painful bone metastasis, and spine disease) can be treated with
                  definitive local therapy prior to enrollment. This lesion will be counted towards
                  the total number of metastatic lesions

          -  Must be able to receive luteinizing hormone-releasing hormone (LHRH) agonist or
             antagonist during the course of the study

          -  Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1

          -  Must be able to swallow tablets

          -  To avoid risk of drug exposure through the ejaculate (even men with vasectomies),
             patients must agree while on study drug and for 3 months following the last dose of
             study drug to:

               -  Use a condom during sexual activity

               -  Not donate sperm

          -  Absolute neutrophil count (ANC) >= 1.0 x 10^9/L

          -  Hemoglobin >= 9.0 g/dL

          -  Platelet count >= 75 x 10^9/L

          -  Serum albumin >= 3 g/dL

          -  Calculated creatinine clearance >= 40 mL/min using the Cockcroft-Gault equation

          -  Serum total bilirubin =<1.5 x upper limit of normal (ULN) or direct bilirubin =< 1.5 x
             ULN (Note: in subjects with Gilbert's syndrome, if total bilirubin is > 1.5 x ULN,
             measure direct and indirect bilirubin, and if direct bilirubin is =< 1.5 x ULN,
             subject may be eligible)

          -  Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =< 3.0 x ULN

          -  Testosterone > 150 ng/dL. For patients treated with ADT with or without short-term
             first generation anti androgens (e.g. bicalutamide) up to 4 weeks prior to
             randomization, a testosterone measurement prior to the ADT treatment will be used to
             determine eligibility, and must have been > 150 ng/dL. If no testosterone level is
             available from before luteinizing hormone-releasing hormone analogue (LHRHa) injection
             and within 6 weeks of randomization, the patient will be ineligible

        Exclusion Criteria:

          -  Histologically confirmed recurrence in a prior definitively irradiated prostate cancer
             field per the judgment of the investigator

          -  Ongoing androgen deprivation therapy (with or without short-term first generation
             anti-androgens) for > 4 weeks at the time of randomization

          -  =< 30 days prior to cycle 1 day 1, patient had:

               -  A transfusion (platelets or red blood cells)

               -  Hematopoietic growth factors

               -  An investigational agent (=< 30 days or 5 half-lives, whichever is longer)

               -  Major surgery

          -  Active hematologic or solid malignancy other than prostate cancer with at least 30%
             chance of recurrence per investigator assessment; (exceptions: adequately treated
             basal cell or squamous cell skin cancer, superficial bladder cancer, or any other
             cancer in situ currently in complete remission)

          -  Known allergies, hypersensitivity, or intolerance to apalutamide or LHRH
             agonist/antagonist or excipients

          -  Current evidence of any of the following:

               -  Uncontrolled hypertension

               -  Gastrointestinal disorder affecting absorption

          -  Corrected QT interval by the Fridericia correction formula (QTcF) > 450 msec on the
             screening electrocardiogram (ECG)

          -  History of clinically significant cardiovascular disease including, but not limited
             to:

               -  Myocardial infarction or unstable angina =< 3 months prior to treatment
                  initiation

               -  Clinically significant cardiac arrhythmia

               -  Pulmonary embolism, stroke =< 3 months prior to treatment initiation

               -  Congestive heart failure (New York Heart Association class III-IV)

          -  Known evidence of an active infection requiring systemic therapy such as human
             immunodeficiency virus (HIV), active hepatitis, or fungal infection

          -  History of seizure disorder

          -  Patients receiving medications known to lower the seizure unless discontinued or
             substituted at least 4 weeks prior to study entry. These medications include:

               -  Aminophylline/theophylline,

               -  Atypical antipsychotics (e.g., clozapine, olanzapine, risperidone, ziprasidone),

               -  Bupropion,

               -  Lithium,

               -  Meperidine and pethidine,

               -  Phenothiazine antipsychotics (e.g., chlorpromazine, mesoridazine, thioridazine),

               -  Tricyclic and tetracyclic antidepressants (e.g., amitriptyline, desipramine,
                  doxepin, imipramine, maprotiline, mirtazapine)

          -  Any contraindication that precludes use or radiotherapy for identified lesion
             treatment per the judgment of the investigator

          -  Any condition for which, in the opinion of the investigator, participation would not
             in the best interest of the subject (e.g., compromise the well-being) or that could
             prevent, limit, or confound the protocol-specified assessments
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:Time to prostate specific antigen (PSA) recurrence
Time Frame:From treatment start with androgen deprivation therapy plus apalutamide until PSA recurrence (> 0.2 ng/ml) for patients who received surgery, or PSA >= nadir+2ng/mL for patients who received only prior definitive radiation of the prostate, up to 4 years
Safety Issue:
Description:Will estimate with the 95% Bayesian credible interval.

Secondary Outcome Measures

Measure:Time to testosterone recovery
Time Frame:From treatment start until testosterone > 150ng/dL, assessed up to 4 years
Safety Issue:
Description:Measured using the Kaplan-Meier method.
Measure:Eugonadal time to PSA recurrence
Time Frame:Up to 4 years
Safety Issue:
Description:Defined as the time to PSA recurrence following testosterone recovery (> 150 ng/dL). Measured using the Kaplan-Meier method.
Measure:Overall survival
Time Frame:Up to 4 years
Safety Issue:
Description:Measured using the Kaplan-Meier method.
Measure:Incidence of adverse events
Time Frame:Up to 4 weeks after last dose of apalutamide
Safety Issue:
Description:Safety data will be summarized by treatment arm, category, grade and attribution. Measured by grade 2 or higher adverse events by Common Terminology Criteria for Adverse Events version 5.0.
Measure:Time to first new metastasis or local/pelvic recurrence
Time Frame:Up to 4 years
Safety Issue:
Description:
Measure:Patient reported outcomes (PRO)
Time Frame:Up to 4 years
Safety Issue:
Description:Patient reported outcomes assessed using the following questionnaires EuroQOL 5 Dimensional Questionnaire (EQ-5D-5L) - EuroQOL 5 Dimensional Questionnaire (EQ-5D-5L); Outcome measure is the index value. Range: -0.573 to 1.
Measure:Patient reported outcomes (PRO)
Time Frame:Up to 4 years
Safety Issue:
Description:Patient reported outcomes assessed using the following questionnaires European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLC-C30): Outcome measure is a raw score, ranging from 0-100.
Measure:Patient reported outcomes (PRO)
Time Frame:Up to 4 years
Safety Issue:
Description:Patient reported outcomes assessed using the following questionnaires European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire EORTC QLQ-ELD14 Outcome measure is a raw score, ranging from 0-100
Measure:Patient reported outcomes (PRO)
Time Frame:Up to 4 years
Safety Issue:
Description:Patient reported outcomes assessed using the following questionnaires Expanded Prostate Cancer Index Composite (EPIC-26): Results are presented in a standardized 0-100 scale.
Measure:Metabolic syndrome changes
Time Frame:Up to 4 years
Safety Issue:
Description:Laboratory parameters that will be measured during screening and active treatment (Lipid panel, blood sugar, HbA1c, Vitamin D, TSH, Testosterone, c-peptide, leptin) as well as measurements of weight and height and bone density measurement results will be used to evaluate changes in parameters predisposing to metabolic syndrome. .Laboratory parameters that will be measured during screening and active treatment (Lipid panel, blood sugar, HbA1c, Vitamin D, TSH, Testosterone, c-peptide, leptin) as well as measurements of weight and height and bone density measurement results
Measure:Change in bone density
Time Frame:Up to 4 years
Safety Issue:
Description:The results from bone density scanning (DXA scan) will be used to evaluate changes in bone density in the patient population
Measure:Imaging changes
Time Frame:Up to 4 years
Safety Issue:
Description:Association of changes between baseline and repeat advanced imaging with outcome will be performed, as well as comparison between fluciclovine and PSMA PET/CT modalities, including detection rates and correlation of detected disease volume at baseline with outcome. These changes will be evaluated in correlation with molecular characteristics explored through interrogation of archival and recurrent tissue samples , exosome, steroid and androgen metabolism. Association of changes between baseline and repeat advanced imaging with outcome will be performed, as well as comparison between fluciclovine and PSMA PET/CT modalities, including detection rates and correlation of detected disease volume at baseline with outcome. These changes will be evaluated in correlation with molecular characteristics explored through interrogation of archival and recurrent tissue samples , exosome, steroid and androgen metabolism.
Measure:Fluciclovine positron emission tomography/computed tomography (PET/CT) modality assessment
Time Frame:Up to cycle 4, day 1 (each cycle = 28 days)
Safety Issue:
Description:Will estimate lesion detection rate based on fluciclovine and prostate-specific membrane antigen (PSMA) PET/CT modalities and the agreement between fluciclovine and PSMA PET/CT results will be assessed through McNemar test.
Measure:PSMA PET/CT modality assessment
Time Frame:Up to cycle 4, day 1 (each cycle = 28 days)
Safety Issue:
Description:Will estimate lesion detection rate based on fluciclovine and PSMA PET/CT modalities and the agreement between fluciclovine and PSMA PET/CT results will be assessed through McNemar test.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated

October 6, 2020