Clinical Trials /

Treating Prostate Cancer That Has Come Back After Surgery With Apalutamide and Targeted Radiation Using PET/CT Imaging

NCT04423211

Description:

This phase III trial compares the addition of apalutamide, with or without targeted radiation therapy, to standard of care treatment versus standard of care treatment alone in patients with prostate cancer biochemical recurrence (a rise in the blood level of prostate-specific antigen [PSA] after treatment with surgery or radiation). Diagnostic procedures, such as positron emission tomography/computed tomography (PET/CT), may help doctors look for cancer that has spread to the pelvis. Androgens can cause the growth of prostate cancer cells. Apalutamide may help fight prostate cancer by blocking the use of androgens by the tumor cells. Targeted radiation therapy uses high energy rays to kill tumor cells and shrink tumors that have spread. This trial may help doctors determine if using PET/CT results to deliver more tailored treatment (i.e., adding apalutamide, with or without targeted radiation therapy, to standard of care treatment) works better than standard of care treatment alone in patients with biochemical recurrence of prostate cancer.

Related Conditions:
  • Prostate Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Treating Prostate Cancer That Has Come Back After Surgery With Apalutamide and Targeted Radiation Using PET/CT Imaging
  • Official Title: Phase III Study of PET-Directed Local or Systemic Therapy Intensification in Prostate Cancer Patients With Post-Prostatectomy Biochemical Recurrence

Clinical Trial IDs

  • ORG STUDY ID: EA8191
  • SECONDARY ID: NCI-2020-02686
  • SECONDARY ID: EA8191
  • SECONDARY ID: EA8191
  • SECONDARY ID: U10CA180820
  • NCT ID: NCT04423211

Conditions

  • Biochemically Recurrent Prostate Carcinoma
  • Prostate Adenocarcinoma

Interventions

DrugSynonymsArms
ApalutamideARN 509, ARN-509, ARN509, Erleada, JNJ 56021927, JNJ-56021927Arm B (EBRT, goserelin, leuprolide, apalutamide)
Goserelin AcetateZDX, ZoladexArm A (EBRT, goserelin, leuprolide)
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, ViadurArm A (EBRT, goserelin, leuprolide)

Purpose

This phase III trial compares the addition of apalutamide, with or without targeted radiation therapy, to standard of care treatment versus standard of care treatment alone in patients with prostate cancer biochemical recurrence (a rise in the blood level of prostate-specific antigen [PSA] after treatment with surgery or radiation). Diagnostic procedures, such as positron emission tomography/computed tomography (PET/CT), may help doctors look for cancer that has spread to the pelvis. Androgens can cause the growth of prostate cancer cells. Apalutamide may help fight prostate cancer by blocking the use of androgens by the tumor cells. Targeted radiation therapy uses high energy rays to kill tumor cells and shrink tumors that have spread. This trial may help doctors determine if using PET/CT results to deliver more tailored treatment (i.e., adding apalutamide, with or without targeted radiation therapy, to standard of care treatment) works better than standard of care treatment alone in patients with biochemical recurrence of prostate cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. For patients without PET-evidence of extrapelvic metastases, to evaluate whether the
      addition of enhanced systemic therapy to standard of care (SOC) salvage radiation therapy
      (RT) could prolong progression-free survival (PFS).

      II. For patients with PET-evidence of extrapelvic metastases, to evaluate whether the
      addition of metastasis-directed RT to enhanced systemic therapy and SOC salvage RT could
      prolong PFS.

      SECONDARY OBJECTIVES:

      I. To evaluate overall survival (OS) in each arm. II. To evaluate event-free survival (EFS)
      in each arm. III. To evaluate time to prostate-specific antigen (PSA) progression using
      Prostate Cancer Working Group (PCWG) 2 criteria in each arm.

      IV. To assess the incidence of adverse events with the addition of enhanced systemic therapy
      in patients without PET-evidence of extrapelvic metastases.

      V. To assess the incidence of adverse events with local ablative metastasis-directed RT for
      PET-positive metastatic disease in patients with PET-evidence of extrapelvic metastases.

      VI. To estimate the detection rate of PET/CT at the patient and regional level, and to
      evaluate its concordance with the follow-up Food and Drug Administration (FDA)-approved
      conventional imaging modalities (CIM) considered standard-of-care per institution, including
      CT, bone scintigraphy, magnetic resonance imaging (MRI) and PET imaging performed as PET/CT
      and/or PET/MR using 11C-choline and/or 18F-sodium fluoride.

      VII. To determine the distribution of PET-positive lesions among anatomic sites (prostate
      fossa, intrapelvic soft tissue/lymph node, extrapelvic soft tissue/lymph node, and bone
      metastases) in patients with post-radical prostatectomy (RP) biochemical recurrence (BCR),
      correlated with PSA (level, doubling time, velocity) and other relevant clinical parameters.

      VIII. To determine the value of repeat PET at 12 months (PET2) to assess response to therapy
      (enhanced systemic therapy +/- focal RT and/or androgen deprivation therapy [ADT]) compared
      to standard response assessments (PSA and CIM).

      OUTLINE:

      STEP 0: Patients receive fluciclovine F18 intravenously (IV) and undergo SOC PET/CT scan at
      baseline. NOTE: Patients randomized to Arms C or D below undergo a repeat fluciclovine F18
      PET/CT at time of second PSA recurrence or 12 months after completion of enhanced systemic
      therapy.

      STEP 1: Patients are randomized to 1 of 4 arms based on results of fluciclovine F18 PET/CT in
      Step 0.

      ARM A (PET NEGATIVE FOR EXTRA PELVIC-METASTASES): Patients undergo SOC external beam
      radiation therapy (EBRT) for 6 months. Patients also receive goserelin acetate subcutaneously
      (SC) or leuprolide acetate intramuscularly (IM) for 6 months starting up to 3 months prior to
      EBRT but no later than the first fraction of EBRT. All treatment continues for 6 months in
      the absence of disease progression or unacceptable toxicity.

      ARM B (PET NEGATIVE FOR EXTRA PELVIC-METASTASES): Patients undergo SOC EBRT and receive
      goserelin acetate SC or leuprolide acetate IM as in Arm A. Patients also receive apalutamide
      orally (PO) once daily (QD) for 6 months in the absence of disease progression or
      unacceptable toxicity.

      ARM C: (PET POSITIVE FOR EXTRA PELVIC-METASTASES): Patients undergo SOC EBRT and receive
      goserelin acetate SC or leuprolide acetate IM as in Arm A. Patients also receive apalutamide
      PO QD as in Arm B.

      ARM D (PET POSITIVE FOR EXTRA PELVIC-METASTASES): Patients undergo SOC EBRT and receive
      goserelin acetate SC or leuprolide acetate IM as in Arm A and apalutamide PO QD as in Arm B.
      Patients also undergo stereotactic body radiation therapy (SBRT) or 3-dimensional (3D)
      conformal radiation therapy (CRT), intensity-modulated radiation therapy (IMRT) (including
      volume modulated arc therapy [VMAT]), and intensity-modulated proton therapy (IMPT) over 3-5
      fractions in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 3 months for years 1-3
      and then every 6 months for years 4-5.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (EBRT, goserelin, leuprolide)Active ComparatorSTEP 0: Patients receive fluciclovine F18 IV and undergo SOC PET/CT scan at baseline. STEP 1: Patients who are PET negative for extra pelvic metastases undergo SOC EBRT for 6 months. Patients also receive goserelin acetate SC or leuprolide acetate IM for 6 months starting up to 3 months prior to EBRT but no later than the first fraction of EBRT. All treatment continues for 6 months in the absence of disease progression or unacceptable toxicity.
  • Goserelin Acetate
  • Leuprolide Acetate
Arm B (EBRT, goserelin, leuprolide, apalutamide)ExperimentalSTEP 0: Patients receive fluciclovine F18 IV and undergo SOC PET/CT scan at baseline. STEP 1: Patients who are PET negative for extra pelvic metastases undergo SOC EBRT and receive goserelin acetate SC or leuprolide acetate IM as in Arm A. Patients also receive apalutamide PO QD for 6 months in the absence of disease progression or unacceptable toxicity.
  • Apalutamide
  • Goserelin Acetate
  • Leuprolide Acetate
Arm C (EBRT, goserelin, leuprolide, apalutamide)ExperimentalSTEP 0: Patients receive fluciclovine F18 IV and undergo SOC PET/CT scan at baseline. NOTE: Patients randomized to Arm C undergo a repeat fluciclovine F18 PET/CT at time of second PSA recurrence or 12 months after completion of enhanced systemic therapy. STEP 1: Patients who are PET positive for extra pelvic metastases undergo SOC EBRT and receive goserelin acetate SC or leuprolide acetate IM as in Arm A. Patients also receive apalutamide PO QD as in Arm B.
  • Apalutamide
  • Goserelin Acetate
  • Leuprolide Acetate
Arm D (EBRT, goserelin, leuprolide, apalutamide, RT)ExperimentalSTEP 0: Patients receive fluciclovine F18 IV and undergo SOC PET/CT scan at baseline. NOTE: Patients randomized to Arm D undergo a repeat fluciclovine F18 PET/CT at time of second PSA recurrence or 12 months after completion of enhanced systemic therapy. STEP 1: Patients who are PET positive for extra pelvic metastases undergo SOC EBRT and receive goserelin acetate SC or leuprolide acetate IM as in Arm A and apalutamide PO QD as in Arm B. Patients also undergo SBRT or 3D CRT, IMRT (including VMAT), and IMPT over 3-5 fractions in the absence of disease progression or unacceptable toxicity.
  • Apalutamide
  • Goserelin Acetate
  • Leuprolide Acetate

Eligibility Criteria

        Inclusion Criteria:

          -  STEP 0: REGISTRATION ELIGIBILITY CRITERIA

          -  Patient must have had a radical prostatectomy (RP) as definitive therapy for
             histopathologically-proven prostatic adenocarcinoma

          -  Patient must have biochemical recurrence (BCR) after RP, with rising PSA defined as
             follows:

               -  If time to biochemical recurrence, (defined as time to first detectable PSA after
                  RP) is < 12 months, a minimum PSA level of >= 0.2 ng/mL and a confirmatory
                  reading of >= 0.2 ng/mL is required, per the American Urological Association
                  (AUA) definition (this includes patients with a persistent PSA reading of at
                  least 0.2 ng/mL)

               -  If time to biochemical recurrence, (defined as time to first detectable PSA after
                  RP) is >= 12 months, a minimum absolute PSA of 0.5 ng/mL is required

                    -  NOTE: Qualifying PSA values per above must be collected at least 4 weeks
                       after RP, with confirmatory persistent or elevated PSA collected at any
                       subsequent time point

          -  Patient must be negative or equivocal for extrapelvic metastatic disease by
             conventional imaging modalities (CIM) (i.e., bone scans, pelvic CT, or pelvic MRI),
             which must be done within 10-12 weeks prior to registration. Extra-pelvic metastases
             is defined as any osseous metastases and/or any extrapelvic soft tissue, lymph nodes
             and organ metastases; extra-pelvic is defined as superior to common iliac bifurcation,
             outside of standard prostate bed + whole pelvis nodal RT fields

          -  Baseline PET/CT scan (PET1) are eligible for this study if the SOC PET scan using
             18F-fluciclovine (Axumin) is completed during step 0 registration or up to 12 weeks
             prior to step 0 registration. The PET/CT scanners must meet scanner qualifications and
             scans must have an interpretation (or confirmation of an institutional clinical read)
             by a nuclear medicine physician or radiologist who has undergone 18F-fluciclovine
             (Axumin) reader training

          -  Patient must be a candidate for standard-of-care (SOC) post-prostatectomy radiation
             therapy (RT) to the prostate bed and pelvic nodes with androgen deprivation therapy
             (adjuvant)

          -  Patient must have the ability to provide written informed consent

          -  Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status 0-2

          -  Patient must be able to lie flat and still for approximately 20-30 minutes or
             otherwise tolerate a PET/CT scan and radiation treatment planning and delivery

          -  Patient must be at a participating institution, which has agreed to perform the
             imaging research studies, completed the ECOG-American College of Radiology Imaging
             Network (ACRIN) defined PET/CT scanner qualification procedures and received
             ECOG-ACRIN PET/CT scanner approval

          -  Leukocytes >= 3,000/mcL (obtained within 4 weeks prior to registration)

          -  Absolute neutrophil count >= 1,500/mcL (obtained within 4 weeks prior to registration)

          -  Platelets >= 100,000/mcL (obtained within 4 weeks prior to registration)

          -  Total bilirubin =< institutional upper limit of normal (ULN) (obtained within 4 weeks
             prior to registration)

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 2.5 x institutional ULN (obtained within 4 weeks prior to registration)

          -  Glomerular filtration rate (GFR) > 35 mL/min estimated by Cockcroft-Gault or measured
             directly by 24 hour urine creatinine (obtained within 4 weeks prior to registration)

          -  Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
             therapy with undetectable viral load within 6 months are eligible for this trial

          -  For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral
             load must be undetectable on suppressive therapy, if indicated

          -  Patients with a history of hepatitis C virus (HCV) infection must have been treated
             and cured. For patients with HCV infection who are currently on treatment, they are
             eligible if they have an undetectable HCV viral load

          -  Patients with known history or current symptoms of cardiac disease, or history of
             treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac
             function using the New York Heart Association Functional Classification. To be
             eligible for this trial, patients should be class I or II (by patient symptoms) or A
             or B (by objective assessment)

          -  STEP 1: RANDOMIZATION ELIGIBILITY CRITERIA

          -  Patient must have completed a baseline SOC PET scan (PET1) with results of
             extra-pelvic metastases involvement known (positive or negative)

          -  For patients with negative extra-pelvic metastases, PET-imaging status of intra-pelvic
             nodes must be known (positive or negative)

          -  For patients with positive extra-pelvic metastases (defined as any PET positive
             lesions outside of standard salvage RT fields [prostate bed +/- typical whole
             pelvis]), the number of extra-pelvic lesions must be known (=< 5 or > 5 pelvic
             lesions)

        Exclusion Criteria:

          -  Patient must not have started androgen deprivation therapy for biochemical recurrence
             prior to baseline study PET/CT imaging

          -  Patient must not be enrolled in another therapeutic clinical trial

          -  Patient must not have any other malignancy within the last 2 years, other than
             superficial bladder cancer and skin basal cell carcinoma or cutaneous superficial
             squamous cell carcinoma that has not metastasized

          -  Patient must not have history of seizures or known condition that may cause
             predisposal to seizures (e.g., stroke or head trauma resulting in loss of
             consciousness) within 1 year of registration

          -  Patient must not have history of inflammatory bowel disease as this would increase
             risk of complication from radiotherapy or any gastrointestinal disorder affecting
             absorption

          -  Patient must not have had prior radiation therapy
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-free survival (PFS)
Time Frame:From randomization to radiographic progression by conventional imaging, symptomatic disease or death, whichever occurs first, assessed up to 10 years
Safety Issue:
Description:The power of the PFS analysis is 85% using one-sided 0.025 level stratified logrank test. The overall type I error will be controlled using an O'Brien-Fleming boundary function

Secondary Outcome Measures

Measure:Overall survival (OS)
Time Frame:From randomization to death or date last known alive, assessed up to 10 years
Safety Issue:
Description:Will be characterized by the method of Kaplan and Meier and a logrank test will be used to compare OS between the two arms in each cohort.
Measure:Event-free survival
Time Frame:From randomization to radiographic progression by conventional imaging, PET progression in the setting of rising PSA, symptomatic disease, initiation of new treatment for the disease or death, whichever occurs first, assessed up to 10 years
Safety Issue:
Description:Will be characterized by the method of Kaplan and Meier and a logrank test will be used to compare EFS between the two arms in each cohort.
Measure:Time to prostate-specific antigen (PSA) progression
Time Frame:From randomization to documented PSA progression or last disease assessment that shows free of PSA progression, assessed up to 10 years
Safety Issue:
Description:Will be characterized by the method of Kaplan and Meier and a logrank test will be used to compare time to PSA progression between the two arms in each cohort.
Measure:Incidence of adverse events
Time Frame:Up to 10 years
Safety Issue:
Description:Toxicity will be defined using the Common Terminology Criteria for Adverse Events.
Measure:Detection rate of fluciclovine F18 (18F-fluciclovine) PET/computed tomography (CT)
Time Frame:At time of PSA recurrence or 12 months after completion of enhanced systemic therapy (whichever occurs first), assessed up to 10 years
Safety Issue:
Description:For the detection rate, the proportion of baseline standard of care 18F-fluciclovine PET/CT (PET1) positive results at the patient and regional (prostate fossa, intrapelvic soft tissue/lymph node, extrapelvic soft tissue/lymph node, and bone metastases) level will be calculated and its 95% confidence interval will be estimated using the Exact method based on the binomial distribution.
Measure:Concordance of detection rate with the follow-up conventional imaging modalities (CIM)
Time Frame:At time of PSA recurrence or 12 months after completion of enhanced systemic therapy (whichever occurs first), assessed up to 10 years
Safety Issue:
Description:Will use Cohen's Kappa coefficient to measure the agreement between dichotomized PET/CT results and the dichotomized CIM results. Baseline CIM comparison will not be performed because as per our study eligibility criteria, baseline CIM will be negative for metastases.
Measure:Distribution of 18F-fluciclovine PET-positive lesions among anatomic sites
Time Frame:Baseline
Safety Issue:
Description:The rate of 18F-fluciclovine PET-positive lesions will be reported for each anatomic site, including prostate fossa, intrapelvic soft tissue/lymph node, extrapelvic soft tissue/lymph node, and bone metastases. Their confidence intervals will be estimated using the Exact method for the binomial distribution. To evaluate if PSA (level, doubling time, velocity) and other relevant clinical parameters affects the positivity distribution, will use the logistic regression to model with the binary outcome (positive vs. negative from PET/CT) and covariates will include anatomic site, PSA, and other clinical parameters. Will test the interactions between anatomic site and PSA (plus other clinical parameters) to see if the positivity distribution across anatomic site may change according to the levels of the interacted terms. Will use the technique of generalized estimating equation to account for the outcome correlations within subjects.
Measure:Value of repeat PET to assess response to therapy compared to standard response assessments
Time Frame:At time of PSA recurrence or 12 months after completion of enhanced systemic therapy (whichever occurs first), assessed up to 10 years
Safety Issue:
Description:Analyses will be conducted to evaluate qualitative visual evidence of 18F-fluciclovine PET positive metastatic lesions and quantitative PET standardized-uptake value (SUV) changes on a lesion-to-lesion basis from 18F-fluciclovine PET1 (baseline) to PET2 on visually determined sites of recurrence and metastatic disease. This will be compared to reference standard-of-care conventional imaging (Prostate Cancer Working Group 2 criteria) and PSA response at PET2 time point to determine PET2 response to therapy. PET2 visual and quantitative assessment will also be compared to PFS in the time-to-event analysis using a log-rank test (PET2 visual assessment) and a Cox proportional hazards regression (PET2 quantitative assessment). PET SUV parameters to be obtained at PET1 and PET2 will include SUVmax, SUVpeak. PET SUV change from PET1 to PET2 will include absolute SUVmax and SUVpeak change (PET2-PET1) and percent change of SUVmax and SUVpeak (% change = 100*[(PET2-PET1)/PET1]).)

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:ECOG-ACRIN Cancer Research Group

Last Updated

October 8, 2020