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Radiation Therapy With or Without Apalutamide in Treating Patients With Stage III-IV Prostate Cancer

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ClinicalTrials.gov Identifier: NCT03371719
Recruitment Status : Recruiting
First Posted : December 13, 2017
Last Update Posted : February 11, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
NRG Oncology

Brief Summary:
This phase II trial studies how well radiation therapy with or without apalutamide works in treating patients with stage III-IV prostate cancer. Radiation therapy uses high energy x-ray to kill tumor cells and shrink tumors. Androgen can cause the growth of prostate cancer cells. Drugs, such as apalutamide, may lessen the amount of androgen made by the body. Giving radiation therapy and apalutamide may work better at treating prostate cancer than radiation alone.

Condition or disease Intervention/treatment Phase
PSA Progression Stage III Prostate Adenocarcinoma Stage IV Prostate Adenocarcinoma Drug: Apalutamide Radiation: External Beam Radiation Therapy Other: Placebo Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine whether, in men with post-prostatectomy PSA recurrences, salvage radiation (SRT) with enhanced anti-androgen therapy with apalutamide will improve biochemical progression-free survival (bPFS) compared to SRT alone.

SECONDARY OBJECTIVES:

I. To assess whether molecular stratification by the PAM50 gene expression clustering will identify subsets of prostate cancer (luminal A or basal, luminal B) which derive the greatest benefit from anti-androgen therapy.

II. To assess overall survival. III. To assess cancer-specific mortality. IV. To assess metastasis-free survival. V. To assess distant metastasis. VI. To assess local-regional progression. VII. To assess PSA nadir during first year of treatment and prior to initiation of any hormonal salvage therapy.

VIII. To assess initiation of salvage hormonal therapy. IX. To assess PSA with a non-castrate testosterone at 1 and 3 years post randomization: PSA < 0.1 ng/ml and testosterone >= 50 ng/dl.

X. To assess acute and late physician-reported morbidity (per the Common Terminology Criteria for Adverse Events [CTCAE] version 5) after SRT +/- apalutamide.

XI. To assess acute and late patient-reported morbidity (per the patient reported outcomes [PRO]-CTCAE) after SRT +/- apalutamide.

XII. To assess testosterone levels at 3, 6, 9, 12, and 36 months post randomization.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM 1: Patients undergo external beam radiation therapy on Day 1 for 7.5 weeks. Beginning on Day 1 of radiation therapy, patients receive placebo orally (PO) once daily (QD) on days 1-30. Treatment repeats every 30 days for up to 6 courses (6 months) in the absence of disease progression or unacceptable toxicity.

ARM 2: Patients undergo external beam radiation therapy on Day 1 for 7.5 weeks. Beginning on Day 1 of radiation therapy, patients receive apalutamide PO QD on Days 1-30. Treatment repeats every 30 days for up to 6 courses (6 months) in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years, then every 6 months for 3 years, and then yearly thereafter.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 324 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Phase II, Double-Blinded, Placebo Controlled Randomized Trial of Salvage Radiotherapy With or Without Enhanced Anti-androgen Therapy With Apalutamide in Recurrent Prostate Cancer
Actual Study Start Date : April 27, 2018
Estimated Primary Completion Date : February 16, 2024
Estimated Study Completion Date : October 31, 2028

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Prostate Cancer
Drug Information available for: Apalutamide

Arm Intervention/treatment
Placebo Comparator: Arm 1 (Radiation Therapy + Placebo)
Patients undergo external beam radiation therapy on Day 1 for 7.5 weeks. Beginning on Day 1 of radiation therapy, patients receive placebo PO QD on Days 1-30. Treatment repeats every 30 days for up to 6 courses (6 months) in the absence of disease progression or unacceptable toxicity.
Radiation: External Beam Radiation Therapy
Undergo external beam radiation therapy
Other Names:
  • Definitive Radiation Therapy
  • EBRT
  • External Beam Radiotherapy
  • External Beam RT
  • external radiation
  • External Radiation Therapy
  • external-beam radiation

Other: Placebo
Given PO
Other Names:
  • placebo therapy
  • PLCB
  • sham therapy

Experimental: Arm 2 (Radiation Therapy + Apalutamide)
Patients undergo external beam radiation therapy on Day 1 for 7.5 weeks. Beginning on Day 1 of radiation therapy, patients receive apalutamide PO QD on Days 1-30. Treatment repeats every 30 days for up to 6 courses (6 months)in the absence of disease progression or unacceptable toxicity.
Drug: Apalutamide
Given PO
Other Names:
  • ARN 509
  • ARN-509
  • ARN509
  • JNJ 56021927
  • JNJ-56021927

Radiation: External Beam Radiation Therapy
Undergo external beam radiation therapy
Other Names:
  • Definitive Radiation Therapy
  • EBRT
  • External Beam Radiotherapy
  • External Beam RT
  • external radiation
  • External Radiation Therapy
  • external-beam radiation




Primary Outcome Measures :
  1. Biochemical Progression-free survival (bPFS) [ Time Frame: From randomization to the first occurrence of a rise in PSA, clinical or radiographic local, regional, or distant metastases, or death from any cause, assessed up to 6 years ]
    bPFS curves will be estimated by the Kaplan-Meier (1958) method and compared between the two treatment arms using a one-sided logrank test at the alpha = 0.12 significance level. Analysis will include evaluation of a potential predictive biomarker (molecular subtype) to inform the design of a subsequent, phase III clinical trial. In addition, a multivariable Cox (1972) regression model will be fit incorporating the three stratification factors used in the randomization (surgical margins, pre-salvage radiation (SRT) PSA, and molecular subtype) as covariates to estimate the adjusted hazard ratio (HR) between the two treatment groups. Additional regression models will be fit including other pretreatment characteristics as covariates.


Secondary Outcome Measures :
  1. Acute Patient-Reported Morbidity (per the patient reported outcomes [PRO]- Common Terminology Criteria for Adverse Events [CTCAE]) [ Time Frame: Up to 30 days after radiation therapy ]
    Adverse events will also be assessed using PRO-CTCAE items. Assessments will be collected before and at the end of radiotherapy treatment and in follow-up. For each symptom and each domain (i.e., frequency, severity, and interference), counts and frequencies will be provided for the worst score experienced by the patient by treatment arm. The proportion of patients with scores >= 1 and >= 3 will be compared between groups using a chi-square test, or Fisher's exact test if cell frequencies are < 5.

  2. Acute Physician-Reported Morbidity (per the Common Terminology Criteria for Adverse Events [CTCAE] version 5) [ Time Frame: Up to 30 days after radiation therapy ]
    Adverse events will be scored according to the National Cancer Institute (NCI)'s CTCAE version 5.0. For each type of adverse event, frequencies will be provided for the worst grade experienced by the patient by treatment arm. The proportion of patients with grades >= 1 and >= 3 will be compared between groups using a chi-square test, or Fisher's exact test.

  3. Late Patient-Reported Morbidity (per the patient reported outcomes [PRO]- Common Terminology Criteria for Adverse Events [CTCAE]) [ Time Frame: From the end of radiation therapy + 30 days up to 6 years ]
    Adverse events will also be assessed using PRO-CTCAE items. Assessments will be collected before and at the end of radiotherapy treatment and in follow-up. For each symptom and each domain (i.e., frequency, severity, and interference), counts and frequencies will be provided for the worst score experienced by the patient by treatment arm. The proportion of patients with scores >= 1 and >= 3 will be compared between groups using a chi-square test, or Fisher's exact test if cell frequencies are < 5.

  4. Late Physician-Reported Morbidity (per the Common Terminology Criteria for Adverse Events [CTCAE] version 4) defined as grade 3+ adverse events occurring more than 30 days after the completion of radiation therapy [ Time Frame: From the end of radiation therapy + 30 days to the time of the first recorded late grade 3+ adverse event, assessed up to 6 years ]
    Adverse events will be scored according to the NCI's CTCAE version 5.0. For each type of adverse event, counts and frequencies will be provided for the worst grade experienced by the patient by treatment arm. The proportion of patients with grades >= 1 and >= 3 will be compared between groups using a chi-square test, or Fisher's exact test.

  5. Cancer-Specific Mortality (CSM) [ Time Frame: From the date of randomization to the date of death due to prostate cancer, assessed up to 6 years ]
    CSM will be estimated by the Kaplan-Meier method and compared between treatment arms via the logrank test. Patients dying from other causes will be censored as of the date of death. Cox regression will be used to obtain HRs for this outcome, both unadjusted and adjusted for covariates. A competing risks analysis will also be performed treating death from prostate cancer and death from all other causes as competing risks. Cumulative incidence curves will be generated (Gooley et al., 1999; Dignam et al., 2004) along with 95% confidence intervals and compared between the two treatment arms using Gray's method (Gray, 1988).

  6. Distant Metastasis [ Time Frame: Up to 6 years ]
    Will also be analyzed under a competing risks framework, treating death without experiencing the event in question as a competing risk.

  7. Initiation of Salvage Hormonal Therapy [ Time Frame: Up to 6 years ]
    Will also be analyzed under a competing risks framework, treating death without experiencing the event in question as a competing risk.

  8. Local-Regional Progression [ Time Frame: From randomization to local or regional recurrence, assessed up to 6 years ]
    Will also be analyzed under a competing risks framework, treating death without experiencing the event in question as a competing risk.

  9. Metastasis-Free Survival (MFS) [ Time Frame: From randomization until distant metastasis (clinical and/or radiographic appearance of disseminated disease) or death from any cause, assessed up to 6 years ]
    MFS will be estimated by the Kaplan-Meier method and compared between treatment arms via the logrank test. Cox regression will be used to obtain HRs for this outcome, both unadjusted and adjusted for covariates.

  10. Overall survival (OS) [ Time Frame: From randomization until death from any cause, assessed up to 6 years ]
    OS will be estimated by the Kaplan-Meier method and compared between treatment arms via the logrank test. Cox regression will be used to obtain HRs for this outcome, both unadjusted and adjusted for covariates.

  11. PSA Nadir During First Year of Treatment and Prior to Initiation of any Hormonal Salvage Therapy [ Time Frame: During first year of treatment ]
    Will be compared between the two groups using a two-sample t-test.

  12. Testosterone Levels [ Time Frame: Every 3 months until 36 months post randomization ]
    Testosterone levels over time will be assessed using mixed effects regression modeling.

  13. Undetectable PSA with a Non-Castrate Testosterone (PSA < 0.1 ng/ml and testosterone >= 50 ng/dl) [ Time Frame: 1 year ]
    The proportion of patients with undetectable PSA and non-castrate testosterone level will be compared between the two treatment arms using chi square tests.

  14. Undetectable PSA with a Non-Castrate testosterone (PSA < 0.1 ng/ml and testosterone >= 50 ng/dl)) [ Time Frame: 3 years ]
    The proportion of patients with undetectable PSA and non-castrate testosterone level will be compared between the two treatment arms using chi square tests.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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

Inclusion Criteria:

  • Pathologically (histologically) proven diagnosis of prostate adenocarcinoma; prostatectomy must have been performed within 10 years prior to Step 1 registration and any type of radical prostatectomy is permitted, including retropubic, perineal, laparoscopic or robotically assisted
  • Post-prostatectomy patients with a detectable serum PSA (≥ 0.1, but ≤ 1.0 ng/mL) at study entry (within 90 days of Step 1 registration) and at least one of the following:

    • Gleason score 7-10 (International Society of Urological Pathology [ISUP] grade group 2 to 5)
    • ISUP grade group:

      • Grade Group 1: Gleason score ≤ 6,
      • Grade Group 2: Gleason score 3 + 4 = 7,
      • Grade Group 3: Gleason score 4 + 3 = 7,
      • Grade Group 4: Gleason score 8,
      • Grade Group 5: Gleason scores 9 and 10
    • >= T3a disease
    • Persistent elevation of PSA after prostatectomy measured within 90 days after surgery (PSA never became undetectable) of > 0.04 but < 0.2 ng/mL (PSA nadir)
  • pN0 or pNx
  • History/physical examination within 90 days prior to Step 1 registration
  • Karnofsky performance status of 70-100 within 90 days prior to Step 1 registration
  • Surgical formalin-fixed paraffin-embedded (FFPE) specimen must be available for submission to GenomeDx for genomic analysis on Decipher GRID platform; Note: if Decipher results have already been obtained, in lieu of tissue, results must be submitted to GenomeDx for validation
  • Prior androgen deprivation therapy (luteinizing hormone-releasing hormone [LHRH] agonist and/or non-steroidal anti-androgen) is allowed if discontinued at least 90 days prior to Step 1 registration and given for ≤ 90 days duration

    • For example: patients on prior LHRH analogs (post-prostatectomy), the discontinuation date should be calculated based on the expected duration of the sustained release injection, not simply the injection date of the drug; for instance, if a 22.5 mg sustained release dose of leuprolide acetate is given (3 month duration), then the expected duration of such a dose would be 90 days after the injection date; for a 7.5 mg leuprolide (1 month duration), the discontinuation date would be 30 days after the injection date
    • Please note: finasteride or dutasteride must be stopped before treatment starts but prior usage will not affect eligibility
  • Hemoglobin ≥ 9.0 g/dL, independent of transfusion and/or growth factors within 90 days prior to Step 1 registration
  • Platelet count ≥ 100,000 x 10^9/uL independent of transfusion and/or growth factors within 90 days prior to step 1 registration
  • Serum albumin ≥ 3.0 g/dL within 90 days prior to Step 1 registration
  • Glomerular filtration rate (GFR) ≥ 35 mL/min estimated by Cockcroft-Gault or measured directly by 24 hour urine creatinine within 90 days prior to Step 1 registration
  • Serum total bilirubin ≤ 1.5 x upper limit of normal (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 is eligible) within 90 days prior to Step 1 registration
  • Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 2.5 x ULN within 90 days prior to Step 1 registration
  • Testosterone > 50 ng/dL within 90 days prior to Step 1 registration
  • Concomitant medications known to lower the seizure threshold discontinued or substituted at least 4 weeks (30 days) prior to Step 1 registration.
  • The patient must agree 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 agree 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
  • The patient must agree not to donate sperm during the study treatment and for 3 months after receiving the last dose of study drug
  • The patient or a legally authorized representative must provide study-specific informed consent prior to study entry

Exclusion Criteria:

  • Definitive clinical, radiologic, or pathologic evidence of metastatic disease (M1) or lymph node involvement (N1)
  • Prior invasive malignancy (except non-melanomatous skin cancer, carcinoma in situ of the male breast, penis, oral cavity, or stage Ta of the bladder, or stage I completely resected melanoma) unless disease free for a minimum of 2 years
  • Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different cancer is allowable
  • Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields
  • History of any of the following:

    • Seizure or known condition that may pre-dispose to seizure (e.g. prior stroke within 1 year prior to Step 1 registration)
    • History of documented inflammatory bowel disease
    • Transmural myocardial infarction within the last 4 months prior to Step 1 registration.
    • Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months prior to Step 1 registration
    • History of any condition that in the opinion of the investigator, would preclude participation in this study
  • Current evidence of any of the following:

    • Known gastrointestinal disorder affecting absorption of oral medications
    • Active uncontrolled infection (eg, human immunodeficiency virus [HIV] or viral hepatitis)
    • Uncontrolled hypertension
    • Any current condition that in the opinion of the investigator, would preclude participation in this study
  • Prior whole gland ablative therapy (i.e. cryoablation or high intensity focused ultrasound [HIFU]) for prostate cancer is not allowed
  • HIV positive with CD4 count < 200 cells/microliter within 30 days prior to registration
  • HIV patients under treatment with highly active antiretroviral therapy (HAART) within 30 days prior to registration regardless of CD4 count. (Note: HIV testing is not required for eligibility for this protocol as it is self-reported.)
  • For patients who have not undergone prior Decipher analysis, submission of the specimen to GenomeDx should be as soon as possible after study registration (Step 1) as these results can take up 21 days after the specimen is received at GenomeDx; Step 2 registration must occur within 6 weeks (42 days) of Step 1 registration; if Decipher results have already been obtained, in lieu of tissue, results must be submitted to GenomeDx for validation

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): NCT03371719


Contacts
Contact: Daniel Spratt, MD 734-232-5244 sprattda@med.umich.edu

  Show 217 Study Locations
Sponsors and Collaborators
NRG Oncology
National Cancer Institute (NCI)
Investigators
Principal Investigator: Daniel Spratt, MD NRG Oncology
Principal Investigator: Felix Feng, MD NRG Oncology

Responsible Party: NRG Oncology
ClinicalTrials.gov Identifier: NCT03371719     History of Changes
Other Study ID Numbers: NRG-GU006
NCI-2017-01268 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
NRG-GU006 ( Other Identifier: NRG Oncology )
NRG-GU006 ( Other Identifier: CTEP )
U10CA180868 ( U.S. NIH Grant/Contract )
First Posted: December 13, 2017    Key Record Dates
Last Update Posted: February 11, 2019
Last Verified: February 2019

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

Additional relevant MeSH terms:
Prostatic Neoplasms
Adenocarcinoma
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Genital Diseases, Male
Prostatic Diseases
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type