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 (BALANCE*)
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 发起方
- NRG Oncology
- 入组人数
- 298
- 试验地点
- 677
- 主要终点
- Biochemical progression-free survival (bPFS)
研究概览
简要总结
This phase II trial studies how well radiation therapy with or without apalutamide works in treating patients with prostate cancer that has come back (recurrent). 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 compared to radiation therapy alone.
详细描述
PRIMARY OBJECTIVE:
I. To determine whether, in men with post-prostatectomy prostate-specific antigen (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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •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 and for GenomeDx to provide the subtyping needed for stratification
- •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
排除标准
- •PRIOR TO STEP 1 REGISTRATION:
- •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 (e.g., 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; this exclusion criterion is necessary because the treatments involved in this protocol may be immunosuppressive and/or interact with HAART)
- •Patients must not plan to participate in any other clinical trials while receiving treatment on this study or being followed post-protocol therapy
- •PRIOR TO STEP 2 REGISTRATION:
- •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
研究组 & 干预措施
Arm 1 (radiation therapy, placebo)
Patients undergo external beam radiation therapy on day 1 for 7-8 weeks. Beginning on day of radiation therapy, patients receive placebo PO QD on days 1-30. Treatment repeats every 30 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
干预措施: Placebo Administration (Other)
Arm 2 (radiation therapy, apalutamide)
Patients undergo external beam radiation therapy on day 1 for 7-8 weeks. Beginning on day of radiation therapy, patients receive apalutamide PO QD on days 1-30. Treatment repeats every 30 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
干预措施: External Beam Radiation Therapy (Radiation)
Arm 1 (radiation therapy, placebo)
Patients undergo external beam radiation therapy on day 1 for 7-8 weeks. Beginning on day of radiation therapy, patients receive placebo PO QD on days 1-30. Treatment repeats every 30 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
干预措施: External Beam Radiation Therapy (Radiation)
Arm 2 (radiation therapy, apalutamide)
Patients undergo external beam radiation therapy on day 1 for 7-8 weeks. Beginning on day of radiation therapy, patients receive apalutamide PO QD on days 1-30. Treatment repeats every 30 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
干预措施: Apalutamide (Drug)
结局指标
主要结局
Biochemical progression-free survival (bPFS)
时间窗: 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 5 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. In addition, a multivariable Cox 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. The goodness-of-fit of the proportional hazards assumption will be evaluating using graphical methods (Kay, 1977), residual plots, and the global test proposed by Grambsch and Therneau (1994). Missing covariates will be handled using multiple imputation as described in White and Royston (1982).
Percentage of Participants Alive Without Biochemical Progression (Biochemical Progression-free Survival)
时间窗: From randomization to biochemical progression or last follow-up if alive. Median follow-up at time of analysis among surviving patients was 5.0 years. Five-year rates are presented.
Biochemical progression is defined as the first occurrence of the following: * A rise in PSA ≥0.2 ng/mL from nadir PSA, confirmed by a second PSA measurement equal to or higher than the first; * Clinical or radiographic local, regional, or distant metastases * Death from any cause. Biochemical progression-free survival rates are estimated using the Kaplan-Meier method, censoring participants alive at time of analysis. Arms are compared within molecular subtype group sequentially based on a study design that determines if and how to incorporate the biomarker in a in a subsequent phase III trial.
次要结局
- Distant metastasis(Up to 5 years)
- PSA nadir during first year of treatment and prior to initiation of any hormonal salvage therapy(During first year of treatment)
- Initiation of salvage hormonal therapy(Up to 5 years)
- Undetectable PSA with a non-castrate testosterone (PSA < 0.1 ng/ml and testosterone >= 50 ng/dl))(3 years)
- Acute patient-reported morbidity symptomatic adverse events (per the patient reported outcomes [PRO]-CTCAE)(Up to 5 years)
- Overall survival (OS)(From randomization until death from any cause, assessed up to 5 years)
- Cancer-specific mortality (CSM)(From the date of randomization to the date of death due to prostate cancer, assessed up to 5 years)
- Metastasis-free survival (MFS)(From randomization until distant metastasis (clinical and/or radiographic appearance of disseminated disease) or death from any cause, assessed up to 5 years)
- Local-regional progression(From randomization to local or regional recurrence ignoring biochemical failure and distant recurrence and censoring for death, assessed up to 5 years)
- Testosterone levels(Every 3 months until 6 months post treatment)
- Undetectable PSA with a non-castrate testosterone (PSA < 0.1 ng/ml and testosterone >= 50 ng/dl)(1 year)
- Acute physician-reported morbidity (per the Common Terminology Criteria for Adverse Events [CTCAE] version 5)(Up to 30 days after radiation therapy)
- Late physician-reported morbidity (per the CTCAE version 5) defined as grade 3+ adverse events occurring more than 30 days after the completion of radiation therapy(From the time protocol treatment started to the time of the first recorded late grade 3+ adverse event, assessed up to 5 years)
- Late patient-reported morbidity symptomatic adverse events (per the PRO-CTCAE)(Up to 5 years)
- Percentage of Participants Alive (Overall Survival)(From randomization to death or last follow-up if alive. Median follow-up at time of analysis among surviving patients was 5.0 years. Five-year rates are presented.)
- Percentage of Participants Who Have Died Due to Prostate Cancer (Cancer-specific Mortality (CSM))(From the date of randomization to the date of death due to prostate cancer or last follow-up if alive. Median follow-up at time of analysis among surviving patients was 5.0 years. Five-year rates are presented.)
- Percentage of Participants Alive Without Distant Metastases (Metastasis-free Survival (MFS))(From randomization to date of first distant metastasis or death, or last follow-up if alive. Median follow-up at time of analysis among surviving patients was 5.0 years. Five-year rates are presented.)
- Percentage of Participants With Distant Metastasis(From randomization to date of first distant metastasis or death, or last follow-up if alive at time of analysis. Median follow-up at time of analysis was 5.0 years. Five-year rates are presented.)
- Percentage of Participants Wtih Local-regional Progression(From randomization to date of first local or regional recurrence or death, or last follow-up if alive at time of analysis. Median follow-up at time of analysis was 5.0 years. Five-year rates are presented.)
- PSA Nadir During First Year of Treatment and Prior to Initiation of Any Hormonal Salvage Therapy(First year of treatment)
- Percentage of Participants That Started Salvage Hormonal Therapy(From randomization to initiation of salvage hormonal therapy or death, whichever occurs first, or last follow-up if alive at time of analysis. Median follow-up at time of analysis among surviving patients was 5.0 years. Five-year rates are presented.)
- Proportion of Participants With Undetectable PSA (< 0.1) and Non-castrate Testosterone (≥ 50 ng/dl) at One and Three Years(One and three years)
- Number of Participants With Grade 3+ Adverse Events Occurring Within 30 Days After the Completion of RT(Up to 30 days after radiation therapy, which lasts approximately 7-8 weeks from treatment start.)
- Number of Participants With Grade 3+ Adverse Events Occurring More Than 30 Days After the Completion of Radiation Therapy(From the end of radiation therapy (approximately 7-8 weeks from treatment start) to last follow-up. Median follow-up at time of analysis among surviving patients was 5.0 years.)
- Testosterone Levels(3, 6, 9, and 12 months)
- Number of Participants With Patient Reported Outcomes-Common Terminology Criteria for Adverse Events (PRO-CTCAE) Severity Score ≥ 3 (or Present) Occurring Within 30 Days After the Completion of RT(Up to 5 years)
- Number of Participants With Patient Reported Outcomes-Common Terminology Criteria for Adverse Events (PRO-CTCAE) Severity Score ≥ 3 (or Present) Occurring More Thant 30 Days After the Completion of RT(From the end of radiation therapy (approximately 7-8 weeks from treatment start) to two years.)