Randomized Phase II Trial of Niraparib With Standard Combination Radiotherapy and Androgen Deprivation Therapy (ADT) in High Risk Prostate Cancer (With Initial Phase I) (NADIR*) *Randomized Phase II Trial of Niraparib With Standard Combination Androgen DeprIvation Therapy (ADT) and Radiotherapy in High Risk Prostate Cancer (With Initial Phase I)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- NRG Oncology
- 入组人数
- 22
- 试验地点
- 186
- 主要终点
- Number of Participants Disease-free Until Completion of Treatment (2 Years From Start of ADT)
研究概览
简要总结
This is a phase I-II trial to find the safety and activity of adding a new drug (neraparib) to the usual treatment (radiation combined with male hormone deprivation therapy) in lowering the chance of prostate cancer growing or returning. Niraparib is an inhibitor of PARP, an enzyme that helps repair deoxyribonucleic acid (DNA) when it becomes damaged. Blocking PARP may help keep cancer cells from repairing their damaged DNA, causing them to die. PARP inhibitors are a type of targeted therapy. Adding niraparib to the usual care may lower the chance of prostate cancer growing or returning.
详细描述
PRIMARY OBJECTIVES:
I. To establish the preferred dose of niraparib in combination with radiation and antiandrogen therapy (ADT). (Phase I) II. To compare the disease-free state, defined as prostate specific antigen (PSA) remaining < 0.1 ng/ml at the end of ADT therapy in men with high risk prostate cancer treated with standard therapy with or without the addition of niraparib. (Phase IIR)
SECONDARY OBJECTIVES:
I. To further establish the safety and toxicity profile of standard treatment with radiation and androgen deprivation therapy specifically, two years from initiation of ADT, plus niraparib at the phase II dose.
II. To compare the overall survival, prostate cancer-specific survival, local/regional or distant progression, and distant metastatic disease rates of standard therapy with or without the addition of niraparib.
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
- None
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
- •Histologically confirmed (within 180 days prior to registration) adenocarcinoma of the prostate at high risk for recurrence as determined by the following criteria, according to American Joint Committee on Cancer (AJCC) 8th edition:
- •Phase I enrollment
- •Gleason >= 9, PSA =< 150 ng/mL, any T-stage
- •Phase II enrollment
- •Gleason >= 9, PSA =< 150 ng/mL, any T-stage
- •Gleason 8, PSA < 20 ng/mL, and >= T2
- •Gleason 8, PSA >= 20-150 ng/mL, any T-stage
- •Gleason 7, PSA >= 20-150 ng/mL, any T-stage
- •No distant metastases as evaluated by:
- •Bone scan 90 days prior to registration
- •Lymph node assessment by computed tomography (CT) or magnetic resonance (MR) of pelvis or nodal sampling within 90 days prior to registration (Please note: Lymph nodes will be considered negative [N0] if they are < 1.5 cm short axis)
- •History/physical examination within 90 days prior to registration
- •Age >= 18
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 180 days prior to registration
- •Pretreatment serum PSA, obtained prior to any androgen suppression therapy and within 180 days of registration
- •Phase I patients: Prior androgen suppression for prostate cancer is not allowed prior to registration
- •Phase II patients: Prior androgen suppression for prostate cancer is allowed =< 45 days prior to registration
- •Hemoglobin >= 9.0 g/dL (within 90 days prior to registration)
- •Platelets >= 100,000 cells/mm^3 (within 90 days prior to registration)
- •Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (within 90 days prior to registration)
- •Serum creatinine =<1.5 x upper limit of normal (ULN) OR a calculated creatinine clearance >= 30 mL/min estimated using Cockcroft-Gault equation (within 90 days prior to registration)
- •Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3.0 x ULN (within 90 days prior to registration)
- •Serum albumin >= 3 g/dL (within 90 days prior to registration)
- •Serum potassium >= 3.5 mmol/L (within 90 days prior to registration)
- •Serum total bilirubin =< 1.5 x ULN or direct bilirubin =< 1 x ULN (Note: in subjects with Gilberts 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) (within 90 days prior to registration)
- •Men of child-producing potential must be willing to consent to use effective contraception while on treatment and for at least 3 months afterwards
- •The patient or a legally authorized representative must provide study-specific informed consent prior to study entry
排除标准
- •PSA > 150 ng/mL
- •Definitive clinical or radiologic evidence of metastatic disease
- •Pathologically positive lymph nodes or nodes > 1.5 cm short axis on CT or MR imaging
- •Prior radical prostatectomy, cryosurgery for prostate cancer, or bilateral orchiectomy for any reason
- •Any active malignancy within 2 years of study registration that may alter the course of prostate cancer treatment
- •Prior systemic therapy for prostate cancer; note that prior therapy for a different cancer is allowable
- •Prior radiotherapy, including brachytherapy, to the region of the prostate that would result in overlap of radiation therapy fields
- •Current treatment with first generation anti-androgens (bicalutamide, nilutamide, flutamide). For patients enrolled to phase II, if prior anti-androgens were administered, a washout period of >= 30 days is required prior to enrollment
- •Severe, active co-morbidity, defined as follows:
- •Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months
- •Transmural myocardial infarction within the last 6 months
- •Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration
- •Uncontrolled acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition
- •Presence of uncontrolled hypertension (persistent systolic blood pressure [BP] >=160 mmHg or diastolic BP >= 100 mmHg). Subjects with a history of hypertension are allowed, provided that BP is controlled to within these limits by anti-hypertensive treatment
- •Prior allergic reaction to the drugs involved in this protocol (including known allergies, hypersensitivity or intolerance to the excipients of niraparib)
- •Human immunodeficiency virus (HIV) positive with CD4 count < 200 cells/microliter
- •Note that patients who are HIV positive are eligible, provided they have a CD4 count >= 200 cells/microliter within 90 days prior to registration. Patients receiving treatment with highly active antiretroviral therapy (HAART) will not be eligible due to concern for radiosensitization
- •Note also that HIV testing is not required for eligibility for this protocol. This exclusion criterion is necessary because the treatments involved in this protocol may be affected by these drugs
- •Any history or current diagnosis of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)
- •Prior or current treatment with PARP inhibitor
研究组 & 干预措施
Phase I, Dose Level 2 (niraparib, GnRH, IMRT)
Patients undergo standard of care GnRH agonist androgen suppression therapy for 24 months and concurrent niraparib PO QD* for the first 12 months. Beginning 8 weeks after starting niraparib, patients undergo standard of care IMRT 5 days per week for about 6-9 weeks depending on type of radiation therapy. Treatment is given in the absence of disease progression or unacceptable toxicity.
*Niraparib dose level 2: 100 mg during IMRT 200 mg otherwise.
干预措施: Gonadotrophin Releasing Hormone (Biological)
Phase I, Dose Level 1 (niraparib, GnRH, IMRT)
Patients undergo standard of care GnRH agonist androgen suppression therapy for 24 months and concurrent niraparib PO QD* for the first 12 months. Beginning 8 weeks after starting niraparib, patients undergo standard of care IMRT 5 days per week for about 6-9 weeks depending on type of radiation therapy. Treatment is given in the absence of disease progression or unacceptable toxicity.
*Niraparib dose level 1: 100 mg.
干预措施: Gonadotrophin Releasing Hormone (Biological)
Phase I, Dose Level 2 (niraparib, GnRH, IMRT)
Patients undergo standard of care GnRH agonist androgen suppression therapy for 24 months and concurrent niraparib PO QD* for the first 12 months. Beginning 8 weeks after starting niraparib, patients undergo standard of care IMRT 5 days per week for about 6-9 weeks depending on type of radiation therapy. Treatment is given in the absence of disease progression or unacceptable toxicity.
*Niraparib dose level 2: 100 mg during IMRT 200 mg otherwise.
干预措施: Intensity-Modulated Radiation Therapy (Radiation)
Phase I, Dose Level 1 (niraparib, GnRH, IMRT)
Patients undergo standard of care GnRH agonist androgen suppression therapy for 24 months and concurrent niraparib PO QD* for the first 12 months. Beginning 8 weeks after starting niraparib, patients undergo standard of care IMRT 5 days per week for about 6-9 weeks depending on type of radiation therapy. Treatment is given in the absence of disease progression or unacceptable toxicity.
*Niraparib dose level 1: 100 mg.
干预措施: Intensity-Modulated Radiation Therapy (Radiation)
Phase I, Dose Level 3 (niraparib, GnRH, IMRT)
Patients undergo standard of care GnRH agonist androgen suppression therapy for 24 months and concurrent niraparib PO QD* for the first 12 months. Beginning 8 weeks after starting niraparib, patients undergo standard of care IMRT 5 days per week for about 6-9 weeks depending on type of radiation therapy. Treatment given in the absence of disease progression or unacceptable toxicity.
*Niraparib dose level 3: 200 mg.
干预措施: Gonadotrophin Releasing Hormone (Biological)
Phase I, Dose Level 3 (niraparib, GnRH, IMRT)
Patients undergo standard of care GnRH agonist androgen suppression therapy for 24 months and concurrent niraparib PO QD* for the first 12 months. Beginning 8 weeks after starting niraparib, patients undergo standard of care IMRT 5 days per week for about 6-9 weeks depending on type of radiation therapy. Treatment given in the absence of disease progression or unacceptable toxicity.
*Niraparib dose level 3: 200 mg.
干预措施: Intensity-Modulated Radiation Therapy (Radiation)
Phase II, Arm I (GnRH, IMRT)
Patients undergo standard of care GnRH agonist androgen suppression therapy for 24 months. Beginning 8-28 weeks after starting GnRH agonist, patients undergo IMRT 5 days per week for about 6-9 weeks depending on type of radiation therapy. Treatment is given in the absence of disease progression or unacceptable toxicity.
干预措施: Gonadotrophin Releasing Hormone (Biological)
Phase II, Arm II (niraparib, GnRH, IMRT)
Patients undergo standard of care GnRH agonist androgen suppression therapy for 24 months and concurrent niraparib PO QD (phase I determined dose level) for the first 12 months. Beginning 8 weeks after starting niraparib, patients undergo standard of care IMRT 5 days per week for about 6-9 weeks depending on type of radiation therapy. Treatment is given in the absence of disease progression or unacceptable toxicity.
干预措施: Niraparib (Drug)
Phase I, Dose Level 2 (niraparib, GnRH, IMRT)
Patients undergo standard of care GnRH agonist androgen suppression therapy for 24 months and concurrent niraparib PO QD* for the first 12 months. Beginning 8 weeks after starting niraparib, patients undergo standard of care IMRT 5 days per week for about 6-9 weeks depending on type of radiation therapy. Treatment is given in the absence of disease progression or unacceptable toxicity.
*Niraparib dose level 2: 100 mg during IMRT 200 mg otherwise.
干预措施: Niraparib (Drug)
Phase I, Dose Level 3 (niraparib, GnRH, IMRT)
Patients undergo standard of care GnRH agonist androgen suppression therapy for 24 months and concurrent niraparib PO QD* for the first 12 months. Beginning 8 weeks after starting niraparib, patients undergo standard of care IMRT 5 days per week for about 6-9 weeks depending on type of radiation therapy. Treatment given in the absence of disease progression or unacceptable toxicity.
*Niraparib dose level 3: 200 mg.
干预措施: Niraparib (Drug)
Phase II, Arm I (GnRH, IMRT)
Patients undergo standard of care GnRH agonist androgen suppression therapy for 24 months. Beginning 8-28 weeks after starting GnRH agonist, patients undergo IMRT 5 days per week for about 6-9 weeks depending on type of radiation therapy. Treatment is given in the absence of disease progression or unacceptable toxicity.
干预措施: Intensity-Modulated Radiation Therapy (Radiation)
Phase II, Arm II (niraparib, GnRH, IMRT)
Patients undergo standard of care GnRH agonist androgen suppression therapy for 24 months and concurrent niraparib PO QD (phase I determined dose level) for the first 12 months. Beginning 8 weeks after starting niraparib, patients undergo standard of care IMRT 5 days per week for about 6-9 weeks depending on type of radiation therapy. Treatment is given in the absence of disease progression or unacceptable toxicity.
干预措施: Gonadotrophin Releasing Hormone (Biological)
Phase II, Arm II (niraparib, GnRH, IMRT)
Patients undergo standard of care GnRH agonist androgen suppression therapy for 24 months and concurrent niraparib PO QD (phase I determined dose level) for the first 12 months. Beginning 8 weeks after starting niraparib, patients undergo standard of care IMRT 5 days per week for about 6-9 weeks depending on type of radiation therapy. Treatment is given in the absence of disease progression or unacceptable toxicity.
干预措施: Intensity-Modulated Radiation Therapy (Radiation)
Phase I, Dose Level 1 (niraparib, GnRH, IMRT)
Patients undergo standard of care GnRH agonist androgen suppression therapy for 24 months and concurrent niraparib PO QD* for the first 12 months. Beginning 8 weeks after starting niraparib, patients undergo standard of care IMRT 5 days per week for about 6-9 weeks depending on type of radiation therapy. Treatment is given in the absence of disease progression or unacceptable toxicity.
*Niraparib dose level 1: 100 mg.
干预措施: Niraparib (Drug)
结局指标
主要结局
Number of Participants Disease-free Until Completion of Treatment (2 Years From Start of ADT)
时间窗: Baseline to completion of treatment (two years from start of ADT)
Participants will be considered disease-free if their PSA values remain below 0.1 ng/ml until the completion of treatment. The proportion of patients disease-free at 24 months were to be compared in the two treatment arms using a non-continuity-corrected chi-square test. PSA levels will be assessed prior to the start of RT, at the end of RT, and every three months for 24 months. all PSA values obtained up to and including the two-year landmark must be \< 0.1 ng/ml. Patients who die prior to two years from prostate cancer will be counted as failures. Patients who die from causes other than prostate cancer will be considered non-evaluable for the primary endpoint. Patients still under follow-up but who have a missing PSA value at two years or more than two missing values prior to two years will also be counted as failures.
次要结局
- Percent of Participants Alive (Overall Survival)(From baseline to death or last follow-up, analyzed after phase II participants have been followed for two years, which was expected to occur 3.5 years from start of phase II component.)
- Percentage of Participants With Prostate Cancer Deaths (Prostate Cancer-specific Survival)(From baseline to death or last follow-up, analyzed after all phase II participants have been followed for two years, which was expected to occur 3.5 years from start of phase II component.)
- Percentage of Participants With Pathologic Complete Response (pCR) at Two Years(At two years)
- Percentage of Participants With Local/Regional or Distant Progression(From baseline to local/regional or distant progression, death, or last follow-up, whichever occurs first, analyzed after all phase II participants have been followed for two years, which was expected to occur 3.5 years from start of phase II component.)
- Percentage of Participants With Distant Metastases(From baseline to distant metastasis, death, or last follow-up, analyzed after all phase II participants have been followed for two years, which was expected to occur 3.5 years from start of phase II component.)
- Percentage of Participants Alive Without Biochemical Progression (Biochemical Progression-free Survival)(From baseline to biochemical progression or last follow-up, analyzed after all phase II participants have been followed for two years, which was expected to occur 3.5 years from start of phase II component.)
- Number of Participants by Highest Grade Adverse Event Reported(From baseline to last follow-up, analyzed after all phase II participants have been followed for two years, which was expected to occur 3.5 years from start of phase II component.)