Testing the Addition of a New Anti-Cancer Drug, Niraparib, to the Usual Treatment (Hormone and Radiation Therapy) for Prostate Cancer With a High Chance of Recurring

Phase 1

Active, not recruiting

Conditions: Prostate Adenocarcinoma
Stage IIC Prostate Cancer AJCC v8
Stage III Prostate Cancer AJCC v8
Stage IIIA Prostate Cancer AJCC v8
Stage IIIB Prostate Cancer AJCC v8
Stage IIIC Prostate Cancer AJCC v8
Stage IVA Prostate Cancer AJCC v8

Interventions: Biological: Gonadotrophin Releasing Hormone
Radiation: Intensity-Modulated Radiation Therapy
Drug: Niraparib

Registration Number: NCT04037254

Lead Sponsor: NRG Oncology

Brief Summary: This is a phase I-II trial to find the safety and activity of adding a new drug (neratinib) 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.

Detailed Description: 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.

EXPLORATORY OBJECTIVE:

I. To identify genomic biomarkers of response to combination therapy with radiation, ADT and PARP inhibition.

OUTLINE: This is a phase I, dose-escalation study of niraparib, followed by a randomized phase II study.

PHASE I: Patients receive niraparib orally (PO) once daily (QD) and receive standard of care gonadotrophin releasing hormone (GnRH) agonist androgen suppression therapy. Treatment with niraparib continues for 12 months, and GnRH agonist therapy for 24 months in the absence of disease progression or unacceptable toxicity. Beginning 8 weeks after starting niraparib and GnRH agonist, patients undergo standard of care intensity-modulated radiation therapy (IMRT) 5 days per week for about 6-9 weeks, depending on type of radiation therapy given, in the absence of disease progression or unacceptable toxicity. Patients also undergo magnetic resonance imaging (MRI) on study.

PHASE II: Patients are randomized to 1 of 2 arms:

ARM I: Patients undergo standard of care GnRH agonist androgen suppression therapy for 24 months in the absence of disease progression or unacceptable toxicity. 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 given in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI on study.

ARM II: Patients undergo standard of care GnRH agonist androgen suppression therapy for 24 months, and niraparib PO QD for 12 months in the absence of disease progression or unacceptable toxicity. 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 given in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI on study.

After completion of study treatment, patients are followed up every 6 months for 3 years, then annually for 3 years.

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: Male

Target Recruitment: 22

Inclusion Criteria

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

Exclusion Criteria

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Phase I, Dose Level 1 (niraparib, GnRH, IMRT)	Gonadotrophin Releasing Hormone	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.
Phase I, Dose Level 1 (niraparib, GnRH, IMRT)	Intensity-Modulated Radiation Therapy	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.
Phase I, Dose Level 1 (niraparib, GnRH, IMRT)	Niraparib	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.
Phase I, Dose Level 2 (niraparib, GnRH, IMRT)	Gonadotrophin Releasing Hormone	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.
Phase I, Dose Level 2 (niraparib, GnRH, IMRT)	Intensity-Modulated Radiation Therapy	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.
Phase I, Dose Level 2 (niraparib, GnRH, IMRT)	Niraparib	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.
Phase I, Dose Level 3 (niraparib, GnRH, IMRT)	Gonadotrophin Releasing Hormone	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.
Phase I, Dose Level 3 (niraparib, GnRH, IMRT)	Intensity-Modulated Radiation Therapy	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.
Phase I, Dose Level 3 (niraparib, GnRH, IMRT)	Niraparib	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.
Phase II, Arm I (GnRH, IMRT)	Gonadotrophin Releasing Hormone	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.
Phase II, Arm I (GnRH, IMRT)	Intensity-Modulated Radiation Therapy	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.
Phase II, Arm II (niraparib, GnRH, IMRT)	Gonadotrophin Releasing Hormone	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.
Phase II, Arm II (niraparib, GnRH, IMRT)	Intensity-Modulated Radiation Therapy	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.
Phase II, Arm II (niraparib, GnRH, IMRT)	Niraparib	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.

Primary Outcome Measures

Name	Time	Method
Number of Participants Disease-free Until Completion of Treatment (2 Years From Start of ADT)	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. Participants with PSA values at baseline, end of RT, and every three months should have PSA values at 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.

Secondary Outcome Measures

Name	Time	Method
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.	Survival rates were to be estimated using the Kaplan-Meier method and the treatment arms were to be compared using a log-rank test.
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.	Prostate cancer death rates were to be estimated using the cumulative incidence method, treating deaths due to other causes as competing risks. The treatment arms were to be compared using the Fine-Gray test
Percentage of Participants With Pathologic Complete Response (pCR) at Two Years	At two years	Complete response was to be determined by a12-core biopsy. Treatment arms were to be compared using a chi-square test.
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.	Progression rates were to be estimated using the cumulative incidence method, treating deaths as competing risks. The treatment arms were to be compared using the Fine-Gray test
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.	Distant metastases rates were to be estimated using the cumulative incidence method, treating death as a competing risk. The treatment arms were to be compared using the Fine-Gray test
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.	Biochemical progression is defined as PSA ≥ 2 ng/ml over the nadir PSA, the presence of local, regional, or distant recurrence, or death from prostate cancer. Biochemical progression-free survival rates were to be estimated using the Kaplan-Meier method and the treatment arms were to be compared using a log-rank test.
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.	Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grades adverse event severity as follows: 1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening, 5 = death related to adverse event. Summary data is provided in this outcome measure; see Adverse Events Module for specific adverse event data. Adverse events were to be categorized as early (within 90 days of completion of radiotherapy) or late (more than 90 days after the completion of radiotherapy).The number of participants per grade was to be compared between the arms for early, late, and all adverse events using chi-square or Fisher exact tests

Trial Locations

Locations (95): Banner MD Anderson Cancer Center
🇺🇸
Gilbert, Arizona, United States
University of Arizona Cancer Center-Orange Grove Campus
🇺🇸
Tucson, Arizona, United States
University of Arizona Cancer Center-North Campus
🇺🇸
Tucson, Arizona, United States
City of Hope Comprehensive Cancer Center
🇺🇸
Duarte, California, United States
Cedars Sinai Medical Center
🇺🇸
Los Angeles, California, United States
Fremont - Rideout Cancer Center
🇺🇸
Marysville, California, United States
University of California Davis Comprehensive Cancer Center
🇺🇸
Sacramento, California, United States
City of Hope Upland
🇺🇸
Upland, California, United States
Helen F Graham Cancer Center
🇺🇸
Newark, Delaware, United States
Medical Oncology Hematology Consultants PA
🇺🇸
Newark, Delaware, United States
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Banner MD Anderson Cancer Center
🇺🇸Gilbert, Arizona, United States