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Standard of Care Treatment (Hormonal Therapy and Stereotactic Ablative Radiation Therapy) Alone or in Combination with Niraparib, Abiraterone and Prednisone for the Treatment of Metastatic Prostate Cancer, KNIGHTS Trial
Trial Status: active
This phase II trial compares the effectiveness of standard of care treatment, hormonal therapy and ablative radiation therapy (SABR), to standard of care treatment in combination with niraparib, abiraterone and prednisone in treating patients with prostate cancer that has spread from where it first started to other places in the body (metastatic). Hormonal therapy, such as leuprolide, goserelin, buserelin, histrelin, triptorelin, degarelix, or relugolix, may lower the amount of testosterone made by the body or block the use of testosterone by the tumor cells. This may help stop the growth of tumor cells that need testosterone to grow. SABR is a type of external radiation therapy that uses special equipment to position a patient and precisely deliver radiation to tumors in the body (except the brain). The total dose of radiation is divided into smaller doses given over several days. This type of radiation therapy helps spare normal tissue. Niraparib is in a class of medications called poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors. Niraparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Abiraterone acetate, an androgen biosynthesis inhibitor, may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Prednisone is in a class of medications called corticosteroids. It is used to reduce inflammation and lower the body's immune response to help lessen the side effects of chemotherapy drugs. Standard of care treatment in combination with niraparib, abiraterone acetate and prednisone may be more effective than standard of care alone in treating patients with metastatic prostate cancer.
Inclusion Criteria
≥ 18 years of age (or the local legal age of consent)
Patient must have at least one and up to three asymptomatic metastatic tumor(s) of the bone, soft tissue, or extra-pelvic nodal region each < 5 cm or < 250 cm^3 that develop within the past 6-months that are seen on imaging. A nodal lesion is defined to include nodal conglomerates located in the same nodal chain such that they can be treated in one SABR field. Up to five lesions are allowed on advanced functional imaging such as fluciclovine (axumin), choline or prostate specific membrane antigen (PSMA) PET-CT scan
* CT or MRI scan within 6 months of enrollment
* Bone scan within 6 months of enrollment
* Fluciclovine (axumin), choline, or PSMA PET-CT scan within 6 months of enrollment (PET-CT scan is reasonable for study entry imaging as an alternative to CT/MRI scan and bone scan)
Must have a high-risk pathogenic mutation (TP53, BRCA1/2, PALB2, ATM, BRIP1, CHEK2, FANCA, RAD51B, RAD54L, MUTYH) by next generation sequencing. ATM mutation enrollment will be capped at 5% of the overall population
Histologic confirmation of prostate adenocarcinoma (primary or metastatic tumor)
Patient may have had prior systemic therapy and/or ADT so long as testosterone is > 100 ng/dl prior to enrollment
PSA > 0.5 but < 50 at enrollment
PSA doubling time (PSADT) < 15 months
Baseline testosterone > 100 ng/dl
Patient must have a life expectancy ≥ 12 months
Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
Absolute neutrophil count ≥ 1.5 x 10^9/L (at screening)
Hemoglobin ≥ 9.0 g/dL, independent of transfusions for at least 28 days (at screening)
Platelet count ≥ 100 x 10^9/L (at screening)
Creatinine < 2 x upper limit of normal (ULN) (at screening)
Serum potassium ≥ 3.5 mmol/L (at screening)
Serum total bilirubin ≤ 1.5 x ULN or direct bilirubin ≤ 1 x ULN (Note: In participants 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, participant may be eligible) (at screening)
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤ 3 x ULN (at screening)
Patient must have the ability to understand and the willingness to sign a written informed consent document
Able to swallow the study medication tablets whole
While on study medication and for 4 months following the last dose of study medication, a male participant must agree to use condom and an adequate contraception method for female partner (WOCBP) A male participant must agree not to donate sperm while on study treatment and for a minimum of 4 months following the last dose of study medication
Exclusion Criteria
Castration-resistant prostate cancer (CRPC)
Prior radiation therapy to an overlapping site of a target lesion that would preclude further radiation therapy
No more than 3 years of ADT is allowed (with the most recent ADT treatment having occurred within 2 months from the start of SABR)
Spinal cord compression or impending spinal cord compression
Suspected intracranial and/or liver metastases (> 10 mm in largest axis)
Patient receiving any other investigational agents
Inability to receive any form of systemic therapy in the opinion of a treating medical oncologist
Unable to lie flat during or tolerate PET/MRI, PET/CT or SABR
Radiographical evidence of cranial parenchymal metastasis
Active second primary malignancy; acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) in medical history
Uncontrolled hypertension and myocardial infarction / pulmonary embolism (PE) / cardiac failure in last 6 months
Prior treatment with PARP inhibitor
Refusal to sign informed consent
Pathological finding consistent with small cell or neuroendocrine carcinoma of the prostate
History of adrenal dysfunction
Long-term use of systemically administered corticosteroids ( > 5mg of prednisone or the equivalent) during the study is not allowed. Short-term use ( ≤ 4 weeks, including taper) and locally administered steroids (eg, inhaled, topical, ophthalmic, and intra-articular) are allowed, if clinically indicated
Active malignancies (ie, progressing or requiring treatment change in the last 24 months) other than the disease being treated under study. The only allowed exceptions are:
* Non-muscle invasive bladder cancer
* Skin cancer (non-melanoma or melanoma) treated within the last 24 months that is considered completely cured
* Malignancy that is considered cured with minimal risk of recurrence
* History or current diagnosis of MDS/AML
Current evidence within 6 months prior to randomization of any of the following:
* Severe/unstable angina, myocardial infarction, symptomatic congestive heart failure
* Clinically significant arterial or venous thromboembolic events (ie. Pulmonary embolism), or clinically significant ventricular arrhythmias
Presence of sustained uncontrolled hypertension (systolic blood pressure > 160 mm Hg or diastolic blood pressure > 100 mm Hg). Participants with a history of hypertension are allowed, provided that blood pressure is controlled to within these limits by an antihypertensive treatment
Known allergies, hypersensitivity, or intolerance to the excipients of niraparib/abiraterone acetate tablets
Current evidence of any medical condition that would make prednisone use contraindicated
Received an investigational intervention (including investigational vaccines) or used an invasive investigational medical device within 30 days before the planned first dose of study medication
Participants who have had the following ≤ 28 days prior to randomization:
* A transfusion (platelets or red blood cells)
* Hematopoietic growth factors
* Major surgery
Human immunodeficiency virus positive participants with 1 or more of the following:
* Not receiving highly active antiretroviral therapy or on antiretroviral therapy for less than 4 weeks
* Receiving antiretroviral therapy that may interfere with the study medication
* CD4 count < 350 at screening
* An acquired immunodeficiency syndrome-defining opportunistic infection within 6 months of the start of screening
* Human immunodeficiency virus load > 400 copies/mL
Active or symptomatic viral hepatitis or chronic liver disease; encephalopathy, ascites or bleeding disorders secondary to hepatic dysfunction
Moderate or severe hepatic impairment (class B and C per Child-Pugh classification system)
Additional locations may be listed on ClinicalTrials.gov for NCT06212583.
Locations matching your search criteria
United States
Maryland
Baltimore
University of Maryland/Greenebaum Cancer Center
Status: Active
Contact: Jason K Molitoris
Phone: 410-328-6080
Maryland Proton Treatment Center
Status: Active
Contact: Jason K Molitoris
Phone: 410-328-6080
Bel Air
UM Upper Chesapeake Medical Center
Status: Active
Contact: Jason K Molitoris
Phone: 410-328-6080
Columbia
Central Maryland Radiation Oncology in Howard County
Status: Active
Contact: Jason K Molitoris
Phone: 410-328-6080
Easton
University of Maryland Shore Medical Center at Easton
Status: Active
Contact: Jason K Molitoris
Phone: 410-328-6080
Glen Burnie
UM Baltimore Washington Medical Center/Tate Cancer Center
I. To compare the 18-month prostate specific antigen (PSA) progression, defined as PSA > 0.2 ng/mL in patients initially treated with radical prostatectomy and greater than nadir + 2 ng/mL for patients initially treated with definitive radiation, with testosterone > 100 ng/dl of men who have oligometastatic castration-sensitive prostate cancer with high-risk mutations (TP53, BRCA1/2, PALB2, ATM, BRIP1, CHEK2, FANCA, RAD51B, RAD54L, MUTYH) treated with androgen deprivation therapy (ADT)+ stereotactic ablative radiation therapy (SABR) metastasis-directed therapy (MDT) (6-months [mos]) versus ADT + SABR MDT + niraparib/abiraterone acetate and prednisone (6-mos).
SECONDARY OBJECTIVES:
I. To assess the toxicity of ADT+ SABR MDT (6-mos) versus (vs) ADT + SABR MDT + niraparib/abiraterone acetate and prednisone (6-mos) in patients with metachronous oligometastatic castration-sensitive prostate cancer (CSPC) disease.
II. To determine local control at 18 months after ADT+ SABR MDT (6-mos) vs ADT + SABR MDT + niraparib/abiraterone acetate and prednisone (6-mos) in patients with metachronous oligometastatic CSPC disease.
III. To assess time to locoregional progression, time to distant progression, time to new metastasis, radiographic progression-free survival and duration of response after randomization to ADT+ SABR MDT (6-mos) vs ADT + SABR MDT + niraparib/abiraterone acetate and prednisone (6-mos).
IV. To assess quality-of-life following completion of ADT+ SABR MDT (6-mos) vs ADT + SABR MDT + niraparib/abiraterone acetate and prednisone (6-mos).
CORRELATIVE OBJECTIVES:
I. To enumerate circulating tumor cells (CTC) at baseline, 3 month follow-up and 6 month follow-up.
II. To bank plasma at baseline, 3 month, 6 month, and 12 month follow-up.
III. To quantitatively sequence T-cell receptor (TCR) repertoires using peripheral blood monocytes and the ImmunoSEQ platform at baseline and 3 month follow-up.
IV. To determine frequency of germline deoxyribonucleic acid (DNA) repair mutations in the oligometastatic state.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I: Patients undergo SABR over 1-5 fractions and receive leuprolide, goserelin, buserelin, histrelin, triptorelin, degarelix, or relugolix per standard of care for 6 months in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo rectal swab and blood sample collection, bone scan, computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET)/CT on study.
ARM II: Patients undergo standard of care SABR over 1-5 fractions then receive leuprolide, goserelin, buserelin, histrelin, triptorelin, degarelix, or relugolix per standard of care for 6 months in the absence of disease progression or unacceptable toxicity. Patients also receive niraparib orally (PO) once daily (QD), abiraterone acetate PO QD, and prednisone PO QD for 6 months in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo rectal swab and blood sample collection, bone scan, CT, MRI, and PET/CT on study.
After completion of study treatment, patients are followed up every 3-6 months for up to 18 months.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationUniversity of Maryland/Greenebaum Cancer Center