Phase IB Trial of Radium-223 and Niraparib in Patients With Castrate Resistant Prostate Cancer (NiraRad)

PRIMARY OBJECTIVES:

I. To determine a safe dose of niraparib when combined with radium Ra 223 dichloride
(radium-223) in patients with metastatic castrate-resistant prostate cancer (mCRPC) that have
and have not received prior chemotherapy.

SECONDARY OBJECTIVES:

I. To determine the proportion of subjects with 50% prostate-specific antigen (PSA) reduction
from baseline in men treated with niraparib and radium 223.

II. To determine the radiographic PFS (rPFS) at 6 months in men treated with niraparib and
radium 223.

III. To determine the proportion of subjects that have circulating tumor cell (CTC)
conversion (>= 5 to < 5/7.5ml) confirmed in a second assessment > 4 weeks later in men
treated with niraparib and radium 223.

IV. To determine the overall progression-free survival in men treated with niraparib and
radium 223.

V. To determine the time to total-ALP (alkaline phosphatase) progression defined in subjects
with no total-ALP decline from baseline as >= 25% increase from the baseline value, at least
12 weeks from baseline.

VI. To determine the time to total-ALP (alkaline phosphatase) progression defined in patient
with an initial total-ALP decline from baselines as >= 25% increase from the nadir value,
which is confirmed by a second value obtained three or more weeks later.

VII. To determine the total-ALP normalization, defined as the return of total-ALP value to
within normal range at 12 weeks in 2 consecutive measurements (at least 2 weeks apart) after
that of treatment in subjects who have their ALP above upper limit of normal (ULN) at
baseline.

VIII. To determine the long term safety-tolerability of the combination of niraparib and
radium 223 in men treated with niraparib and radium 223.

TERTIARY OBJECTIVES:

I. Study of deoxyribonucleic acid (DNA) repair aberrations; whole exome and transcriptome in
pre-therapy tumor biopsy samples.

II. Compare changes in bone marrow micro-environment (hematopoietic stem cell [HSC] niche\
C-X-C motif chemokine ligand 12 [CXCL12]/C-X-C motif chemokine receptor 4 [CXCR4] axis) pre
and post therapy in up to 10 men treated with niraparib and radium 223.

III. Evaluate the baseline plasma cell-free (cf)-DNA for aberrations in DNA repair genes such
as breast cancer (BRCA)1, BRCA2, ataxia telangiectasia mutated (ATM), ataxia-telangiectasia
and rad3-related (ATR), partner and localizer of brca2 gene (PALB2) as well as the androgen
receptor (AR) gene via next generation sequencing.

IV. Compare gene expression changes in baseline and serial (at end of cycle 1 and 3) whole
blood ribonucleic acid (RNA) (collect blood in edetic acid [EDTA] tubes and RNA-later) using
Nanostring PanCancer and immunology panel.

V. Evaluate the baseline CTCs for nuclear androgen receptor (AR), phosphorylated (p) nuclear
factor kappa-beta (NF-kB), and gamma-H2A histone family member X (H2AX) foci via
immunostaining.

Inclusion Criteria:

- Histologic or cytologic diagnosis of adenocarcinoma of the prostate without
neuroendocrine differentiation or small cell features

- Bone metastases

- Documented progressive metastatic CRPC based on at least one of the following
criteria:

- PSA progression defined as a miminum of 2 rising PSA levels with a minimum of a 1
week interval and a minimum PSA of 2 ng/mL

-1.0 ng/mL is the minimal starting PSA value if confirmed rise is the only
indication of progression

- Soft-tissue progression defined as an increase >= 20% in the sum of the longest
diameter (LD) of all target lesions based on the smallest sum LD since treatment
started or the appearance of one or more new lesions or the appearance of new
lesions

- Documented appearance of new lesions by bone scan

- Agree to undergo a tumor/bone marrow biopsy or submit archival tissue. Note: Tissue
sample collected from primary or metastatic site is acceptable on study. Once each
stratum begins enrollment at the 300mg dose level, 5 subjects from each stratum will
complete a bone marrow biopsy. Due to the dose assignment method used in this study,
the 10 subjects requiring a bone marrow biopsy on study will be determined on a case
by case basis after consent

- Age ≥ 18 years.

- Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

- Must have received at least 1 line of AR-targeted therapy or androgen bio-synthesis
inhibitor (e.g., abiraterone acetate, enzalutamide, apalutamide) for prostate cancer

- Testosterone =< 50 ng/dL; subjects must continue primary androgen deprivation with an
luteinizing hormone-releasing hormone (LHRH) analogue (agonist or antagonist) if they
have not undergone orchiectomy

- Subjects on long term (>= 6 months) first generation anti-androgen therapy (e.g.
flutamide, bicalutamide, nilutamide) will need to discontinue anti-androgen therapy
for 4 weeks (wash out period) and show evidence of disease progression off the
anti-androgen; subjects that have been on a first generation anti-androgen 6 months or
less will need to discontinue therapy prior to registration (no wash out period
required)

- Subjects on second generation anti-androgen therapy (enzalutamide) or androgen
bio-synthesis inhibitor (abiraterone acetate) will need to discontinue therapy 2 weeks
prior to registration (wash out period)

- Subjects on treatment with chemotherapy or any investigational therapeutic agent will
need to discontinue therapy 4 weeks prior to registration (wash out period)

- Absolute neutrophil count (ANC) >= 1,500/uL

- Hemoglobin >= 10 g/dL

- Platelet count >= 150,000/uL

- Creatinine =< 1.5 x the institutional ULN

- Potassium > 3.5 mmol/L (within institutional normal range)

- Total Bilirubin =< 1.5 ULN (unless documented Gilbert's disease)

- Serum glutamic oxaloacetic transaminase (SGOT) aspartate aminotransferase (AST) =< 2.5
x ULN

- Serum glutamate pyruvate transaminase (SGPT) alanine aminotransferase (ALT) =< 2.5 x
ULN

- Men must agree to use adequate contraception prior to study entry, for the duration of
study participation and for at least 6 months after last radium 223 dose

- Must be able to take oral medication without crushing, dissolving or chewing capsules

- May have received prior radiation therapy or surgery; however, at least 21 days must
have elapsed since completion of radiation therapy or surgery and patient must have
recovered from all side effects at the time of registration

- Ability to understand and the willingness to sign a written informed consent document
that is approved by the local institutional review board

Exclusion Criteria:

- Concurrent treatment with any other investigational therapeutic agents

- More than one prior line of chemotherapy

- More than one prior line of therapy with a second generation anti-androgen
(enzalutamide, ARN-509, etc.) or androgen bio-synthesis inhibitor (abiraterone
acetate, TAK 700, etc.); patient may have had one second generation anti-androgen or
androgen bio-synthesis inhibitor but not both sequentially; subjects that have
received combination therapy with second generation anti-androgen plus an androgen
bio-synthesis inhibitor would be eligible (e.g., enzalutamide plus abiraterone acetate
as one line of therapy on a clinical trial). Note, subjects who have had one line of
therapy in a hormone-sensitive setting or one line of therapy in castrate resistant
setting are eligible for study.

- Prior isotope therapy with strontium-89, samarium or RAD223

- Subjects with known symptomatic brain metastases

- All herbal, alternative and food supplements (i.e. PC-Spes, saw palmetto, St. John's
wort, etc.) must be discontinued before registration; Subjects may continue on a daily
multi-vitamin, calcium and vitamin D

- Pre-planned concurrent cytotoxic chemotherapy, surgery, or radiation therapy during
protocol treatment; radiation therapy is not permitted while on study

- All hormonal-acting agents (including diethylstilbestrol/DES, aldosterone, and
spironolactone) must be discontinued before registration; no washout period will be
required for any of these agents

- Initiation of bisphosphonate/denosumab therapy during the study; subjects on stable
doses of bisphosphonates or the tumor necrosis factor receptor superfamily member 11a,
subfamily L (RANK-L) inhibitor, denosumab, which have been started no less than 4
weeks prior to registration, may continue on this medication

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure (New York Heart Association class III
and IV heart failure), unstable angina pectoris, cardiac arrhythmia, or psychiatric
illness/social situations that would limit compliance with study requirements or
concurrent medications that alter cardiac conduction

- Subjects with a "currently active" second malignancy other than non-melanoma skin or
superficial urothelial cancers are not eligible; Subjects are not considered to have a
"currently active" malignancy if they have completed therapy and are now considered
without evidence of disease for 2 years

- Subjects with any known history of myelodysplastic syndrome (MDS) or acute myeloid
leukemia (AML)

- Subjects with known persistent (> 4 weeks) >= grade 2 toxicity from prior cancer
therapy

- Subjects with known >= grade 3 hematological toxicity lasting greater than 7 days with
the last chemotherapy regimen

- Subjects with chronic conditions associated with non-malignant abnormal bone growth
(e.g., Paget's disease of bone)

- Subjects who have used any of the following within 4 weeks prior to registration:
blood or platelet transfusions, erythropoietin, and biologic response modifiers such
as granulocyte macrophage colony-stimulating factor (GM-CSF) or granulocyte
colony-stimulating factor (G-CSF)

- Subjects with baseline QT prolongation > 470 msec

- Subjects receiving concomitant medications that prolong corrected QT interval (QTc)

- Subjects with bulky visceral disease defined as > 4 cm

- Known disorder affecting gastrointestinal absorption

- Subjects with known allergies, hypersensitivity, or intolerance to niraparib or its
excipients

- Subjects requiring escalating doses of prednisone or steroids for control of disease
at the time of screening. Note: If subjects are receiving prednisone or steroids, they
must continue on the same dose they were receiving at the time of screening while
being treated on study

- HIV positive subjects with 1 or more of the following:

- Not receiving highly active antiretroviral therapy

- A change in antiretroviral therapy within 6 months of the start of screening
(except if, after consultation with the sponsor on exclusion criterion 26c. a
change is made to avoid a potential drug-drug interaction with the study drug)

- receiving antiretroviral therapy that may interfere with the study drug (consult
the sponsor for review of medication prior to enrollment)

- CD4 cont <350 at screening

- An acquired autoimmunodeficiency syndrome-defining opportunistic infection within
6 months of the start of screening