Pharmacodynamic Study of Radium-223 in Men With Bone Metastatic Castration-Resistant Prostate Cancer

This study will examine biomarkers involved in osteomimicry in bone metastases and circulating tumor cells (CTCs) of men with mCRPC before and during therapy with the bone-targeting radiopharmaceutical radium-223. This study will also examine the bio-distribution of radium-223 in bone and bone metastases of men with mCRPC.

The investigators hypothesize that bone metastases and CTCs in men with mCRPC will commonly express markers of EMT/plasticity and osteomimicry, not just in the normal surrounding osteoblastic stroma but in the epithelial tumor cells themselves and that radium-223 will target both of these compartments including the more mesenchymal/osteoblastic tumor cells and the surrounding osteoblasts in the active bone microenvironment, with a relative sparing of normal bone and bone marrow.

Study Overview

• Status: Completed
• Conditions: Bone Metastatic Castration-Resistant Prostate Cancer
• Intervention / Treatment: Device: Biomarker analysis; Drug: Administration of radium-223

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

1. Age ≥ 18 years.
2. Life expectancy of at least 12 weeks (3 months).
3. Subjects must be able to understand and be willing to sign the written informed consent form. A signed informed consent form must be appropriately obtained prior to the conduct of any trial-specific procedure.
4. Histologically confirmed diagnosis of adenocarcinoma of the prostate. Histologic variants of prostate cancer, including neuroendocrine features are permitted; however, pure small cell carcinoma of the prostate is excluded.
5. Presence of >2 sites of metastatic disease in bone as determined by bone scan or CT, and for men who opt-in for bone biopsy, they must have at least one site amenable to radiographically-guided metastatic biopsy as determined by the study radiologist.
6. Symptomatic castration-resistant bone metastatic disease as determined by the provider.
7. Prior or concurrent therapy with either abiraterone acetate or enzalutamide.
8. Ongoing ADT using an LHRH agonist (e.g. leuprolide, goserelin) or antagonist (e.g. degarelix) must continue on therapy unless prior bilateral orchiectomy has been performed.

9. Current evidence of disease progression as evidenced by one of the following:

   1. 2 consecutive rising PSA levels separated at least 1 week apart above nadir PSA on last systemic therapy. If no nadir, then 2 rising PSA values greater than baseline pretreatment value is required from the most immediate prior therapy, OR
   2. CT or bone scan based evidence of disease progression with bone metastasis (new lesions or growth of existing lesions), OR
   3. Evidence of symptomatic progression (increased pain in an area with known lesions confirmed on imaging).
10. All acute toxic effects of any prior treatment have resolved to NCI-CTCAE v4.0 Grade 2 or less.
11. Men of childbearing potential must agree to use adequate contraception beginning at the signing of the ICF until at least 30 days after the last dose of study drug. The definition of adequate contraception will be based on the judgment of the principal investigator or a designated associate.

12. Acceptable hematology and serum biochemistry screening values:

    • White Blood Cell Count (WBC) ≥ 3,000/mm3
    • Absolute Neutrophil Count (ANC) ≥ 1,500/mm3
    • Platelet (PLT) count ≥ 100,000/mm3
    • Hemoglobin (HGB) ≥ 9.0 g/dl
    • Total bilirubin level ≤ 1.5 x institutional upper limit of normal (ULN)
    • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN
    • Creatinine ≤ 1.5 x ULN
    • Albumin > 2.5 g/dL
13. Willing and able to comply with the protocol, including follow-up visits and examinations

Exclusion Criteria:

1. Treatment with cytotoxic chemotherapy within previous 4 weeks, or failure to recover from AEs down to grade 2 or less due to cytotoxic chemotherapy administered more than 4 weeks previous (however, ongoing neuropathy is permitted)
2. Receiving concurrent systemic therapy with radionuclides (e.g., strontium-89, samarium-153, rhenium-186, or rhenium-188) for the treatment of bony metastases. Prior therapy with radium-223 is not permitted.
3. Other malignancy treated within the last 3 years (except non melanoma skin cancer or low-grade superficial bladder cancer)
4. Visceral (i.e. liver, lung, etc) metastases (pulmonary nodules ≤1cm are permitted) as assessed by chest, abdominal or pelvic computed tomography (CT) (or other imaging modality)
5. Presence of active untreated CNS parenchymal or epidural spinal metastases
6. Lymphadenopathy exceeding 3 cm in short-axis diameter
7. Imminent spinal cord compression based on clinical findings and/or magnetic resonance imaging (MRI). Treatment should be completed for spinal cord compression.

8. Any other serious illness or medical condition, such as but not limited to:

   • Any infection ≥ National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0 Grade 2
   • Cardiac failure New York Heart Association (NYHA) III or IV
   • Crohn's disease or ulcerative colitis
   • Bone marrow dysplasia
   • Fecal incontinence
9. Inability to comply with the protocol and/or not willing or not available for follow-up assessments.
10. Any condition which, in the investigator's opinion, makes the subject unsuitable for trial participation.
11. Concurrent cytotoxic chemotherapy or anticancer therapies other than abiraterone, prednisone or other glucocorticoids, enzalutamide, androgen deprivation therapy, bisphosphonates, and denosumab.
12. Concurrent use of another investigational drug or device therapy (i.e., outside of study treatment) during, or within 2 weeks of treatment initiation.
13. Major surgery within 30 days prior to start of study drug.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Bone Biopsy and Circulating Tumor Cell Samples	Device: Biomarker analysis; Pharmacodynamic study of Radium-223 in bone biopsy and circulating tumor cell samples; Drug: Administration of radium-223; Subjects will receive radium-223 treatment for their disease as standard of care in this protocol. They will be receiving this treatment regardless of their participation in this protocol.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients who overexpress alkaline phosphatase (ALP) in Circulating Tumor Cells (CTCs) at each time point	The proportion of patients who over-express ALP in the CTCs, defined as any over-expression, will be estimated using descriptive statistics at each time point. ALP expression will be concurrently examined in the bone metastatic biopsies of men as well, if evaluable tissue is available.	Cycle 1 Day 1, Cycle 3 Day 1 and Cycle 6 Day 1 or disease progression

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in biomarkers of epithelial plasticity and osteomimicry expressed in the bone metastases of men with bone metastatic CRPC	Summary statistics of other biomarkers involved in epithelial plasticity and osteomimicry in the tumor tissue of men with bone metastatic CRPC including expression of ALP, PSA, CK, O-cadherin, N-cadherin, vimentin, TWIST, SNAIL, beta-catenin, ZEB1, androgen receptor (AR), AR variants (ARv) and γ-H2AX will be completed.	At time of optional biopsy, pre- and post-treatment with Radium-223. Post-treatment biopsies will be approximately 10 and 22 weeks after first treatment.

Collaborators and Investigators

• Sponsor: Duke University
• Collaborators: Bayer
• Investigators: Principal Investigator: Andrew Armstrong, MD, Duke University

Publications and helpful links

General Publications

• Armstrong AJ, Gupta S, Healy P, Kemeny G, Leith B, Zalutsky MR, Spritzer C, Davies C, Rothwell C, Ware K, Somarelli JA, Wood K, Ribar T, Giannakakou P, Zhang J, Gerber D, Anand M, Foo WC, Halabi S, Gregory SG, George DJ. Pharmacodynamic study of radium-223 in men with bone metastatic castration resistant prostate cancer. PLoS One. 2019 May 28;14(5):e0216934. doi: 10.1371/journal.pone.0216934. eCollection 2019.

Study record dates

Study Major Dates

• Study Start (Actual): May 6, 2015
• Primary Completion (Actual): July 31, 2017
• Study Completion (Actual): July 31, 2017

Study Registration Dates

• First Submitted: July 28, 2014
• First Submitted That Met QC Criteria: July 30, 2014
• First Posted (Estimate): July 31, 2014

Study Record Updates

• Last Update Posted (Actual): June 8, 2018
• Last Update Submitted That Met QC Criteria: June 7, 2018
• Last Verified: June 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Prostatic Neoplasms
• Other Study ID Numbers: Pro00053925

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: Yes