Clonal Emergence and Regression During Radium-223 Therapy for Metastatic Prostate Cancer

This study is for patients with metastatic prostate cancer receiving radium-223 as their standard of care therapy. The researchers will collect blood and urine samples from patients before, during and after the radium-223 therapy. The researchers will compare these samples to observe how the treatment has affected different cancer markers.

Study Overview

• Status: Completed
• Conditions: Prostate Cancer
• Intervention / Treatment: Other: Ancillary/Correlative

Detailed Description

This study proposes to document the presence of clonal emergence and regression during radium-223 therapy for metastatic prostate cancer by serial ctDNA analysis of tumor-associated mutations, using the clinically-available Guardant 360 platform. These data may provide important mechanistic insights into radium-223 therapy by 1) identifying mutations associated with radium-223 resistance or sensitivity, 2) providing new markers of treatment response in an individual, and 3) revealing antitumor effects from radium-223 that are not easily recognized with standard tumor response metrics. Positive finding based on this clinically-available platform will be readily applied by the oncology treatment community.

• Study Type: Observational
• Enrollment (Actual): 14

Contacts and Locations

Study Locations

• United States
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina

Participation Criteria

Eligibility Criteria

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

• Sampling Method: Probability Sample

Study Population

adult males with prostate cancer receiving radium223 treatment

Description

INCLUSION CRITERIA

1. Prostate adenocarcinoma by history or medical records.
2. Two or more bone metastases as demonstrated by imaging studies (technetium bone scan, fluoride PET scan, FDG PET scan, fluciclovine PET scan, CT scan, or MRI scan) or by biopsy.
3. Patients must be on ADT with a GnRH receptor agonist/antagonist or orchiectomy, with or without an anti-androgen or testosterone synthesis inhibitor. Patients must have a documented castrate level of testosterone (<50ng/dL) and be willing to continue their GnRH agonist/antagonist during the course of radium-223 therapy.
4. Patients may have had localized external beam radiation to as much as 20% of the skeleton

5. Adequate hematopoietic, renal, and hepatic function. These parameters include:

   • Hemoglobin ≥ 10gm/dL
   • WBC ≥ 3.0K/mcL
   • ANC ≥ 1.5K/mcL
   • Platelet count ≥ 100K/mcL
   • Creatinine < 1.5 ng/mL
   • Total bilirubin <1.5 ng/mL.
   • Albumin > 25 g/L
6. Patients should have an elevated, relevant tumor marker such as PSA, CEA, or LDH.
7. Age ≥18 years old
8. Life expectancy of at least 24 weeks
9. 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 procedures. Subjects must be willing and able to comply with the protocol, including follow-up visits and examinations.
10. Men of childbearing potential must agree to use adequate contraception beginning at the signing of the informed consent until at least 30 days after the last dose of radium-223 treatment or during the course of radium-223 treatment.
11. Subjects must have had a Guardant 360 ctDNA-based genomic profile performed up to four months prior to the first dose of radium-223, with no new therapy started in the interim. This assay must show at least one single nucleotide variant, either missense or synonymous, or one amplification.
12. Subjects should continue any previously-started bone-hardening agents (zoledronic acid or denosumab) during radium-223 therapy.
13. All acute toxic effects of any prior treatment have resolved to NCI-CTCAE v 5.0 Grade 1 or less at the time of signing the Informed Consent Form (ICF).

EXCLUSION CRITERIA

1. Initiation of any additional anti-tumor therapy within 2 months of starting radium-223 treatment
2. Presence of only lytic bone metastases
3. Prior cytotoxic chemotherapy for metastatic PCa
4. Prior systemic therapy with radionuclides (e.g., strontium-89, samarium-153, rhenium-186, or rhenium-188, or Radium Ra 223 dichloride) for the treatment of bony metastases
5. Other malignancy requiring systemic therapy within the last 3 years (except non melanoma skin cancer or low-grade superficial bladder cancer)
6. Visceral (i.e. liver, lung, brain, adrenal, brain, but not lymph node) metastases as assessed by chest, abdominal, or pelvic computed tomography, or other imaging modality)
7. Lymphadenopathy exceeding 6 cm in short-axis diameter, or any size pelvic lymphadenopathy if it is thought to be a contributor to concurrent hydronephrosis
8. Imminent spinal cord compression based on clinical findings and/or MRI. Treatment should be completed for spinal cord compression.
9. Any infection ≥ Grade 2 per NCI-CTCAE version 5.0
10. Cardiac failure NYHA III or IV
11. Crohn's disease or ulcerative colitis
12. Bone marrow dysplasia, myelodysplasia
13. Fecal incontinence
14. Inability to comply with the protocol and/or not willing or not available for follow-up assessments.
15. Any condition which, in the investigator's opinion, makes the subject unsuitable for trial participation.
16. Concurrent use of abiraterone or enzalutamide. A 28-day washout period is required for both agents.

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Only
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Ancillary/Correlative; Patients will complete questionnaires and have research blood drawn.	Other: Ancillary/Correlative; Collection of research blood and urine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Minor allele frequency (MAF) in ctDNA	The primary objective is to estimate average change in MAF in one or more clonal SNVs, comparing baseline to on-treatment, and baseline to post-treatment samples	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in MAF of clonal SNV	• Determine if changes from baseline in MAF of clonal SNVs during therapy and post-treatment differ significantly from 0.	24 months
Change in clonal mutation MAF and change in pain	• Evaluate the association between change from baseline in clonal mutation MAF and change in pain (evaluated by VAS pain score and analgesic usage diary), measured both during therapy and post-treatment.	24 months
Change in clonal mutation MAF and change in tumor markers	• Evaluate the association between change in clonal mutation MAF and change in tumor markers, including prostate specific antigen (PSA), CEA and LDH, measured by standard biochemical assays both during therapy and post-treatment.	24 months
Change in clonal mutation MAF and markers of bone metabolism	• Evaluate the association between change in clonal mutation MAF and markers of bone metabolism including urine N-telopeptide and serum bone-specific alkaline phosphatase, measured by ELISA assays both during therapy and post-treatment.	24 months
Change in clonal mutation MAF and presence of the TMPRSS2-ERG fusion gene	• Evaluate the association between change in clonal mutation MAF and presence of the TMPRSS2-ERG fusion gene, measured in plasma/urine by digital PCR Evaluate the association between change in clonal mutation MAF and clinical benefit, (time from the last dose of radium-223 to the initiation of a new systemic therapy, measured at least 60 days after final dose) and change in QOL (measured by FACT-P instrument).	24 months

Collaborators and Investigators

• Sponsor: Medical University of South Carolina
• Investigators: Principal Investigator: Michael Lilly, MD, Medical University of South Carolina

Study record dates

Study Major Dates

• Study Start (Actual): March 4, 2019
• Primary Completion (Actual): December 31, 2023
• Study Completion (Actual): December 31, 2023

Study Registration Dates

• First Submitted: September 18, 2018
• First Submitted That Met QC Criteria: September 18, 2018
• First Posted (Actual): September 19, 2018

Study Record Updates

• Last Update Posted (Actual): January 17, 2024
• Last Update Submitted That Met QC Criteria: January 16, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Urogenital Diseases; Male Urogenital Diseases; Genital Diseases, Male; Genital Diseases; Prostatic Neoplasms
• Other Study ID Numbers: 102691; IIR-US-2017-4183 (Other Identifier: Bayer)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No