Treatment of Cancer-Related Bone Pain by Using Bone-Targeted Radiation-Based Therapy (Sn-117m-DTPA) in Patients With Prostate Cancer That Has Spread to Bones

Study Overview
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Brief Summary
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This phase II trial studies the effect of Sn-117m-DTPA on bone pain in patients with prostate cancer that has spread to the bones. Sn-117m-DTPA is a radioactive therapeutic agent that localizes to bones when given to patients. Sn-117m-DTPA may help reduce bone pain in patients with prostate cancer that has spread to the bones.

Detailed Description
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PRIMARY OBJECTIVE: I. To evaluate the efficacy of tin-117m diethylenetriaminepentaacetic acid (Sn-117m-DTPA) on sustained pain response in patients with castration-resistant prostate cancer (CRPC) metastatic to at least two bone sites with at least one clinically meaningful pain at baseline (>= 4 on an 11-point pain intensity scale). SECONDARY OBJECTIVES: I. To assess the safety and tolerability of Sn-117m-DTPA per Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0. II. To measure Sn-117m-DTPA activity by gamma-camera dosimetry scans (serial full body planar images) obtained at 1 hour, 4 hours (or within 4-6 hours), 24 hours (or within 16-24 hours), 48 hours (or within 36-48 hours), 72 hours (or within 60-72 hours), 1 week (+/- 2 days), and 4 weeks (+/- 2 days) after the first Sn-117m-DTPA administration. III. To evaluate the therapeutic efficacy of Sn-117m-DTPA at 24 weeks as measured by Prostate Cancer Working Group 3 (PCWG3) criteria. IV. To evaluate time to the first symptomatic skeletal event defined as i) the first use of external-beam radiation therapy to relieve skeletal symptoms; ii) new symptomatic pathologic vertebral or nonvertebral bone fractures; iii) spinal cord compression; or iv) tumor-related orthopedic surgical intervention. V. To evaluate the overall pain response rate at 24 weeks. VI. To evaluate the duration of pain response defined as from the time of improvement in pain response (pain index =< 3) until the pain recurs. VII. To measure changes and time to progression in serum prostate-specific antigen (PSA) and serum alkaline phosphatase (ALP) levels. VIII. To measure patient-reported outcomes (PROs) and adverse events (AEs) (PRO-CTCAE) captured by digital instruments. IX. To evaluate progression-free survival (PFS) and overall survival (OS). EXPLORATORY OBJECTIVES: I. To examine any tumor genomic alterations that may be associated with response or resistance to Sn-117m-DTPA, a radiopharmaceutical agent. II. To examine the changes in systemic inflammatory markers (such as interferon [IFN]-gamma, tumor necrosis factor [TNF]-alpha, interleukins [IL]-8, IL-10, and IL-17) by flow cytometry, and changes in markers of immune function by measuring the percentage and absolute number of CD4+ T helper cells, CD8+ T cytotoxic cells, T regulatory cells, polymorphonuclear (PMN) myeloid-derived suppressor cells (MDSCs), and mononuclear MDSCs (M-MDSCs) prior to treatment versus (vs.) end of cycle 1, end of cycle 2, and at week 24 and correlate values and/or changes with treatment outcomes. III. To evaluate the feasibility of measuring polo-like kinase 1 (Plk1) expression via immunohistochemistry (IHC) staining on archival tissues. OUTLINE: Patients receive tin Sn 117m DTPA intravenously (IV) over 5-10 minutes on day 1. Treatment repeats every 8 weeks for 2 cycles in the absence of disease progression or unacceptable toxicity. Patients may receive tin Sn 117m DTPA for an additional 2 cycles if pain recurs within 6 months after a 16-week pain observation period and no disease progression on bone scans, or evidence of clinical progression. After completion of study, patients are followed up every 4 weeks until week 28, and then every 3 months for up to 12 months after the first dose of tin Sn 117m DTPA.

Official Title
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A Single Arm Phase II Study of Bone-Targeted Sn-117m-DTPA in Symptomatic Castration Resistant Prostate Cancer With Skeletal Metastases

Conditions
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Castration-Resistant Prostate Carcinoma, Metastatic Malignant Neoplasm in the Bone, Metastatic Prostate Adenocarcinoma, Stage IV Prostate Cancer AJCC v8, Stage IVA Prostate Cancer AJCC v8, Stage IVB Prostate Cancer AJCC v8

Intervention / Treatment
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* Other: Questionnaire Administration
* Radiation: Tin Sn 117m Pentetate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically or cytologically confirmed adenocarcinoma of the prostate that is castration-resistant, defined as: A castrate serum testosterone level =< 50 ng/dL or 1.7 nmol/L Bilateral orchiectomy or maintenance on androgen ablation therapy with luteinizing hormone-releasing hormone (LHRH). Androgen deprivation therapy needs to be maintained throughout the study unless a patient has had orchiectomy by surgery Serum PSA progression defined as two consecutive increases in PSA over a previous reference value, each measurement at least 1 week apart Progression after androgen receptor blockers (enzalutamide, apalutamide, or darolutamide) or androgen synthesis blockers (abiraterone acetate) or chemotherapy (docetaxel or cabazitaxel). There are no maximum number of prior therapies Progressive castration-resistant prostate cancer with two or more skeletal metastases identified by Tc-99m bone scintigraphy or prostate specific membrane antigen (PSMA) positron emission tomography (PET) scan Patients must have self-reported moderate to severe pain at trial entry (baseline weekly average worst pain in the past 24-hours scores of >= 4 on an 11-point numeric rating scale [NRS], the Brief Pain Inventory - Short Form [BPI-SF] item #3 for worst pain) Patients must either currently employ regular (not occasional) analgesic medication use for cancer-related bone pain or have undergone treatment with external beam radiation therapy (EBRT) for bone pain within 4 weeks before starting study treatment Age >= 18 years. Children < 18 years of age are excluded from the study as the prevalence of prostate cancer is extremely rare in this age group Patients must have a life expectancy >= 3 months Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) Patients must have a serum PSA value >= 1 ng/mL Absolute neutrophil count >= 1,000/mcL Platelets >= 100,000/mcL Hemoglobin > 10.0 g/dL Total bilirubin =< 2.5 x institutional upper limit of normal (ULN) Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase [SGPT]) =< 5 x institutional ULN Creatinine =< 1.7 mg/dL OR glomerular filtration rate (GFR) >= 50 mL/min/1.73 m^2 Patients receiving bisphosphonates prior to enrollment can maintain bisphosphonate therapy throughout all or part of the study. The bisphosphonate may be stopped or started at the discretion of the investigator throughout the study (i.e., both treatment phase and follow-up). Injection of bisphosphonates should be done at least 2 hours before or after study drug administration Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association functional classification. To be eligible for this trial, patients should be class 2B or better The effects of Sn-117m-DTPA on the developing human fetus are unknown. For this reason and because radionuclides are known to be teratogenic, male participants and their female partners must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while her male partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 6 months after completion of Sn-117m-DTPA administration Patients must be willing and able to comply with the protocol and agree to return to the hospital for follow-up visits and examinations Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: Patients must not have visceral metastases (such as liver and lung) as assessed by abdominal/pelvic computed tomography (CT) or chest X-ray within 12 weeks before starting study treatment Patients must not have malignant lymphadenopathy exceeding 3 cm in short-axis diameter Patients must not have imminent or established spinal cord compression based on clinical findings and/or magnetic resonance imaging (MRI) Patients who have had chemotherapy, immunotherapy, or external radiotherapy within 4 weeks prior to entering the study Patients must not have received systemic radiotherapy with radium-223, strontium-89, samarium-153, rhenium-186, or rhenium-188 for the treatment of bony metastases within 24 weeks before starting study treatment Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia Patients must not have received any investigational agents within 4 weeks before starting study treatment, nor be scheduled to receive one during the planned treatment period Patients must not have unmanageable urinary incontinence Patients must not have had known non-pathological bone fractures within 2 months before starting study treatment Patients must not have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to Sn-117m-DTPA Patients must not have uncontrolled intercurrent illness, including: Any uncontrolled infection Grade 2 or greater motor or sensory neuropathy Crohn's disease or ulcerative colitis Patients with psychiatric illness/social situations that would limit compliance with study requirements

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Supportive care (tin Sn 117m DTPA)<br>Patients receive tin Sn 117m DTPA IV over 5-10 minutes on day 1. Treatment repeats every 8 weeks for 2 cycles in the absence of disease progression or unacceptable toxicity. Patients may receive tin Sn 117m DTPA for an additional 2 cycles if pain recurs within 6 months after a 16-week pain observation period and no disease progression on bone scans, or evidence of clinical progression. | Other: Questionnaire Administration<br>* Ancillary studies<br>Radiation: Tin Sn 117m Pentetate<br>* Given IV<br>* Other names: Tin Sn 117m DTPA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sustained pain response | Defined as achieving pain index =< 3 within a 12-week period, maintaining that pain index =< 3 over a 16-week time period. Will also be summarized by the point estimation of the overall response rate (ORR) with the corresponding 95% confidence intervals. Patients who received any amount of study drug will be included in the denominator for the calculation of ORR. | Baseline to 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events (AEs) | Safety and toxicity will be assessed through the frequency and percent of AEs, serious adverse events, and adverse events of special interests. Toxicity will be assessed using Common Terminology Criteria for Adverse Events. Will be assessed by patient reported outcomes (PROs) and AEs (PRO-Common Terminology Criteria for Adverse Events). | Up to 6 months post-therapy | 
| Tin Sn 117m diethylenetriaminepentaacetic acid (DTPA) (Sn-117m-DTPA) activity | Gamma camera dosimetry will be used to evaluate whole-body distribution of Sn-117m-DTPA. Pearson's correlation coefficient method will be used to assess the correlation between the baseline technetium-99 bone scintigraphy measurement and the Sn-117m-DTPA uptake. If the observed data distribution is not appropriate to calculate the Pearson's correlation, post hoc analysis will be conducted using non-parametric methods or other methods suitable to the observed data distribution. The gamma dosimetry scan measurements will be reported descriptively as the average and standard deviation of dosimetry scan measurements and plotted over time and grouped by organ systems. | Up to 4 weeks after the first Sn-117m-DTPA administration | 
| Overall response rate | A Fisher's exact 95% confidence interval will be calculated for the overall response rate. The denominator will include all patients who received at least one dose of study treatment and do not have major protocol deviations. Patients who do not have observed clinical response will be counted as negative responses. | Up to 12 months after the first dose of tin Sn 117m DTPA | 
| Time to first symptomatic skeletal event | The time from study enrollment to the first use of external-beam radiation therapy to relieve skeletal symptoms, new symptomatic pathologic vertebral or non-vertebral bone fractures, spinal cord compression, or tumor-related orthopedic surgical intervention will be evaluated. Will be analyzed using the Kaplan-Meier method. Estimation and confidence intervals for the median time to first symptomatic skeletal event will be provided. | Up to 12 months | 
| Overall pain response rate | The rate of achievement of pain index =< 3 within 12 weeks from the first Sn-117m-DTPA will be evaluated. | Within 12 weeks from first dose of Sn-117m-DTPA | 
| Duration of pain response |  | Time from the achievement of pain response (pain index =< 3) to the recurrence of pain (pain index >= 4), assessed up to 16 weeks | 
| Prostate specific antigen (PSA) response rates | Will be determined for the following benchmarks: >= 30% reduction of the blood level, compared to the baseline value; >= 50% reduction of the blood level, compared to the baseline value; confirmed PSA response: >=50% reduction of the blood level, compared to the baseline value, and confirmed by a second PSA value approximately 4 or more weeks later. | Up to 28 weeks | 
| Alkaline phosphatase (ALP) response rate | Will be determined for the following benchmarks: >= 50% reduction of the blood level, compared to the baseline value; confirmed ALP response: >= 50% reduction of the blood level, compared to the baseline value, and confirmed by a second ALP value approximately 4 or more weeks later. | Up to 28 weeks | 
| Clinical progression-free survival | Defined as symptomatic progression (increasing pain from a metastatic lesion); progression of bone lesions assessed per Prostate Cancer Working Group 3 criteria; or progression of soft-tissue lesions assessed per Response Evaluation Criteria in Solid Tumors version 1.1 criteria. PSA progression without progression on bone lesions nor symptomatic is not considered as clinical progression. Will be summarized by Kaplan-Meier methods. | Time of study enrollment until disease progression, assessed up to 12 months | 
| Overall survival | Will be summarized by Kaplan-Meier methods. | Time of the first study treatment until the date of death, assessed up to 12 months |