IL-15 Superagonist With or Without Vaccine in Biochemically Recurrent Prostate Cancer After Previous Stereotactic Body Radiation Therapy

Phase II Trial of IL-15 Superagonist With or Without Vaccine in Biochemically Recurrent Prostate Cancer After Previous Stereotactic Body Radiation Therapy

Background:

Biochemically recurrent prostate cancer (BCR) occurs when prostate-specific antigen (PSA) levels in the blood rise after surgery or radiation. BCR affects 30,000 to 50,000 men each year. Researchers want to know if a drug (N-803) alone or combined with a vaccine (ETBX-071) can reduce PSA in BCR prostate cancer after radiation.

Objective:

To test a study drug alone and combined with a vaccine in people with BCR prostate cancer who have been treated with targeted radiation to areas of recurrent prostate cancer in the past.

Eligibility:

People aged 18 years and older with BCR prostate cancer who have previously undergone treatment with stereotactic body radiation therapy (SBRT).

Design:

Participants will be screened. They will have a physical exam with blood tests. They will have tests of their heart and kidney function. They will have 3 different imaging scans of their tumors.

N-803 is injected under the skin of the abdomen. ETBX-071 is injected under the skin of thigh.

Participants will be divided into 2 groups: 1 group will get N-803 alone; 1 group will get both N-803 and ETBX-071.

The drug or drugs will be given on the first day of 21-day treatment cycles. Participants will have 8 treatment cycles.

Participants will have a follow-up visit 3 weeks after their last dose of the study drugs. Blood tests and all 3 imaging scans will be repeated.

Follow-up visits will continue every 4 to 8 weeks for 5 years. These visits will include a positron emission tomography (PET) scan every 6 months.

Study Overview

• Status: Not yet recruiting
• Conditions: Recurrent Prostate Cancer; Prostate Cancer
• Intervention / Treatment: Drug: N-803; Radiation: 18F-DCFPyL; Drug: ETBX-71 Vaccine

Detailed Description

Background:

• Biochemical recurrence (BCR) denotes rising prostate serum antigen (PSA) and negative computed tomography (CT) and Tc99 bone scan following radical prostatectomy and/or definitive local radiation.
• Beyond local salvage radiation options, the management of BCR has not been clearly defined.
• As BCR is an asymptomatic stage of disease which can take years to progress to overt metastatic disease, treatment for this stage should have minimal side effects and only be for a limited duration of time.
• The advent of prostate-specific membrane antigen (PSMA)-based imaging has driven stereotactic body radiation therapy (SBRT) in BCR despite lack of robust evidence.
• Further study is required to ascertain the role of SBRT in BCR.
• Due to the presence of only microscopic disease, BCR may be the ideal stage of the disease to evaluate immunotherapy.
• Previous studies in the GMB have demonstrated that vaccine can lead to delayed declines in PSA.
• N-803 is an IL-15 superagonist which increases the number of natural killer (NK) and CD8 T cells without expanding regulatory T-cells. The net effect is to increase the inflammatory milieu of the tumor microenvironment and this is FDA approved for the treatment of superficial bladder cancer. There is clinical evidence of the activity of N-803 in prostate cancer.
• The ETBX-071 is an adenoviral-based vaccine against PSA.
• We have previously demonstrated the effects of vaccine in BCR. N-803 has demonstrated preclinical synergy with vaccine and has also been associated with PSA declines in a combination immunotherapy trial in metastatic prostate cancer.

Objectives:

-To estimate efficacy of N-803 alone or with ETBX-071 vaccine, each administered for 6 months, in participants with biochemically recurrent prostate cancer following PSA progression after SBRT

Eligibility:

• Biochemically recurrent prostate cancer, defined as PSA over 0.8 ng/ml following radical prostatectomy or >= 2 ng/ml above the nadir following definitive radiotherapy.
• No evidence of soft tissues disease on CT scan and bone metastasis on technetium-99m (Tc99) bone scan.
• PSA rise of at least 25% of nadir following prior SBRT treatment for recurrent prostate cancer
• Eastern Cooperative Oncology Group (ECOG) performance score 0-1.
• No active or organ-threatening autoimmune disease.

Design:

• This is an open-label phase 2 study in which all participants have received prior SBRT and experienced subsequent PSA progression.
• Participants will be randomized between two treatments: N-803 for 6 months versus N-803 with ETBX-071 vaccine for 6 months.

• Study Type: Interventional
• Enrollment (Estimated): 65
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Amy R Hankin, P.A.-C; Phone Number: (240) 858-3149; Email: amy.hankin@nih.gov
• Study Contact Backup: Name: Melissa L Abel, M.D.; Phone Number: (240) 447-5353; Email: melissa.abel@nih.gov

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center
      • Contact: National Cancer Institute Referral Office; Phone Number: 888-624-1937; Email: NCIMO_Referrals@mail.nih.gov

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

• INCLUSION CRITERIA:
• Histopathological confirmation of prostate adenocarcinoma by the Laboratory of Pathology at the National Institutes of Health (NIH) Clinical Center prior to the study treatment initiation. If no pathologic specimen is available, participants may enroll with a pathologist s report showing a histologic diagnosis of prostate adenocarcinoma and a clinical course consistent with the disease from any outside site.
• Biochemically recurrent prostate cancer, defined as PSA over 0.8 ng/ml following radical prostatectomy or >= 2 ng/ml above the nadir following definitive radiotherapy or definitive radiotherapy (including brachytherapy) for localized prostate cancer.
• Participants must be at least 1 year removed from definitive local therapy before the study treatment initiation.
• Recovery to baseline from acute toxicity related to prior therapy, including surgery and radiation.
• Hepatic function eligibility parameters: Bilirubin (total and direct) <= upper limit of normal (ULN) (OR in participants with Gilbert s syndrome, a total bilirubin <= 3.0), aspartate transaminase (AST) and alanine transaminase (ALT) <= 1.5 times upper limit of normal.
• Adequate renal function defined by a calculated creatinine clearance > 50 mL/min according to the Cockcroft-Gault formula or by measure of creatinine clearance from 24-hour urine collection.
• ECOG performance score 0-1.
• No other active malignancies within the 36 months prior to the study treatment initiation (with the exception of nonmelanoma skin cancers or carcinoma in situ of the bladder).
• 18 years of age or older.
• Individuals must agree to use effective contraception (barrier, vasectomy and/or abstinence) for the duration of study therapy and for four months after the last treatment administration. Individuals with partners with birthing potential will be recommended that their partner use a highly effective contraception (includes use of oral, injected or implanted hormonal methods of contraception, placement of certain intrauterine devices (IUD) or intrauterine systems (IUS), hysterectomy, oophorectomy, salpingectomy.
• Individuals must agree to not donate sperm during the restricted period (for the duration of study therapy and for four months after the last dose of study treatment).
• Negative CT scan/ Magnetic resonance imaging (MRI) for evidence of soft tissue metastasis (visceral or lymph node).
• Negative Tc99 for evidence of bone disease.
• Participants must have had prior SBRT to PSMA+ findings beyond the prostate and have had a documented 25% or more PSA rise from post-SBRT nadir
• Baseline testosterone >= 100 ng/dl.

• Hematological parameters:

  • Granulocyte count >= 1000/mm^3
  • Platelet count >= 100000/mm^3
  • Hemoglobin (Hgb) >= 10 g/dL
• Participants must be able to understand and willing to sign a written informed consent document.

EXCLUSION CRITERIA:

• Immunocompromised status due to:

  • Human immunodeficiency virus (HIV) seropositivity
  • HBV or HCV seropositivity
  • Other immunodeficiency diseases
• Active autoimmune diseases such as Addison's disease, Hashimoto's thyroiditis, systemic lupus erythematosus, Sjogren syndrome, scleroderma, myasthenia gravis, Goodpasture syndrome or active Grave's disease. Participants with a history of autoimmunity that has not required systemic immunosuppressive therapy or does not threaten vital organ function including central nervous system (CNS), heart, lungs, kidneys, skin, and gastrointestinal (GI) tract will be allowed. Participants with diabetes type I, vitiligo, or alopecia are allowed.
• Receipt of any organ transplantation, including allogeneic stem-cell transplantation, but with the exception of transplants that do not require immunosuppression (e.g., corneal transplant, hair transplant).
• Chronic administration (defined as daily or every other day for continued use > 14 days) of systemic corticosteroids within 28 days before the study treatment initiation. Note: Use of corticosteroids with minimal systemic absorption (e.g., inhaled steroids, nasal sprays, and topical agents) is allowed.
• Other medications used for urinary symptoms including 5-alpha reductase inhibitors (finasteride and dutasteride) and alternative medications known to alter PSA (e.g., phytoestrogens and saw palmetto) within 28 days prior to the study treatment initiation.
• Major surgery within 28 days prior to study treatment initiation.
• Systemic therapy, including any investigational therapy within 28 days prior to the study treatment initiation.
• Radiation therapy within 14 days prior to the study treatment initiation.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to the study drugs.
• Clinically significant cardiovascular/cerebrovascular disease as follows: cerebral vascular accident/stroke (< 6 months prior to the first planned dose of study drugs), myocardial infarction (< 6 months prior to the first planned dose of study drugs), or any of the following at time of enrollment: unstable angina, congestive heart failure (New York Heart Association Classification Class >= II), serious cardiac arrhythmia, or uncontrolled hypertension (SBP>170/ DBP>105).
• Serious intercurrent medical illness evaluated by medical history and physical exam that would interfere with participant's ability to carry out the treatment program.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: N803	Drug: N-803; 15 mg/kg subcutaneous on Day 1 of every 3-week cycle for up to 8 cycles; Radiation: 18F-DCFPyL; Single IV dose of 18F-DCFPyL by bolus injection. The target administered activity will be 6.5 mCi with a lower limit of 6 mCi
Experimental: N803+ETBX-071 vaccine	Drug: N-803; 15 mg/kg subcutaneous on Day 1 of every 3-week cycle for up to 8 cycles; Radiation: 18F-DCFPyL; Single IV dose of 18F-DCFPyL by bolus injection. The target administered activity will be 6.5 mCi with a lower limit of 6 mCi; Drug: ETBX-71 Vaccine; The dose to be injected is 5(SqrRoot) 10^11 viral particles (VP) per 1 mL. Injected subcutaneously on Day 1 of every 3-week cycle for a total of up to 8 cycles

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy of N-803 alone or with ETBX-071 vaccine	PSA30 response- defined as a >= 30% reduction in PSA from PSA at C1D1 of immunotherapy (comparing C1D1 PSA to timepoints during and after immunotherapy). The fractions with PSA30 response will be reported along with a 95% confidence interval, separately for the two randomized treatment groups.	D1 of each cycle of immunotherapy, at the end of treatment and every 4-8 weeks during follow-up until up to 5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of PSA50 response	Duration of PSA response will be evaluated using the Kaplan-Meier method unless all participants are identified as having an end to their response (no censoring). The median duration of PSA response will be reported, starting at the date the PSA30 response was identified, along with a 95% confidence interval for the median, separately for the two randomized treatment groups.	D1 of each cycle of immunotherapy, at the end of treatment and every 4-8 weeks during follow-up until up to 5 years
Time to PSA progression	Time to PSA progression after immunotherapy will be evaluated using the Kaplan-Meier method unless all participants are identified as having an end to their response (no censoring). The median time to PSA progression will be reported, starting at the date Cycle 1 began, along with a 95% confidence interval for the median.	D1 of each cycle of immunotherapy, at the end of treatment and every 4-8 weeks during follow-up until up to 5 years
PSA doubling timing	PSA doubling time at randomization, compared to PSA doubling time at the end of treatment (EOT) visit.	D1 of each cycle of immunotherapy, at the end of treatment and every 4-8 weeks during follow-up until up to 5 years
Proportion of participants with 30% PSA decline receiving immunotherapy treatment after SBRT	The median changes in PSA doubling time (in months) will be determined separately for both treatment groups with paired differences compared within participants using a Wilcoxon signed rank test.	D1 of each cycle of immunotherapy, at the end of treatment and every 4-8 weeks during follow-up until up to 5 years
Safety	The number, grades, and types of adverse events will be reported separately for participants assigned to each treatment group using descriptive statistics.	C1D1 of each cycle during immunotherapy and at the end of treatment
Changes in PSMA PET scans	These will be summarized descriptively.	Prior to treatment, at end of treatment and in follow-up every 6 months

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Melissa L Abel, M.D., National Cancer Institute (NCI)

Publications and helpful links

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Estimated): July 12, 2026
• Primary Completion (Estimated): January 30, 2029
• Study Completion (Estimated): January 30, 2029

Study Registration Dates

• First Submitted: July 3, 2026
• First Submitted That Met QC Criteria: July 6, 2026
• First Posted (Actual): July 7, 2026

Study Record Updates

• Last Update Posted (Actual): July 7, 2026
• Last Update Submitted That Met QC Criteria: July 6, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: N-803; Recurrent Prostate Cancer; ETBX-071; IL-15 Superagonist; PSA Vaccine
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Prostatic Diseases; Male Urogenital Diseases; Prostatic Neoplasms; ALT-803; 2-(3-(1-carboxy-5-((6-fluoropyridine-3-carbonyl)amino)pentyl)ureido)pentanedioic acid
• Other Study ID Numbers: 10002231; 002231-C

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: This study will comply with the NIH Data Management and Sharing (DMS) Policy, which applies to all new and ongoing NIH-funded research in the IRP, as of January 25, 2023, that is associated with a ZIA, with a clinical protocol that undergoes scientific review and/or will involve genomic data sharing.
• IPD Sharing Time Frame: Data will be made available as soon as possible or at the time of associated publication. Data not published in a manuscript will be shared via public source once the data set completes QC.@@@@@@
• IPD Sharing Access Criteria: Clinical data will be made available upon request and with the permission of the study PI. Genomic data are made available via dbGAP through requests to the data custodians.@@@@@@
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

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