Immunotherapy With N 803, ETBX-071, and M-CENK in Combination With Radiation for Participants With High-Risk Prostate Cancer.

Open-Label, Phase 2 Clinical Trial of Pre-Radiation and Post-Radiation Immunotherapy With N-803, ETBX-071, and M-CENK in Combination With Radiation for Participants With High-Risk Prostate Cancer

This study tests a new treatment for men with high-risk prostate cancer who can't have surgery. The treatment combines three experimental drugs and radiation therapy. Researchers will track how well the treatment works and how safe it is. The study will last about five years.

This study (ResQ110B-PROS, IND 027158) is a Phase 2, open-label clinical trial designed to assess the safety and efficacy of a novel, multi-component treatment strategy for men with high-risk prostate cancer who are unsuitable for prostatectomy. The experimental treatment combines three investigational products with standard external beam radiation therapy (EBRT). The study is interventional, not observational.

The Investigational Products:

N-803 (nogapendekin alfa inbakicept): A soluble complex of an IL-15 variant bound to a human IL-15 receptor alpha subunit/human IgG1 Fc fusion protein. It acts as a growth and activation factor for NK cells and effector and memory T cells, aiming to stimulate the immune system's response to the cancer. Administered subcutaneously (SC).

ETBX-071 (hAd5 [E1-, E2b-, E3-]-PSA): A replication-defective human adenovirus serotype 5 (hAd5) vector modified to encode human prostate-specific antigen (PSA). This acts as a cancer vaccine, designed to generate an immune response targeting PSA-expressing prostate cancer cells. Administered subcutaneously (SC).

M-CENK (cytokine-induced memory-like NK cells): Autologous natural killer (NK) cells expanded and modified ex vivo using a cytokine cocktail (IL-12, IL-15, and IL-18) to enhance their cytotoxic activity and persistence. These cells are administered intravenously (IV).

Treatment Regimen:

The study employs a staged treatment approach:

Screening and Baseline Assessments: Participants undergo screening to confirm eligibility, including PSMA-PET scans, genomic testing, and PSA level assessment. Baseline assessments are collected before starting treatment.

Apheresis: Autologous peripheral blood mononuclear cells (MNCs) are collected from participants for the generation of M-CENK cells.

Pre-Radiation Immunotherapy: Participants receive N-803, ETBX-071, and M-CENK according to a specified schedule over a 6-week period. A targeted biopsy is performed before radiation.

Radiation Therapy (EBRT): Participants undergo EBRT (either a standard 2-week course or an extended 9-week course, as determined by the investigator).

Post-Radiation Immunotherapy: Following radiation, participants receive N-803, ETBX-071, and M-CENK for four 6-week cycles. Androgen deprivation therapy (ADT) may be initiated 6 months after completing radiotherapy.

Follow-up: Participants are followed for up to 5 years after the end of treatment (EOT).

Endpoints:

Primary: Complete pathologic response (CPR) after pre-radiation immunotherapy and PSA30 response at EOT after post-radiation immunotherapy.

Secondary: Clinical pathologic response, time to recurrence interval (TTRI), and safety.

Exploratory: Quality of life (QoL), sexual function, immune responses (including changes in immune subsets and antigen-specific responses), tumor microenvironment (TME), and circulating tumor DNA (ctDNA).

Study Population and Duration:

The study plans to enroll up to 20 participants. The total study duration is up to 303 weeks, including treatment and 5 years of follow-up.

The inclusion criteria:

• Age: ≥18 years old.
• Ability to understand and provide informed consent: Participants must be able to understand the study and provide written informed consent fulfilling all relevant Institutional Review Board (IRB) or Independent Ethics Committee (IEC) guidelines.
• Histologically confirmed prostate adenocarcinoma: A diagnosis confirmed through a pathology report or a clinical course consistent with the disease, as determined by a local pathologist, if a pathology specimen is unavailable.
• ECOG performance status: 0 or 1 (fully active or restricted in strenuous activity but ambulatory).
• Life expectancy: >5 years.
• Germline testing: Must have germline testing completed at the time of initial diagnosis and, if applicable, at recurrence.
• No evidence of distant metastasis: No evidence of soft tissue disease metastasis (visceral or lymph nodes) on CT/MRI scan.
• No active or organ-threatening autoimmune disease: Participants must not have an active or organ-threatening autoimmune disease.
• High-risk or very high-risk prostate cancer: Based on 2024 NCCN guidelines: PSA >20 ng/mL or Gleason Grade Group ≥4 or ≥cT3a.
• Adequate hematologic and organ function: Defined by specific laboratory values (ANC, lymphocyte count, platelet count, hemoglobin, INR/aPTT, AST, ALT, alkaline phosphatase) obtained within 14 days prior to baseline, with specific exceptions stated in the protocol for participants with liver or bone metastases or those with known Gilbert disease.
• Ability to attend study visits and return for adequate follow-up.
• Agreement to practice effective contraception: Non-sterile males must agree to use effective contraception (condom, vasectomy, or other barrier methods) for up to 7 months after treatment.

Exclusion Criteria:

• Prior treatment for prostate cancer: Participants who have undergone any prior surgical, cryotherapy, or high-intensity focused ultrasound treatment for prostate cancer are excluded.
• Prior hormonal therapy: Prior orchiectomy or hormonal therapy (GnRH agonists, NSAA) is an exclusion criterion.
• Prior treatment with androgen receptor (AR) inhibitors: Prior treatment with first-generation (bicalutamide, flutamide, nilutamide, cyproterone acetate) or second-generation (enzalutamide, apalutamide, or darolutamide) AR inhibitors is an exclusion criterion.
• Organ transplantation: Receipt of any organ transplantation (excluding those not requiring immunosuppression, such as corneal or hair transplants) excludes participants from the study.
• Chronic systemic corticosteroid use: Chronic administration (>14 days) of systemic corticosteroids within 28 days of study treatment initiation excludes participants. However, minimal systemic absorption (inhaled steroids, nasal sprays, topical agents) is permitted.
• Active autoimmune disease: Active autoimmune diseases (Addison's disease, Hashimoto's thyroiditis, systemic lupus erythematosus, Sjögren syndrome, scleroderma, myasthenia gravis, Goodpasture syndrome, or active Grave's disease) exclude participants. However, a history of autoimmunity that did not require systemic immunosuppression and did not threaten vital organ function is permitted.
• Use of medications affecting PSA: Use of medications known to alter PSA levels (5-alpha reductase inhibitors, phytoestrogens, saw palmetto) within 28 days before study treatment initiation excludes participants.
• Major surgery: Major surgery within 28 days of study treatment initiation excludes participants.
• Systemic therapy: Systemic therapy (including any investigational therapy) within 28 days of study treatment initiation is an exclusion criterion.
• Allergic reactions: A history of allergic reactions to compounds with similar chemical or biologic composition to the study drugs excludes participants.
• Clinically significant cardiovascular/cerebrovascular disease: This includes cerebral vascular accident/stroke, myocardial infarction, or unstable angina, congestive heart failure, or uncontrolled hypertension within specific timeframes before study enrollment.
• Serious intercurrent medical illness: Any serious intercurrent medical illness that could interfere with treatment participation.
• Active infections: Active HIV, hepatitis B (positive HBsAg), or hepatitis C infections exclude participation.
• Live attenuated vaccine administration: Administration of a live, attenuated vaccine within 3 weeks prior to study entry or anticipated during the study.
• Inability or unwillingness to comply: Participants assessed by the investigator as unable or unwilling to comply with the study requirements are excluded.