Safety and Efficacy of AGN-INM176 in Prostate Patients With Rising PSA

The study is designed as a Phase I/II open-label trial to assess the safety and preliminary efficacy of the herbal supplement INM176 in intercepting prostate cancer-specific PSA levels. The primary objective of the Phase I stage is to determine the recommended Phase II dose (RP2D) through a 3+3 dose escalation design while evaluating the safety of INM176 during a 4-week cycle for dose-limiting toxicities (DLTs) in patients with a history of prostate cancer or those under active surveillance for low-risk disease.

In the Phase II stage, the primary objective is to evaluate the efficacy of INM176 at the RP2D in stabilizing or reducing plasma PSA levels after six cycles of treatment in post-RP and post-RT patients experiencing a rise in PSA.

Secondary objectives include pharmacokinetic (PK) evaluations following the first dose (Cycle 1 Day 1) in both Phase I and Phase II subjects, with an additional PK assessment on Cycle 1 Day 28 for Phase I subjects and on Cycle 2 Day 1 for Phase II subjects. Acute and chronic exposure PK parameters (including Cmax and AUC) will be correlated with safety outcomes and prostate-specific antigen (PSA) efficacy measures, when applicable, stratified by CYP2C19 and CYP3A4 metabolizer status.

Additional secondary objectives include evaluation of PSA change from baseline at protocol-specified timepoints; immunophenotyping of blood natural killer (NK) cells and other immune cell subsets; assessment of NK functional activity, plasma IL-8, and select cytokines; and measurement of male hormones and hormone-binding proteins. These pharmacodynamic biomarkers will be analyzed in relation to PSA response and PK metrics, with assessments conducted according to Phase I and Phase II study schedules.

Inclusion criteria

Phase I Inclusion Criteria

• Willingness and ability to give informed consent.
• Agree to comply with all study procedures and attend all study visits.
• Male aged >=40 years.
• History of prostate cancer diagnosis: Subjects with treated prostate cancer are eligible. Prior prostate cancer treatments must be clearly defined. Acceptable treatment modalities include surgery, radiation therapy, and previous use of antiandrogen therapy. Subjects with localized prostate cancer in low-risk group who were not on treatment or declined any treatment are eligible. Subjects with localized prostate cancer in the favorable intermediate-risk group who declined any treatment are eligible. Subjects with localized prostate cancer in the high-risk or unfavorable intermediate-risk group who have declined definitive therapy, including surgery, radiation therapy, or androgen deprivation therapy (ADT), are eligible.
• Subjects must not be undergoing concurrent radiation therapy or androgen deprivation therapy (ADT) at the time of enrollment.
• ECOG performance status 0-2.
• Subjects must have normal liver and kidney function at baseline: Total bilirubin within normal institutional limits. AST(SGOT)/ALT(SGPT) < 2.5 X upper limit of normal (ULN). Creatinine < 1.5 ULN or creatinine clearance > 50 mL/min/1.73 m2. Adequate bone marrow function: Hgb ≥ 9.0 g/dL, Platelets ≥ 100 x 109/L, absolute neutrophil count of ≥ 1.0 x 109/L).International Normalized Ratio (INR), Prothrombin Time (PT), and Partial Thromboplastin Time (PTT)within normal institutional limits.
• Subjects and their partners must agree to use two medically accepted methods of contraception and must agree to continue use these methods during the trial and for at least one week after the last dose of study drug. Acceptable methods of contraception include abstinence, barrier method with spermicide, intrauterine device (IUD) known to have a failure rate of less than 1% per year, or steroidal contraceptive (oral, transdermal, implanted, or injected) in conjunction with a barrier method. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post ovulation methods) withdrawal, spermicides only, or lactational amenorrhea are not acceptable methods of contraception.
• Subjects taking strong inhibitors or inducers of CYP3A4 or CYP2C19 must be evaluated for potential drug interactions with the study drug. Essential medications, such as statins, that cannot be discontinued may be allowed at the investigator's discretion.
• Subjects currently taking herbal supplements containing AGN extract, such as Cogni.Q, Decursinol-50, Ache Action, Fast-Acting Joint Formula, must discontinue these or any other supplements containing these products at least 4 weeks prior to starting study drug.

Phase II Inclusion Criteria

• Willingness and ability to give informed consent.
• Agree to comply with all study procedures and attend all study visits.
• Male aged >=40 years.
• Histologically confirmed adenocarcinoma of prostate (neuroendocrine or small cell prostate cancer excluded).
• Any T stage, N0-1, M0, any Gleason grade.
• Subjects must meet one of the following: Post-radical prostatectomy (RP) and/or post-radiation therapy (RT), including those with local recurrence declining further treatment. Localized prostate cancer who declined any treatment after physician discussion. Non-castrate status required: eligible subjects must have a serum total testosterone >50 ng/dL measured within 6 months prior to enrollment and must not have received systemic ADT (LHRH agonist/antagonist) within the prior 6 months. Subjects with bilateral orchiectomy are ineligible.
• No distant metastases disease confirmed by imaging (CT or MRI and bone scan or prostate-specific PET scan such as PSMA PET scan or Axumin PET scan) within 5 years prior to enrollment.
• Blood PSA level rising over 2 consecutive tests within the past 6 months, at least one week apart, with values ≥ 0.1 ng/mL.
• Not currently receiving concurrent androgen deprivation therapy (ADT). For subjects with a prior history of ADT, screening testosterone levels must be obtained and must be within a non-castrate range (>50 ng/dL) to be eligible for Phase II. Subjects without a history of ADT are not required to undergo testosterone screening.
• ECOG performance status 0-2.
• Subjects must have normal liver, kidney, and bone marrow function at baseline: Total bilirubin within institutional limits. AST(SGOT)/ALT(SGPT) < 2.5 X upper limit of normal (ULN). Creatinine < 1.5 ULN or creatinine clearance > 50 mL/min/1.73 m2. Adequate bone marrow function: Hgb ≥ 9.0 g/dL, Platelets ≥ 100 x 109/L, absolute neutrophil count ≥ 1.0 x 109/L.
• No evidence of any active secondary malignancy requiring ongoing treatment.
• Subjects must agree to use two medically accepted method of contraception and must agree to continue use this method while on the trial and through at least one week after the last dose of study drug. Acceptable methods of contraception include abstinence, barrier method with spermicide, intrauterine device (IUD) known to have a failure rate of less than 1% per year, or steroidal contraceptive (oral, transdermal, implanted, or injected) in conjunction with a barrier method. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post ovulation methods) withdrawal, spermicides only, or lactational amenorrhea are not acceptable methods of contraception.
• Subjects taking strong inhibitors or inducers of CYP3A4 or CYP2C19 will be evaluated for potential drug interactions with the study drug. Essential medications, such as statins, that cannot be discontinued may be allowed at the investigator's discretion.
• Subjects currently taking herbal supplements containing AGN extract, including Cogni.Q, Decursinol-50, Ache Action, Fast-Acting Joint Formula, must discontinue these or any other supplements containing these products at least 4 weeks prior to starting study drug.
• Prior Phase I subjects: must have completed ≥90 days washout from the last investigational product dose and meet all of the following: No treatment-related Grade 3 or higher adverse events occurred during Phase I, Any treatment-related adverse events have resolved to Grade 1 or less prior to Phase II enrollment, hepatic and renal function tests within protocol-defined limits, and investigator confirmation of clinical stability.

Phase I and II Exclusion Criteria:

• Subjects with distant metastatic cancer. Node-positive prostate cancer patients are allowed after completion of treatment.
• Subjects who are receiving systemic treatments such as chemotherapy, androgen deprivation therapy (ADT) or anti-androgen therapy including LHRH agonist, antagonist, GNRH analogs, and antiandrogens, or immunotherapy (checkpoint inhibitor) or investigational agents.
• Participants will be excluded if they have any uncontrolled intercurrent illness at the discretion of the treating investigator. This may include, but is not limited to, the following conditions: ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, uncontrolled diabetes mellitus (DM) with an HbA1C >9, uncontrolled asthma, or significant psychiatric illness that would limit compliance with study requirements.
• History of New York Heart Association Class III or IV heart failure, history of a myocardial infarction within 6 months, or any other cardiac-related problem that would be considered a contraindication for participation in the opinion of the treating physician.
• Any active secondary malignancy requiring treatment.
• Chronic kidney disease with calculated GFR <30 mL/min/1.73 m(2) using Cockcroft-Gault formula, or measured GFR <30 mL/min/1.73 m(2) using a 24-hour urine collection. The hospital's lab measured GFR can be used if a 24-hour collection is not possible.
• Subjects who are taking Warfarin/coumadin.