This study is to obtain acute dose safety and pharmacokinetics/pharmacodynamics (PK/PD) data in a dose-response trial in prostate cancer patients.

The long-term goal of the study is to conduct human clinical trials to test Angelica gigas Nakai (AGN) root alcoholic extract herbal supplement product (AGN-Cogni.Q, or Cogni.QTM, made with INM®176 proprietary ingredient, Quality of Life Laboratories, Purchase, NY) as a safe and potential efficacious modality for prostate cancer interception akin to secondary prevention to delay hormonal therapy or avoid it entirely after patients have developed recurrent disease following their standard of care (SOC) surgery and radiation curative treatment. The acute dose safety and pharmacokinetics (PK) and pharmacodynamics (PD) information in the target patient population from the current proposed acute PK dose-response trial will inform the optimal design and execution of the longer-term safety and efficacy (phase I/II) trials.

Inclusion Criteria:

1. Willingness and ability to give informed consent.

2. Agree to comply with all study procedures and attend all study visits to the best of their ability.

3. Male with age >=40 years.

4. History of prostate cancer diagnosis. Subjects with history of neuroendocrine or small cell prostate cancer will be excluded. Subjects are eligible if meet one or more of the below criteria:

   1. Patients treated forprostate cancer and no detectable disease on imaging and clinical determination are eligible for enrollment, regardless of risk category.
   2. Patients in the low-risk and favorable intermediate-risk groups who are not currently receiving any treatment or have declined any treatment.

5. Not on concurrent androgen deprivation therapy.

6. ECOG performance status 0-2.

7. Life expectancy of greater than 12 months.

8. Subjects must have normal liver and kidney function as defined below:

   • a) total bilirubin within normal institutional limits,
   • b) AST(SGOT)/ALT(SGPT) < 2.5 X institutional upper limit of normal,
   • c) Creatinine within 1.5 ULN of institutional limits OR creatinine clearance > 50 mL/min/1.73 m2 for subjects with creatinine levels above institutional normal.
   • d) Adequate bone marrow function (Hgb ≥ 9.0 g/dL, Platelets ≥ 100 x 109/L, absolute neutrophil count (ANC) of ≥ 1.5 x 109/L), except for subjects with a history of chronic benign neutropenia, where an ANC of ≥ 1.0 x 109/L are eligible.

9. 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.

10. Subjects must stop the CYP3A4 and CYP2C19 strong inhibitors or inducers 2 weeks prior to the start of the study and during the study.

11. Subjects currently taking herbal supplements containing AGN extract, including CognI.Q, Decursinol-50, Ache Action, Fast-Acting Joint Formula, EstroG-100/Profemin must discontinue these or any other supplements containing these products 4 weeks prior to starting study drug.

Exclusion Criteria:

1. Subjects with distant metastatic cancer. Node positive prostate cancer patients are allowed after completion of treatment.
2. Subjects who are receiving chemotherapy, or oral TKI, or immunotherapy (checkpoint inhibitor).
3. Subjects who are receiving any other investigational agents.
4. Uncontrolled intercurrent illness that would limit compliance with study requirements.
5. All vulnerable patient populations.
6. History of New York Heart Association Class III or IV heart failure, history of a myocardial infarction within 6 months, any uncontrolled cardiac arrhythmia, or any other cardiac related problem that would be considered a contraindication for participation in the opinion of the treating physician.
7. Use of androgen deprivation therapy (ADT) or anti-androgen therapy including LHRH agonist, antagonist, GNRH analogs, and antiandrogens.
8. Subjects who are taking Warfarin/Coumadin.

participant eligibility is based on self-representation of gender identity.

All research materials and data, generated by this grant, will be distributed freely or deposited into a repository/stock center making them available to the broader scientific community, either before or immediately after publication.

One year after publication

Deidentified individual participant data will be available to qualified researchers upon reasonable request to the study investigators, following publication and in accordance with institutional and NIH data sharing policies.

The baseline analysis population includes all subjects who were enrolled and received at least one dose of the study intervention (800 mg). This population (N=12) was used for all demographic and baseline safety characteristic assessments.

Adverse events were monitored from the first dose of the study drug until 4 weeks (± 7 days) following the final dose for each participant.

Adverse events were graded using CTCAE v5.0. Both related and unrelated events are included. Events were identified through systematic assessments including laboratory tests, ECGs, and physical examinations. This was a sequential dose-escalation study in which participants could receive multiple dose levels; therefore adverse events are summarized across doses rather than reported separately by dose.

The second participant of the trial experienced an herbal-drug adverse interaction at the first dose of AGN-Cogni.Q (800 mg) with warfarin (7.5 mg) anti-coagulant maintenance medication, leading to increased bleeding risk as measured by PT/INR (from 2 to 8). Persons taken warfarin blood thinner drug should not take AGN supplement to avoid this bleeding risk.