Determine Function of Antroquinonol in Combination With SOC in First Line Metastatic Pancreatic Cancer

A Phase I/II Study to Determine the MTD and to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy of Antroquinonol in Combination With SOC in First Line Metastatic Pancreatic Cancer

Antroquinonol is proposed for the treatment of neoplasms. The proposed clinical trial is a Phase I/II study designed to evaluate antroquinonol in combination with nab-paclitaxel and gemcitabine in first line treatment naïve subjects with Stage IV metastatic pancreatic carcinoma. The first part of study will focus on the treatment of pancreatic cancer with 200 mg TID and 300 mg TID, clinical treatment duration of 4 weeks, to determine the MTD or MFD (based on PK and capsules strength) of antroquinonol in combination with a standard dose regimen of nab-paclitaxel and gemcitabine. The extended Phase II will focus on the efficacy of antroquinonol with SOC. Safety and pharmacokinetic profiles will be studied in the proposed clinical trial.

Study Overview

• Status: Active, not recruiting
• Conditions: Pancreatic Neoplasm
• Intervention / Treatment: Drug: Antroquinonol

Detailed Description

Golden Biotech are planning a Phase I/II study to determine the maximum tolerable dose (MTD) and to evaluate safety/tolerability, pharmacokinetics, pharmacodynamics and preliminary efficacy of antroquinonol in combination with nab-paclitaxel-gemcitabine in first line metastatic pancreatic cancer.

Phase I

Run-in DDI and dose escalation:

The dose escalation part of the study will be conducted to characterize the safety of antroquinonol in combination with the standard of care (SOC) (nab-paclitaxel + gemcitabine) and to identify the MTD of antroquinonol in patients with metastatic pancreatic cancer. The MTD is the dose level at which <33% (2/6) of patients experience a DLT. Within the dose escalation part of the study, a total of 6 patients will be enrolled in a run-in DDI portion to assess the effect of antroquinonol (a cytochrome P450 [CYP]3A4/CYP2C8 inhibitor) on the PK of paclitaxel (a CYP3A4/CYP2C8 substrate). Patients within this cohort (Cohort 1) will receive treatment as follows:

• Cycle 0 (28-day cycle): nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2 (as per SOC) via intravenous (IV) infusion on Days 1, 8, and 15.
• Cycle 1 (28-day cycle): antroquinonol 200 mg administered TID on Days 1 through 28 and nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2 via IV infusion on Days 1, 8, and 15.

Intense PK sampling to assess the PK of paclitaxel will be conducted in Cycles 0 and 1. The primary PK endpoints will include Cmax, AUC0-t, and AUCinf. Available bioanalytical data will be assessed in an ongoing manner to assess the effect of antroquinonol on the systemic exposure (Cmax and AUCs) of paclitaxel. Data will be reviewed by the Safety Monitoring Committee (SMC) prior to enrollment of additional patients into the dose-escalation part of the study.

For Cohort 1, the occurrence of DLTs will be assessed from Day 1 to Day 28 of Cycle 1. If ≤1 patient experiences a DLT, dosing in the dose escalation part will proceed. If ≥2 patients experience a DLT, dosing in the dose escalation part of the study will be discontinued. If ≤1 patient in Cohort 1 experiences a DLT then dosing in Cohort 2 of the dose escalation part will proceed as follows: - All Cycles: antroquinonol 300 mg administered TID on Days 1 through 28 and nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2 via IV infusion on Days 1, 8, and 15 (ie, 1 cycle = weekly for 3 weeks, then 1 week off) .

Three patients will be enrolled initially into Cohort 2, these patients will be assessed for DLTs within the first 28-day dosing cycle. This cohort will be expanded to 6 total patients if 1 DLT is observed in the first 3 patients within Cohort 2. If ≤1 DLT is observed at the 300 mg dose then the 300 mg dose will be considered the MFD. If >1 DLT is observed at the 300 mg group then 200 mg will be considered the MTD and/or the SMC will review the available data and determine the MTD/recommended dose (RD).

Patients enrolled into the dose escalation part of the study (Cohorts 1 and 2) will continue to receive treatment with antroquinonol (200 or 300 mg, respectively) in combination with nab-paclitaxel + gemcitabine in 28-day cycles at the discretion of the Investigator without a maximum duration until unacceptable toxicity or progressive disease (PD).

The total number of patients to be entered in the dose escalation part of the study will depend on the emergence of DLTs at each dose level and the total number of dose levels investigated. Up to 12 patients are planned to be treated in the dose-escalation part if no patient needs to be replaced for DLT and safety evaluation.

Phase II

Cohort expansion:

During the cohort expansion part of the study, up to an additional 40 patients will be enrolled at the MTD or MFD/RD. The dose level in the cohort expansion phase will not exceed the MTD, or highest safe dose tested in the dose-escalation phase if MTD is not reached. Patients in the cohort expansion will receive treatment as follows:

- All Cycles: antroquinonol at the MTD or MFD/RD administered TID on Days 1 through 28 and nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2 via IV infusion on Days 1, 8, and 15 (ie, 1 cycle = weekly for 3 weeks, then 1 week off) .

Patients enrolled into the cohort expansion part of the study will continue to receive treatment with antroquinonol at the MTD or MFD/RD in combination with nab-paclitaxel + gemcitabine in 28-day cycles at the discretion of the Investigator without a maximum duration until unacceptable toxicity or PD.

• Study Type: Interventional
• Enrollment (Estimated): 52
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of, 5505
    • Asan Medical Center
  • Seoul, Korea, Republic of, 3722
    • Severance Hospital
  • Gyeonggi-do
    • Goyang-si, Gyeonggi-do, Korea, Republic of, 10408
      • National Cancer Center
• Taiwan
  • Tainan, Taiwan, 704
    • National Cheng Kung University Hospital
  • Taipei, Taiwan, 11217
    • Taipei Veterans General Hospital
• United States
  • Florida
    • Tampa, Florida, United States, 33613
      • Florida Hospital Tampa
  • Georgia
    • Newnan, Georgia, United States, 30265
      • CTCA Southeastern Regional Medical Center
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19124
      • Cancer Treatment Centers of America - Eastern Regional Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Male and female patients ≥18 years of age.
2. Histologically or cytologically confirmed metastatic adenocarcinoma of the pancreas, measurable according to the RECIST 1.1.
3. Diagnosed with metastatic disease within 6 weeks before enrollment.
4. Treatment-naïve patients with metastatic pancreatic adenocarcinoma who have received no previous systemic therapy (except adjuvant or neoadjuvant therapy if progression occurred >6 months from last treatment or surgery, respectively, and no prior nab-paclitaxel).

5. Adequate hematologic, hepatic, and renal function, including:

   • Hemoglobin ≥9 g/dL
   • Absolute neutrophil count ≥1500/mm3
   • Platelet count ≥100 000/mm3
   • Total bilirubin ≤1.25 × upper limit of normal (ULN)
   • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN; for patients with hepatic metastases, ALT and AST ≤5 × ULN
   • Albumin ≥3 mg/dL
   • Serum creatinine ≤1.5 mg/dL or calculated creatinine clearance ≥50 mL/min as determined by the Cockcroft-Gault equation.
6. ECOG performance status of 0 or 1.
7. For women of childbearing potential, a negative serum pregnancy test result at Screening.

8. Willing to use 2 medically accepted and effective methods of contraception from the list below during the study (both men and women as appropriate) and for 3 months after the last dose of study drug:

   1. Established use of oral, injected, or implanted hormonal methods of contraception
   2. Placement of an intrauterine device or intrauterine system
   3. Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository
   4. Male sterilization (with the appropriate postvasectomy documentation of the absence of sperm in the ejaculate)
   5. True abstinence (when this is in line with the preferred and usual lifestyle of the patient).
9. Patient must be able to provide written informed consent for participation in the study.
10. Life expectancy ≥12 weeks as assessed by the Investigator.

Exclusion Criteria:

1. Islet-cell neoplasms or locally advanced disease.
2. Chemo-, hormone-, or immunotherapy or investigational drug at Screening or prior to enrollment.
3. Treatment with any drug(s) known to be a strong inhibitor or inducer of CYP2C19,CYP3A4, CYP2C8, and CYP2E1 within 14 days of the date of first administration of study drug and during study treatment.
4. Other malignancies diagnosed within the past 5 years (other than curatively treated cervical cancer in situ, nonmelanoma skin cancer, superficial bladder tumors Ta [noninvasive tumor] and TIS [carcinoma in situ], or nonmetastatic prostate cancer Stage 1 to 2, which has been previously treated with surgery or radiation therapy, and serum prostate-specific antigen is within normal limits [test performed within the past 12 months prior to the date of first administration of study drug]).
5. Patients with any serious active infection (ie, requiring an IV antibiotic, antifungal, or antiviral agent).
6. Patients with known human immunodeficiency virus, active hepatitis B, or active hepatitis C.
7. Patients who have any other life-threatening illness or organ system dysfunction, which in the opinion of the Investigator, would either compromise patient safety or interfere with the evaluation of the safety of the study drug.
8. Known or suspected substance abuse or alcohol abuse.
9. Uncontrolled intercurrent illness, including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs from study treatment, or compromise the ability of the patient to give written informed consent.
10. Inability to swallow oral medications or a recent acute gastrointestinal disorder with diarrhea, (eg, Crohn's disease), malabsorption, or CTCAE Grade >2 diarrhea of any etiology at baseline.
11. Female patients who are pregnant or breastfeeding, or male or female patients of reproductive potential who are not employing an effective method of contraception.
12. Any known hypersensitivity to any component of nab-paclitaxel, gemcitabine, or antroquinonol.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Antroquinonol with SOC; Antroquinonol will first be conducted by dose escalation(200mg TID and 300mgTID) to characterize the safety of antroquinonol in combination with the standard of care (SOC) (nab-paclitaxel + gemcitabine) and to identify the MTD of antroquinonol in patients with metastatic pancreatic cancer. At the cohort expansion part of the study, up to an additional 40 patients will be enrolled at the MTD or MFD/RD.

Drug: Antroquinonol; Antroquinonol: 100 mg and corn oil 100 mg encapsulated in a gelatin capsule administered orally. Dose will be selected(200mg TID or 300mg TID with SOC) after phase I, then follow up the best dose for 40 Patients for the efficacy.; Other Names: Hocena

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MTD( phase I)	The MTD is the dose at which <33% of patients experience a dose limiting toxicity (DLT) within the first 28-day cycle of antroquinonol and nab-paclitaxel + gemcitabine combined treatment	4 weeks
tumor assessment in millimeters	measure tumor size by CT or MRI	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Body Surface Area in meter^2	measure patient's weight and height and calculated by {[Height (cm) × Adjusted Body Weight] × 1/3,600}^1/2	up to 48 weeks
Maximum Plasma Concentration	maximum observed plasma concentration of antroquinonol and paclitaxel	3 weeks
Area Under the Curve	Plasma concentrations of antroquinonol and paclitaxel will be measured and PK parameters calculated where applicable.	3 weeks
CA19-9 level in units per milli-liter	blood will be draw and measured. Other emerging antroquinonol biomarkers may be evaluated.	up to 48 weeks
Eastern Cooperative Oncology Group (ECOG) status	Medical Doctors judged the patient's performance status	up to 48 weeks

Collaborators and Investigators

• Sponsor: Golden Biotechnology Corporation
• Collaborators: Covance

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2017
• Primary Completion (Actual): November 1, 2023
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: October 1, 2017
• First Submitted That Met QC Criteria: October 10, 2017
• First Posted (Actual): October 16, 2017

Study Record Updates

• Last Update Posted (Actual): September 25, 2024
• Last Update Submitted That Met QC Criteria: September 23, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: metastatic pancreatic cancer; Antroquinonol; Hocena
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Endocrine System Diseases; Digestive System Neoplasms; Endocrine Gland Neoplasms; Pancreatic Diseases; Pancreatic Neoplasms
• Other Study ID Numbers: GHPanc-1-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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