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.
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.
