Safety and Efficacy Study of PRI-724 Plus Gemcitabine in Subjects With Advanced or Metastatic Pancreatic Adenocarcinoma

• Pharmacokinetic parameters of C max , T max , AUC (tau), and t ½. [ Time Frame: C 1 D 1 hrs 0, 1, 2, D 8 hrs 0, :15, :30, 1, 2, 4, 6, D 9 hrs 24, D 15 at hrs 0 ] [ Designated as safety issue: No ]
  The secondary outcome measures of PKs, PDs, MMP7, hair follicle sampling, and Response Criteria by RECIST comprise the correlative studies of this trial and are designed to evaluate PK profiles, assess and evaluate the utility of potential biomarkers, and evaluate antineoplastic activity of PRI-724 + Gemcitabine.
• Pharmacodynamic mRNA expression of survivin [ Time Frame: C 1 D 1, D 8, D 15, D 22, All Cycles D 22, end of treatment ] [ Designated as safety issue: No ]
  The secondary outcome measures of PKs, PDs, MMP7, hair follicle sampling, and Response Criteria by RECIST comprise the correlative studies of this trial and are designed to evaluate PK profiles, assess and evaluate the utility of potential biomarkers, and evaluate antineoplastic activity of PRI-724 + Gemcitabine
• Evaluation of antineoplastic activity of PRI-724 + gemcitabine per RECIST 1.1 criteria [ Time Frame: Screening, end of C 2, every 2 cycles, end of treatment ] [ Designated as safety issue: No ]
  The secondary outcome measures of PKs, PDs, MMP7, hair follicle sampling, and Response Criteria by RECIST comprise the correlative studies of this trial and are designed to evaluate PK profiles, assess and evaluate the utility of potential biomarkers, and evaluate antineoplastic activity of PRI-724 + Gemcitabine
• MMP7 levels in blood as ng/ml [ Time Frame: C 1 Wk 1, Wk 4, Wk 4 all cycles, end of treatment ] [ Designated as safety issue: No ]
  The secondary outcome measures of PKs, PDs, MMP7, hair follicle sampling, and Response Criteria by RECIST comprise the correlative studies of this trial and are designed to evaluate PK profiles, assess and evaluate the utility of potential biomarkers, and evaluate antineoplastic activity of PRI-724 + Gemcitabine.
• Gene expressions in hair follicle epithelial cells [ Time Frame: Screening, C 1 D 14, C 2 Wk 4, end of treatment ] [ Designated as safety issue: No ]
  The secondary outcome measures of PKs, PDs, MMP7, hair follicle sampling, and Response Criteria by RECIST comprise the correlative studies of this trial and are designed to evaluate PK profiles, assess and evaluate the utility of potential biomarkers, and evaluate antineoplastic activity of PRI-724 + Gemcitabine

Laboratory studies suggest that the study drug may stop cancer cells from growing by affecting an interaction between proteins in the cells referred to as cAMP-response element-binding protein and ß-catenin.

The purpose of this research study is to determine the highest safe dose of study drug that may be used when it is given together with a chemotherapy drug to patients with cancer of the pancreas.

PRI-724 is a small molecule antagonist that binds to the co-activator CBP thereby specifically inhibiting the subset of Wnt/β-catenin-driven genes that are up-regulated in cancer cells. PRI-724 is being developed as a potential antineoplastic agent.

Purpose:

To determine the safety, tolerability, dose-limiting toxicities (DLTs), and maximum tolerated dose (MTD) of sequential escalating doses per cohort of PRI-724 administered in combination with gemcitabine to patients with adenocarcinoma of the pancreas that is locally advanced, metastatic, or otherwise inoperable, who are candidates for second-line therapy after failing first-line therapy with FOLFIRINOX (i.e., folinic acid [leucovorin], fluorouracil, irinotecan, oxaliplatin)

• PRI-724: 320, 640, 905 mg/m2/day, continuous intravenous (CIV) infusion over 24 h, daily × 7 days, 1 week on with 1 week recovery × 2 (4 weeks equals 1 cycle)
• Gemcitabine: 1000 mg/m2 IV over 30 minutes; 3 weeks on with 1 week recovery (4 weeks equals 1 cycle)

Patients with documented, measurable or evaluable adenocarcinoma of the pancreas that is locally advanced, metastatic, or otherwise inoperable, who are candidates for second-line therapy after failing first-line therapy with FOLFIRINOX, will be entered into this phase 1b, multicenter, open-label, non-randomized, dose-escalation per cohort study. The trial is designed to evaluate the safety, tolerability, DLT(s), and MTD of escalating doses of PRI-724, a CBP/ β- catenin inhibitor, when administered in combination with a standard dose of gemcitabine. Correlative studies include characterization of the PK profiles of PRI-724 and gemcitabine, evaluation of the utility of potential PD markers of PRI-724 activity, as well as preliminary assessment of the antineoplastic activity of PRI-724 plus gemcitabine in this patient population.

• Advanced Pancreatic Cancer
• Metastatic Pancreatic Cancer
• Pancreatic Adenocarcinoma

Inclusion Criteria:

1. Male or female patients, > 18 years of age.
2. Patients with a documented (histologically- or cytologically-proven) epithelial cell/adenocarcinoma of the pancreas that is relapsed, locally advanced, or metastatic.
3. Patients with measurable or evaluable disease according to the response evaluation criteria in solid tumors
4. Patients eligible for second-line therapy after failing first-line therapy with the regimen FOLFIRINOX.
5. Patients with a malignancy that is currently not amenable to surgical intervention, due to either medical contraindications or non-resectability of the tumor.
6. Patients with a Karnofsky Performance Status of 70% to 100% (or equivalent, Eastern Cooperative Oncology Group [ECOG] performance status of 0 or 1); Performance Status Evaluation), and an anticipated life expectancy of ≥ 3 months.
7. Patients, both male and female, who are either not of childbearing potential or who agree to use a medically effective method of contraception during the study and for 3 months after the last dose of study drug.
8. Patients with the ability to understand and give written informed consent for participation in this trial, including all evaluations and procedures as specified by this protocol.

Exclusion Criteria:

1. Women who are pregnant or lactating. Women of child-bearing potential (WOCBP) and fertile men with a WOCBP partner, not using adequate birth control.
2. Patients with islet cell tumors or other non-epithelial cell malignancies of the pancreas.
3. Patients with known CNS (or leptomeningeal) metastases not controlled by prior surgery or radiotherapy, or patients with symptoms suggesting CNS involvement for which treatment is required.

4. Patients with an active second malignancy within the last 2 years with the exception of:

   • Treated, non-melanoma skin cancers
   • Treated CIS of the breast or cervix
   • Controlled, superficial bladder carcinoma
   • T1a or b prostate carcinoma involving < 5% of resected tissue and PSA within normal limits (WNL) since resection

5. Patients with any of the following hematologic abnormalities at baseline:

   • Hemoglobin < 9.0 g/dL
   • Absolute neutrophil count (ANC) < 1,500 per mm3
   • Platelet count < 100,000 per mm3

6. Patients with any of the following serum chemistry abnormalities at baseline:

   • Total bilirubin > 1.5× the ULN for the institution, unless considered due to Gilbert's Syndrome
   • AST or ALT > 3× the ULN for the institution (> 5× ULN if due to hepatic involvement by tumor)
   • Serum albumin < 2.5 g/dL
   • Serum creatinine > 1.5× ULN (or a calculated creatinine clearance < 60 mL/min/1.73 m2)

7. Patients with a significant cardiovascular disease or condition, including:

   • Congestive heart failure (CHF) currently requiring therapy
   • Need for anti-arrhythmic therapy for a ventricular arrhythmias
   • Severe conduction disturbances
   • Angina pectoris requiring therapy
   • Left ventricular ejection fraction (LVEF) < 50% by MUGA or echocardiogram
   • QTcF interval > 450 msec (males) or > 470 msec (females)
   • Uncontrolled hypertension (per Investigator's discretion)
   • Class III or IV cardiovascular disease according to the New York Heart Association's (NYHA) Functional Criteria.
   • Myocardial infarction (MI) within 6 months prior to first study drug administration
8. Patients with known osteopenia or osteoporosis.
9. Patients with a known or suspected hypersensitivity to either gemcitabine or any of the components of PRI-724.
10. Patients with a history of human immunodeficiency virus (HIV) or active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV).
11. Patients with any other serious/active/uncontrolled infection, any infection requiring parenteral antibiotics, or unexplained fever > 38ºC within 2 weeks prior to first study drug administration.
12. Patients with inadequate recovery from acute toxicity associated with any prior antineoplastic therapy
13. Patients with inadequate recovery from any prior surgical procedure, or patients having undergone any major surgical procedure within 1 month prior to first study drug administration.
14. Patients with any other life-threatening illness, significant organ system dysfunction, or clinically significant laboratory abnormality, which, in the opinion of the Investigator, would either compromise the patient's safety or interfere with evaluation of the safety of the study drug
15. Patients with a psychiatric disorder or altered mental status that would preclude understanding of the informed consent process and/or completion of the necessary studies
16. Patients with the inability, in the opinion of the Investigator, to comply with the protocol requirements