Study of Lonsurf in Combination With Gemcitabine and Nab-Paclitaxel in Patients With Advanced (PDAC)

The purpose of this study is to determine the recommended phase 2 dose (RP2D) of the combination of lonsurf, gemcitabine and nab-paclitaxel in Pancreatic ductal adenocarcinoma (PDAC)

This is a single-institution, prospective, phase I dose escalation trial of lonsurf combined with gemcitabine and nab-paclitaxel using the 3+3 design. This study will enroll 18 patients over 12-15 months.

Primary Objective To determine the recommended phase 2 dose (RP2D) of the combination of lonsurf, gemcitabine and nab-paclitaxel

Secondary Objectives

1. Examine safety and toxicity of the combination
2. Estimate response rate to the combination
3. Estimate median overall survival (mOS) of the treated population
4. Estimate median progression free survival (mPFS) of the treated population
5. Estimate disease control rate (DCR) at 8 weeks
6. Evaluate quality of life while receiving the combination therapy

Eligibility Criteria:
Inclusion Criteria:

1. ≥ 18 years old at the time of informed consent
2. Ability to provide written informed consent and HIPAA authorization
3. Untreated locally advanced Pancreatic Ductal Adenocarcinoma (PDAC) as defined by National Comprehensive Cancer Network (NCCN) guidelines or, untreated metastatic PDAC (prior adjuvant therapy is permitted if it's been greater than 6 months since completion)
4. Histologically or cytologically confirmed PDAC
5. Confirmed PDAC that is measurable or evaluable per RECIST 1.1
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
7. Gastrointestinal symptoms (nausea, vomiting, and diarrhea) of Grade 1 or less
8. Adequate organ function as defined by:

   1. Aspartate transaminase (AST) and alanine transaminase (ALT) levels ≤ 2.5 x upper limits of normal (ULN)
   2. Total bilirubin level ≤ 1.5 x ULN
   3. Creatinine level \< 1.0 x ULN or creatinine clearance \> 60 mL/min/1.73 m2 for patients with creatinine levels above or below the institutional normal (as determined by Cockcroft-Gault equation). For patients with a Body Mass Index (BMI) \> 30 kg/m2, lean body weight should be used to calculate the glomerular filtration rate (GFR).
   4. Hemoglobin (Hgb) ≥ 9 g/dl
   5. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
   6. Platelets ≥ 100 x 109/L
   7. Acceptable coagulation studies as demonstrated by prothrombin time (PT) within normal limits (+/-15%) unless they are on anticoagulation therapy
9. Life expectancy estimated at ≥ 3 months
10. Women of childbearing potential definition (WOCBP) must have a negative serum or urine pregnancy test performed within 14 days prior to initiation of study treatment.

    Any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) is classified as WOCBP if she meets the following criteria:
    1. Has not undergone a hysterectomy or bilateral oophorectomy; or
    2. Has not been naturally postmenopausal for at least 24 consecutive months (i.e. has had menses at any time in the preceding 12 consecutive months).
11. WOCBP and men must agree to use adequate contraception prior, to study entry, for the duration of study participation, and 8 weeks after the end of treatment.

Exclusion Criteria:

1. Neuropathy \> Grade 1 at baseline
2. Prior systemic chemotherapy for any other malignancy (aside from adjuvant therapy for PDAC) in the last 3 years
3. Active malignancy other than PDAC (other than adequately treated cervical or vulvar carcinoma in situ, treated basal cell or squamous carcinoma of the skin, superficial bladder tumors (Ta, Tis \& T1), ductal carcinoma in situ (DCIS) of the breast and low grade prostate cancer. Any cancer curatively treated \>3 years prior to entry with no clinical evidence of recurrence is permitted)
4. Prior exposure to nab-paclitaxel, paclitaxel, or other taxanes
5. History of bowel obstruction in the preceding 3 months of therapy, including gastric outlet obstruction related to PDAC
6. Large, uncontrolled ascites requiring paracentesis
7. Major surgery, other than diagnostic or laparoscopic surgery, within 4 weeks prior to first dose. (Port placement would not be considered a surgery.)
8. Any known untreated brain metastases including leptomeningeal metastases
9. Pregnant or breastfeeding
10. Significant gastrointestinal disorder(s) that would, in the opinion of the Principal Investigator, prevent absorption of an orally available agent (e.g., Crohn's disease, ulcerative colitis, extensive gastric resection, and small intestinal resection)
11. Uncontrolled chronic diarrhea \> Grade 1 at baseline.
12. Uncontrolled intercurrent illness including, but not limited to uncontrolled active infection, clinically significant non-healing or healing wounds, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, significant pulmonary disease, uncontrolled infection, or psychiatric illness/social situations that would limit compliance with study requirements.
13. Interstitial pneumonia or extensive and symptomatic interstitial fibrosis of the lung
14. History of posterior reversible encephalopathy syndrome
15. Enrollment on any additional investigational agent study
16. Known hypersensitivity to gemcitabine or taxanes
17. Significant cardiac disease including the following: unstable angina, New York Heart Association class III-IV congestive heart failure, myocardial infarction \< 6 months prior to study enrollment
18. History of hemolytic-uremic syndrome
19. Known infection with Human Immunodeficiency Virus (HIV) and/or active infection with hepatitis B or hepatitis C