Lonsurf, Gemcitabine, and Nab-Paclitaxel for the Treatment of Patients with Advanced Pancreatic Ductal Adenocarcinoma
- Ability to provide written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization.
- 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).
- Histologically or cytologically confirmed PDAC.
- Confirmed PDAC that is measurable or evaluable per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
- Gastrointestinal symptoms (nausea, vomiting, and diarrhea) of grade 1 or less.
- Aspartate transaminase (AST) and alanine transaminase (ALT) levels =< 2.5 X upper limits of normal (ULN).
- Total bilirubin level =< 1.5 X ULN.
- Creatinine level < 1.0 X ULN or creatinine clearance > 60 mL/min/1.73 m^2 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/m^2, lean body weight should be used to calculate the glomerular filtration rate (GFR).
- Hemoglobin (Hgb) >= 9 g/dl.
- Absolute neutrophil count (ANC) >= 1.5 X 10^9 /L.
- Platelets >= 100 X 10^9 /L.
- Acceptable coagulation studies as demonstrated by prothrombin time (PT) within normal limits (+/- 15%) unless they are on anticoagulation therapy.
- Life expectancy estimated at >= 3 months.
- 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: * Has not undergone a hysterectomy or bilateral oophorectomy; or * 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).
- 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.
- Neuropathy > grade 1 at baseline.
- Prior systemic chemotherapy for any other malignancy (aside from adjuvant therapy for PDAC) in the last 3 years.
- 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)
- Prior exposure to nab-paclitaxel, paclitaxel, or other taxanes.
- History of bowel obstruction in the preceding 3 months of therapy, including gastric outlet obstruction related to PDAC.
- Large, uncontrolled ascites requiring paracentesis.
- Major surgery, other than diagnostic or laparoscopic surgery, within 4 weeks prior to first dose (PORT placement would not be considered a surgery).
- Any known untreated brain metastases including leptomeningeal metastases.
- Pregnant or breastfeeding.
- 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).
- Uncontrolled chronic diarrhea > grade 1 at baseline.
- 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.
- Interstitial pneumonia or extensive and symptomatic interstitial fibrosis of the lung.
- History of posterior reversible encephalopathy syndrome.
- Enrollment on any additional investigational agent study.
- Known hypersensitivity to gemcitabine or taxanes.
- 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.
- History of hemolytic-uremic syndrome.
- Known infection with human immunodeficiency virus (HIV) and/or active infection with hepatitis B or hepatitis C.
I. To determine the recommended phase 2 dose (RP2D) of the combination of trifluridine and tipiracil hydrochloride (Lonsurf), gemcitabine and nab-paclitaxel.
I. Examine safety and toxicity of the combination.
II. Estimate response rate to the combination.
III. Estimate median overall survival (mOS) of the treated population.
IV. Estimate median progression free survival (mPFS) of the treated population.
V. Estimate disease control rate (DCR) at 8 weeks.
VI. Evaluate quality of life while receiving the combination therapy.
I. Serial blood samples will be collected and stored for future correlative studies.
OUTLINE: This is a dose-escalation study.
Patients receive nab-paclitaxel intravenously (IV) over approximately 30 minutes on days 1 and 15, gemcitabine IV over approximately 30 minutes on days 1 and 15, and trifluridine and tipiracil hydrochloride orally (PO) twice daily (BID) on days 2-6 and 16-20. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days and then every 3 months for 2 years.
Trial Phase Phase I
Trial Type Treatment
Indiana University / Melvin and Bren Simon Cancer Center
Patrick J. Loehrer
- Primary ID IUSCC-0664
- Secondary IDs NCI-2019-03668
- Clinicaltrials.gov ID NCT04046887