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

Study Overview
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Brief Summary
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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)

Detailed Description
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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 Examine safety and toxicity of the combination Estimate response rate to the combination Estimate median overall survival (mOS) of the treated population Estimate median progression free survival (mPFS) of the treated population Estimate disease control rate (DCR) at 8 weeks Evaluate quality of life while receiving the combination therapy

Official Title
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Phase I Study of Lonsurf in Combination With Gemcitabine and Nab-Paclitaxel in Patients With Advanced Pancreatic Ductal Adenocarcinoma (PDAC)

Conditions
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Pancreatic Cancer, Pancreatic Ductal Adenocarcinoma

Intervention / Treatment
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* Drug: Lonsurf
* Drug: Gemcitabine
* Drug: Nab-Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥ 18 years old at the time of informed consent Ability to provide written informed consent and 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 RECIST 1.1 Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 Gastrointestinal symptoms (nausea, vomiting, and diarrhea) of Grade 1 or less Adequate organ function as defined by: 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 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). Hemoglobin (Hgb) ≥ 9 g/dl Absolute neutrophil count (ANC) ≥ 1.5 x 109/L Platelets ≥ 100 x 109/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. Exclusion Criteria: 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Interventional Model Description: Initially 3 patients will be enrolled to the starting cohort. If 1 of 3 patients experience a dose-limiting toxicity (DLT) in the first cycle, then an additional 3 evaluable patients will be accrued to that dose level. Dose reductions are not permitted during cycle 1. If 2 or more patients in a cohort experience a DLT, then the previous dose will be considered the recommended phase 2 dose (PR2D) and dose escalation will terminate. Dose escalation will proceed according to the scheme above only after all patients (3 or 6 evaluable patients, depending on the incidence of DLT) have been followed for at least 1 full cycle. Once dose escalation has been completed, if only 2 dose levels were used to determine the RP2D and depending on how many patients were replaced, additional patients will be enrolled at the RP2D in order to obtain data for 18 patients total.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Combination of lonsurf + gemcitabine + nab-paclitaxel<br> | Drug: Lonsurf<br>* Lonsurf will be administered orally twice a day on days 2-6 and 16-20 of every 28-day cycle at a dose of 25 mg/m2, 20 mg/m2 or 30 mg/m2 depending on cohort assignment.<br>Drug: Gemcitabine<br>* Gemcitabine will be intravenously administered on Days 1 and 15 of every 28-day cycle at a dose of 800 mg/m2, 600 mg/m2 or 1000 mg/m2 depending on cohort assignment.<br>Drug: Nab-Paclitaxel<br>* Nab-Paclitaxel will be intravenously administered on Days 1 and 15 of every 28-day cycle at a dose of 100 mg/m2, 75 mg/m2 or 125 mg/m2 depending on cohort assignment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of Dose Limiting Toxicities (DLTs) | Number of DLTs observed | 28 days (Cycle 1) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of adverse events in the safety evaluable population | safety and toxicity data will be assessed using NCI CTCAE v5.0 | from start of treatment until 30 days after treatment discontinuation (i.e up to 2 years) | 
| Response rate to the combination of lonsurf, gemcitabine, and nab-paclitaxel in the efficacy evaluable population | Using RECIST 1.1 | from start of treatment until treatment discontinuation (i.e. up to 2 years) | 
| Median Overall Survival (mOS) of the treated population |  | from start of treatment until death or last known follow up (i.e up to 2 years) | 
| Median Progression-free Survival (mPFS) of the treated population |  | from start of treatment until disease progression or last follow up (i.e. up to 2 years) | 
| Disease control rate (DCR) | Disease control rate (DCR) as defined by (complete response + partial response + stable disease) | 8 weeks | 
| European Organization for Research and Treatment of Cancer quality of life questionnaire | Scale scores were calculated by averaging items within scales and transforming average scores linearly. All of the scales range in score from 0 to 100. A high score for a functional scale represents a high/healthy level of functioning whereas a high score for a symptom scale or item represents a high level of symptomatology or problems. | Day 1 of each cycle(each cycle is 28 days),from start of treatment until disease progression or discontinuation of treatment (i.e. up to 2 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pancreatic Ductal Adenocarcinoma, Pancreatic Cancer, Metastatic Pancreatic Cancer, Locally Advanced Pancreatic Cancer