Intra-arterial Gemcitabine vs. IV Gemcitabine and Nab-Paclitaxel Following Radiotherapy for LAPC

Study Overview
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Brief Summary
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The study is a multi-center, un-blinded, randomized control study of subjects with locally advanced pancreatic adenocarcinoma which is unresectable.

Detailed Description
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All subjects will receive induction therapy of IV gemcitabine plus nab-paclitaxel, as well as radiation therapy for approximately four months. Subjects who remain eligible will then be randomized to receive either intra-arterial chemotherapy with gemcitabine; or to continue gemcitabine plus nab-paclitaxel. Subjects will receive the randomized treatments for up to 16 weeks or until progression. Both groups will receive either IV gemcitabine and nab-paclitaxel or oral capecitabine following the 16 week treatment course until disease progression at the discretion of the Investigator.

Official Title
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Targeted Intra-arterial Gemcitabine vs. Continuation of IV Gemcitabine Plus Nab-Paclitaxel Following Induction With Sequential IV Gemcitabine Plus Nab-Paclitaxel and Radiotherapy for Locally Advanced Pancreatic Cancer

Conditions
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Locally Advanced Pancreatic Cancer

Intervention / Treatment
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* Drug: Gemcitabine
* Drug: nab-paclitaxel
* Device: RenovoCath


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or Cytopathology confirmed pancreatic adenocarcinoma with initial diagnosis within 6 weeks of consent. Locally advanced, unresectable disease at screening and prior to randomization, as defined by NCCN criteria determined by an on-site, experienced, multidisciplinary team ECOG performance status 0-1 Age ≥ 18 years Adequate laboratory values prior to starting the first dose of nab-paclitaxel and gemcitabine: Absolute neutrophil count ≥ 1,500/μL Platelet count ≥ 100,000/μL Hemoglobin ≥ 9.0 g/dL Serum creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 50 mL/min/1.73 m2 for subjects with creatinine >1.5 mg/dL AST and ALT ≤ 3.0 X the upper normal limit of institution's normal range Total bilirubin ≤ 1.5 X the upper normal limit of institution's normal range -OR- If biliary stent placed or planned to be placed within 6 weeks of Cycle 1 Day 1, total bilirubin ≤ 2.0 X the upper normal limit of institution's normal range PT and PTT must be ≤ 1.5 X upper normal limit of institution's normal range INR ≤ 1.5 Life expectancy > 12 weeks Negative pregnancy test for women of childbearing potential (either serum or urine) within 1 day prior to administration of the first dose of chemotherapy. Women of childbearing potential should only use highly effective methods of contraception during treatment and for up to 6 months following treatment cessation. Provide written informed consent Subjects willing to participate in the study for at least 8 months Exclusion Criteria: Any prior treatment for pancreatic cancer OR more than one cycle of gemcitabine and nab-paclitaxel treatment. For subjects who have started on first cycle of gemcitabine and nab-paclitaxel treatment prior to consent, Inclusion Criterion #1 only applies in that the first gemcitabine and nab-paclitaxel dose must be within 6 weeks of confirmed diagnosis. Any evidence of metastatic disease or another active malignancy within the past one year except for cervical cancer in situ, in situ carcinoma of the bladder or non-melanoma carcinoma of the skin. Subjects unable or unwilling to have their first randomized treatment within 3 weeks of the post induction imaging and within 5 weeks of their last induction treatment Subjects without baseline tumor imaging To be determined by the sponsor and not by the site: Arterial anatomy unsuitable for IA delivery of gemcitabine to the intended tumor site, determined by CT or MRI, as determined and approved by the sponsor, which includes the following: Stenosis or occlusion in intended artery for treatment Inability to exclude major side branches in the area of the intended RenovoCath® catheter occlusion No suitable artery with a diameter greater than 3mm in proximity of at least one side of the tumor Superior mesenteric vein occlusion or stenosis that cannot be resolved with medication or intervention prior to randomization, if the superior mesenteric artery is the only viable treatment artery Note: Arterial Anatomy will be reviewed by the core imaging lab, RenovoRx Imaging Advisor, and RenovoRx Medical Monitor for approval Contraindications for SBRT planning which includes the following: Gastrointestinal mucosal infiltration evident at the time of diagnostic endoscopy Prior abdominal radiotherapy judged to have clinically significant degree of overlap with planned SBRT dose distribution Note: Primary tumors with a diameter greater than 7cm must be assessed on a case-by-case basis with the Central Radiation Reviewer prior to excluding patient from trial. Subjects with known HIV or active viral hepatitis Severe infections within 4 weeks prior to the first study treatment, including but not limited to hospitalization for complications of infection, bacteremia or severe pneumonia Signs or symptoms of infection within 2 weeks prior to the first study treatment Received oral or IV antibiotics for an infection within 2 weeks prior to the first study treatment. Subjects receiving prophylactic antibiotics are eligible History of severe allergic, anaphylactic, or other hypersensitivity reactions to gemcitabine or nab-paclitaxel Any anti-cancer therapy including chemotherapy, hormonal therapy, or radiotherapy within 2 weeks prior to initiation of study treatment; or herbal therapy intended as anti-cancer therapy within 1 week prior to initiation of study treatment Subjects with uncontrolled seizures Cardiovascular disease including unstable angina or life-threatening cardiac arrhythmia, myocardial infarction, stroke; or NYHA Class III or IV congestive heart failure within the last 3 months prior to the first study treatment. Subjects with prior history of Myocardial Infarction, congestive heart failure, coronary artery bypass grafting, or prior valve surgery need to have assessment of ejection fraction to ensure EF is not ≤ 40% (based upon MRI, ECHO, or Nuclear Scan), within last 3 months prior to the first study treatment Other severe concurrent disease, or comorbidities which make it difficult to participate in this study. Any of the following procedures prior to initiation of study treatment: Catheterization, endoscopy, stent or drain placement, within 48 hours. (Diagnostic laparoscopy without surgical intervention and/or port placement do not require any wait time prior to study treatment.) Minor surgery requiring light sedation (such as surgical laparoscopy) within 2 weeks Major surgery within 4 weeks Women who are breastfeeding Male or female subjects of reproductive potential who do not agree to either remain abstinent or employ highly effective and acceptable forms of contraception throughout their participation in the study and for 6 months after the last study treatment Subjects receiving any other investigational agents within 2 weeks prior to the first study treatment Any social situations or psychiatric illness that would limit compliance with study requirements Subjects unable or unwilling to have standard catherization procedure

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Subjects with stable or responding disease after approximately four months of induction therapy, and who are not surgical candidates will then be randomized to be in either the test group or control group. Crossovers are not allowed.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IA Therapy<br>IA Treatments with 1,000 mg/m2 gemcitabine administered through RenovoCath every other week for a maximum of 8 treatments for approximately 16 weeks. | Drug: Gemcitabine<br>* Chemotherapy<br>* Other names: Gemzar;Device: RenovoCath<br>* Intra-arterial catheter<br>* Other names: RenovoCath RC120;|
| Active Comparator: IV Therapy<br>IV gemcitabine and nab-paclitaxel will be administered for 16 weeks on days 1, 8, and 15 of a 28 day cycle. Nab-paclitaxel will be administered intravenously following pre-medication at a dose of 125 mg/m2 over 30 minutes followed by an infusion of gemcitabine at a dose of 1000 mg/m2 over 30 minutes. | Drug: Gemcitabine<br>* Chemotherapy<br>* Other names: Gemzar;Drug: nab-paclitaxel<br>* Chemotherapy<br>* Other names: Abraxane;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | OS from time of randomization will be calculated using the Kaplan-Meier method and compared between the test and control groups using the stratified Log-Rank Test | 3 Years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival for treatment received and unresected populations | The primary endpoint analysis will be repeated for the Treatment Received and Unresected Subject populations. | 3 Years | 
| Progression Free Survival | To compare the Progression Free Survival of intra-arterial delivery of gemcitabine using the RenovoCath™ device vs. continuation of IV gemcitabine and nab-paclitaxel following induction therapy with gemcitabine and nab-paclitaxel and radiation treatment for locally advanced pancreatic adenocarcinoma. Disease response and progression will be assessed according to RECIST 1.1. | 3 Years | 
| Objective response rate and duration of response | Objective response is defined as a complete response, CR, or partial response, PR, determined by Investigator assessment and confirmed by repeat assessment ≥ 4 weeks after initial documentation. | 3 Years | 
| Health Related Quality of Life | The EORTC questionnaire will be used to assess health related quality of life. The summary scores for the EORTC questionnaire will be calculated at baseline and follow-up. | 3 Years | 
| Neuropathy Assessment | The degree of neuropathy will be measured by the FACT/GOG-NTX-4 (version 4). The results will be cross tabulated by randomized treatment group for each study visit. | 1 Year | 
| Frequency of neutropenia | Neutropenia with onset after randomization requiring the use of filgrastim or other medications for white blood cell stimulation will be compared between the test and control groups through progression of disease. | 1 Year | 
| Patient reported symptoms | Symptoms reported by subjects using the PRO-CTCAE questionnaire will be compared between the test and control groups through progression of disease. | 3 years | 
| Safety, defined as adverse event rate, and tolerability, defined as occurrence of treatment discontinuation | Safety and tolerability will be assessed by the occurrence of treatment discontinuation and the presence of adverse events | 3 years |