Clinical trial NCT03257033: Intra-arterial Gemcitabine vs. IV Gemcitabine and Nab-Paclitaxel Following Radiotherapy for LAPC
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Locally Advanced Pancreatic Cancer
Lead sponsor: RenovoRx
Sponsor class: INDUSTRY
First posted: 2017-08-22
Enrollment: 190
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: TREATMENT

Brief summary: The study is a multi-center, open-label, randomized active controlled study of subjects with locally advanced pancreatic adenocarcinoma which is unresectable.

Detailed description: All subjects will receive induction therapy of IV gemcitabine plus nab-paclitaxel, as well as SBRT radiation therapy for approximately a total of 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 and then followed for survival for five years.

Eligibility criteria: Inclusion Criteria:

1. Histologically or Cytopathology confirmed pancreatic adenocarcinoma with initial diagnosis within 6 weeks of consent for patients who enroll at cycle 1, and from the start of cycle 1 of gemcitabine + nab-paclitaxel chemotherapy for patients who enroll at cycle 2
2. Locally advanced, unresectable disease at screening and prior to randomization, as defined by NCCN criteria determined by an on-site, experienced, multidisciplinary team (as confirmed by CT or MRI within 30 days of the start of cycle 1)
3. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1
4. Age ≥ 18 years
5. Adequate laboratory values prior to receiving the first dose of nab-paclitaxel and gemcitabine: (criterion must be met prior to cycle 2.) For a subject with elevated bilirubin, AST or ALT, who has had a biliary stent placed, if the subject's lab values have returned to within the required range for eligibility noted below in sub-criteria e and f \[(AST) ALT ≤ 3.0 X the upper normal limit, and total bilirubin ≤ 1.5 X the upper normal limit\] after placement of stent and prior to cycle 2, he/she is eligible for the study. Additional detail regarding eligibility for subjects who have had biliary stents recently placed is outlined in sub-criteria f and h below.

   1. Absolute neutrophil count (ANC) ≥ 1,500/μL
   2. Platelet count ≥ 100,000/μL
   3. Hemoglobin ≥ 9.0 g/dL
   4. Serum creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 50 mL/min/1.73 m2 for subjects with creatinine \>1.5 mg/dL
   5. \*Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3.0 X the upper normal limit of institution's normal range
   6. \*Total bilirubin ≤ 1.5 X the upper normal limit of institution's normal range -OR- If biliary stent is placed or planned to be placed within 6 weeks of Cycle 1 Day 1 (C1D1), total bilirubin ≤ 2.0 X the upper normal limit of institution's normal range (see section 9.1.4 for dose modification due to elevated bilirubin)
   7. Prothrombin time (PT) and partial thromboplastin time (PTT) must be ≤ 1.5 X upper normal limit of institution's normal range. Subjects who are currently taking anti-coagulant therapy are eligible if not meeting this criterion
   8. International normalized ration (INR) ≤ 1.5 X upper normal limit of institution's normal range. Subjects who are currently taking anti-coagulant therapy are eligible if not meeting this criterion \*For elevated AST, ALT, and total bilirubin at screening, subject must have a normalized result prior to initiation of Cycle 2 if abnormal labs are considered related to bile duct obstruction and a biliary stent has been placed
6. Life expectancy \> 12 weeks
7. Negative pregnancy test for women of childbearing potential (either serum or urine) within one day prior to administration of the first dose of chemotherapy. Women of childbearing potential should use highly effective methods of contraception during treatment and for up to 6 months following treatment cessation
8. Provide written informed consent
9. Subjects willing to participate in the study for at least 8 months if randomized to IA gemcitabine OR IV gemcitabine + nab-paclitaxel

Exclusion Criteria:

1. Any prior treatment for pancreatic cancer OR more than one cycle of gemcitabine and nab-paclitaxel treatment. For subjects who have started on their first cycle of gemcitabine and nab-paclitaxel treatment prior to consent, Inclusion Criterion #1 only applies to the first gemcitabine and nab-paclitaxel dose and must be within 6 weeks of confirmed diagnosis
2. 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.
3. 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
4. Subjects without baseline tumor imaging
5. As determined by the Sponsor:

   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 Imaging Advisor, which includes the following:
   1. Stenosis or occlusion in the intended artery for treatment
   2. Inability to exclude major side branches in the area of the intended RenovoCath® catheter occlusion
   3. No suitable artery with a diameter greater than 3 mm in proximity of at least one side of the tumor
   4. Superior mesenteric vein (SMV) occlusion or stenosis that cannot be resolved with medication or intervention prior to randomization, if the superior mesenteric artery (SMA) is the only viable treatment artery Note: Arterial Anatomy will be reviewed by the Sponsor, RenovoRx Imaging Advisor, and RenovoRx Medical Monitor for approval
6. Contraindications for SBRT planning which includes the following:

   1. Gastrointestinal mucosal infiltration evident at the time of diagnostic endoscopy
   2. Prior abdominal radiotherapy judged to have clinically significant degree of overlap with planned SBRT dose distribution Note: Primary tumors with a diameter greater than 7 cm must be assessed on a case-by-case basis with the RenovoRx Imaging Advisor prior to excluding the subject from the trial.
7. Subjects with known HIV infection or active viral hepatitis
8. Severe infections requiring hospitalization within 4 weeks prior to the first study treatment, including but not limited to complications of infection, bacteremia or severe pneumonia
9. Signs or symptoms of infection within 2 weeks prior to the first study treatment, as assessed by the Investigator
10. Received antibiotics for treatment of an infection within 48 hours prior to initiation of study treatment. Subjects receiving prophylactic antibiotics are eligible
11. History of severe allergic, anaphylactic, or other hypersensitivity reactions to gemcitabine or nab-paclitaxel
12. Any anti-cancer therapy including chemotherapy, hormonal therapy for prostate cancer, 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
13. Subjects with uncontrolled seizures
14. Cardiovascular disease including unstable angina or life-threatening cardiac arrhythmia, myocardial infarction, stroke; or New York Heart Association (NYHA) Class III or IV congestive heart failure (CHF) within the last 3 months prior to the first study treatment. Subjects with prior history of Myocardial Infarction (MI), congestive heart failure (CHF), coronary artery bypass grafting, or prior valve surgery need to have assessment of ejection fraction (EF) to ensure EF is not ≤ 40% (as determined by MRI, ECHO, or Nuclear Scan), within the last 3 months prior to the initiation of study treatment
15. Other severe concurrent disease or comorbidities which make it difficult to participate in this study, as assessed by Investigator
16. Any of the following procedures prior to initiation of study treatment:

    1. 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)
    2. Minor surgery requiring light sedation (such as surgical laparoscopy) within 2 weeks
    3. Major surgery within 4 weeks
17. Women who are breastfeeding
18. 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
19. Subjects receiving any other investigational agents within 2 weeks prior to the initiation of treatment
20. Any social situations or psychiatric illness that would limit compliance with study requirements
21. Subjects unable or unwilling to have standard catheterization procedure

Primary outcomes:
measure: Overall Survival
timeFrame: Up to Five Years
Secondary outcomes:
measure: Overall Survival for treatment received and unresected populations
timeFrame: Up to Five Years
measure: Progression Free Survival
timeFrame: Up to Five Years
measure: Objective response rate and duration of response
timeFrame: Up to Five Years
measure: Health Related Quality of Life
timeFrame: Up to Five Years
measure: Neuropathy Assessment
timeFrame: 1 Year
measure: Frequency of neutropenia
timeFrame: 1 Year
measure: Patient reported symptoms
timeFrame: Up to Five Years
measure: Safety, defined as adverse event rate, and tolerability, defined as occurrence of treatment discontinuation
timeFrame: Up to Five Years
Other outcomes:
Locations:
city: Loma Linda
country: United States
facility: VA Loma Linda Healthcare System
state: California
city: Sacramento
country: United States
facility: Sutter Cancer Center Sacramento
state: California
city: Denver
country: United States
facility: Rocky Mountain Cancer Centers
state: Colorado
city: Englewood
country: United States
facility: Comprehensive Cancer Care and Research Institute of Colorado, CCCRIC
state: Colorado
city: Washington
country: United States
facility: Sibley Memorial Hospital - a member of Johns Hopkins medicine
state: District of Columbia
city: Washington
country: United States
facility: Georgetown University
state: District of Columbia
city: Fort Myers
country: United States
facility: 21st Century Oncology
state: Florida
city: Miami
country: United States
facility: Miami Cancer Center
state: Florida
city: Sarasota
country: United States
facility: Sarasota Memorial Health Care System
state: Florida
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Weeki Wachee
country: United States
facility: ASCLEPES Research Centers
state: Florida
city: Columbus
country: United States
facility: Piedmont-Columbus Regional - John B. Amos Cancer Center
state: Georgia
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics - Holden Comprehensive Cancer Center
state: Iowa
city: New Orleans
country: United States
facility: Ochsner Clinic Foundation
state: Louisiana
city: Shreveport
country: United States
facility: LSU Health Shreveport
state: Louisiana
city: Baltimore
country: United States
facility: Medstar Franklin Square
state: Maryland
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Lebanon
country: United States
facility: Dartmouth-Hitchcock Medical Center
state: New Hampshire
city: Camden
country: United States
facility: MD Anderson Cancer Center at Cooper Hospital
state: New Jersey
city: Morristown
country: United States
facility: Atlantic Health System - Morristown Medical Center
state: New Jersey
city: Albany
country: United States
facility: Albany Stratton VA Medical Center
state: New York
city: Bronx
country: United States
facility: Montefiore Hospital
state: New York
city: Manhasset
country: United States
facility: Feinstein Institutes for Medical Research - Northwell Health
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Charlotte
country: United States
facility: Levine Cancer Institute - Atrium Health
state: North Carolina
city: Greenville
country: United States
facility: East Carolina University
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest Baptist Comprehensive Cancer Center
state: North Carolina
city: Oklahoma City
country: United States
facility: Oklahoma University - Stephenson Cancer Center
state: Oklahoma
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina - Hollings Cancer Center
state: South Carolina
city: Greenville
country: United States
facility: Prisma Health (formerly Greenville Health System)
state: South Carolina
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Seattle
country: United States
facility: VA Puget Sound Health Care System
state: Washington
city: Morgantown
country: United States
facility: West Virginia University Medicine
state: West Virginia
city: Brugge
country: Belgium
facility: AZ Sint-Lucas
city: Edegem
country: Belgium
facility: UZ Antwerp
city: Gent
country: Belgium
facility: AZ Maria Middelares
city: Gent
country: Belgium
facility: UZ Gent
city: La Louvière
country: Belgium
facility: Jolimont Hospital
city: Roeselare
country: Belgium
facility: AZ Delta
Study officials:
affiliation: Johns Hopkins Kimmel Cancer Center
name: Michael J Pishvaian
role: STUDY_CHAIR
References: