This is a phase II, multicenter, double-blinded, randomized, 2-arm trial evaluating the
efficacy and safety of mFOLFIRINOX plus ramucirumab (Arm A) vs. mFOLFIRINOX plus placebo (Arm
B) in 94 subjects with advanced pancreatic cancer, not amenable to curative treatment. Both
arms will continue treatment until disease progression or unacceptable toxicity.
OUTLINE: This is a multi-center study.
EXPERIMENTAL ARM A:
- Oxaliplatin 85 mg/m^2 over 2-4 hours
- Irinotecan 165 mg/m^2 over 90 minutes
- 5-FU 2,400 mg/m^2 as a 46-hour continuous infusion without the 5-FU bolus to decrease
the risk of neutropenia.
- Arm A will receive ramucirumab (RAM) administered as an intravenous infusion over 60
minutes (infusion rate should not exceed 25 mg/min), at a fixed dose of 8 mg/kg every 2
weeks.
CONTROL ARM B :
- Oxaliplatin 85 mg/m2 over 2-4 hours
- Irinotecan 165 mg/m2 over 90 minutes
- 5-FU 2,400 mg/m2 as a 46-hour continuous infusion without the 5-FU bolus to decrease the
risk of neutropenia.
- Arm B will receive a placebo infusion every 2 weeks. Due to the double-blinded nature of
this study, the volume of placebo will be calculated as if it were RAM.
In order to demonstrate adequate organ function, all screening labs must be obtained within 7
days prior to registration:
Hematological:
- Hemoglobin ≥ 9 g/dL
- Absolute Neutrophil Count (ANC) ≥ 1,500/mm^3
- Platelet Count (PLT) ≥ 100,000/mm^3
Renal:
- Creatinine ≤ 1.5 mg/dL or Creatinine clearance^1 ≥ 40 mL/min
- Albumin ≥ 2.5 g/dL
Hepatic:
- Bilirubin ≤ 1.5 mg/dL
- Aspartate aminotransferase (AST) ≤ 3 × ULN or < 5 xULN in the setting of liver
metastases
- Alanine aminotransferase (ALT) ≤ 3 × ULN or < 5 xULN in the setting of liver metastases
Coagulation:
- International Normalized Ratio (INR) (Patients receiving warfarin must be switched to
low molecular weight heparin and have achieved stable coagulation profile prior to first
dose of protocol therapy) ≤1.5 and a partial thromboplastin time (PTT) (PTT/aPTT) < 1.5
x ULN
Inclusion Criteria:
- Written informed consent and Health Insurance Portability and Accountability Act
(HIPAA) authorization for release of personal health information. .
- Age ≥ 18 years at the time of consent.
- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1 within 7 days
prior to registration.
- Histologic or cytological diagnosis of recurrent or metastatic pancreas adenocarcinoma
(PCA) who present for first line chemotherapy treatment.
- No prior first line systemic treatment (prior adjuvant or neoadjuvant treatment is
permitted). Subjects whose disease has progressed after 6 months of last systemic
chemotherapy or chemo-radiation in the adjuvant or neoadjuvant setting are eligible.
- Measurable disease determined using guidelines of Response Evaluation Criteria In
Solid Tumors (RECIST 1.1). Baseline tumor assessment should be performed using high
resolution computed tomography (CT) scans or magnetic resonance imaging (MRI).
- Urine protein < 1+ on dipstick test or routine urinalysis. If the proteinuria on these
tests is ≥2+, then a 24-hour urine test must be collected and must demonstrate < 1g
proteins in 24 hours to allow participation.
- Estimated life expectancy of >12 weeks, as assessed by the site investigator.
- If sexually active, must be postmenopausal, surgically sterile, or using effective
contraception (hormonal or barrier methods) due to unknown risk of teratogenicity of
ramucirumab
Exclusion Criteria:
- Subjects with histology other than adenocarcinoma; Examples include: neuroendocrine
tumors, acinar cell cancer, sarcoma or lymphoma of the pancreas.
- Ongoing or active infection.
- Symptomatic congestive heart failure, unstable angina pectoris, symptomatic or poorly
controlled cardiac arrhythmia. Symptomatic heart failure per New York Heart
Association (NYHA) Class II-IV.
- Uncontrolled or poorly-controlled hypertension (>160 mmHg systolic or > 100 mmHg
diastolic for >4 weeks) despite standard medical management.
- Acute or sub-acute intestinal obstruction.
- Interstitial pneumonia or interstitial fibrosis of the lung, which in the opinion of
the site investigator could compromise the subject or the study.
- Pleural effusion or ascites that causes > grade 1 dyspnea.
- Cirrhosis at a level of Child-Pugh B (or worse) or cirrhosis (any degree) with a
history of hepatic encephalopathy or clinical meaningful ascites resulting from
cirrhosis; clinically meaningful ascites is defined as ascites resulting from
cirrhosis and requiring ongoing treatment with diuretics and/or paracentesis.
- Grade 3 or higher bleeding event ≤ 3 months prior to randomization.
- Experience of any arterial thrombotic or arterial thromboembolic events, including,
but not limited to myocardial infarction, transient ischemic attack, or
cerebrovascular accident, ≤ 6 months prior to randomization.
- History of deep vein thrombosis, pulmonary embolism, or any other significant
thromboembolism (venous port or catheter thrombosis or superficial venous thrombosis
are not considered "significant") during the 3 months prior to randomization.
- Documented and/or symptomatic or known brain or leptomeningeal metastases.
- GI perforation/fistula
- Documented and/or symptomatic or known brain or leptomeningeal metastases.
- Severely immune-compromised (other than being on steroids), including known HIV
infection.
- Concurrent active malignancy other than adequately treated non-melanoma skin cancer,
other noninvasive carcinoma, or in situ neoplasm. A subject with previous history of
malignancy is eligible, provided that he/she has been disease free for > 3 years.
- Breast-feeding or pregnant.
- Prior autologous or allogeneic organ or tissue transplantation.
- Known allergy to any of the treatment components.
- Major surgery within 28 days prior to the first dose of protocol therapy, or minor
surgery/subcutaneous venous access device placement within 2 days prior to first dose
of protocol therapy. The patient has elective or planned major surgery to be performed
during the course of the clinical trial.
- Any condition that does not permit compliance with the study schedule including
psychological, geographical or medical.
- Receiving medications that can effect clotting ability: warfarin, aspirin (once-daily
aspirin use- maximum dose 325 mg/day is permitted), nonsteroidal anti-inflammatory
drugs (NSAIDs, including ibuprofen, naproxen, and others), dipyridamole or
clopidogrel, or similar agents. .
- Serious or non-healing wound, ulcer, or bone fracture within 28 days prior to first
dose of protocol therapy.
