Pancreatic Cancer
Conditions
Keywords
mFOLFIRINOX, Ramucirumab
Brief summary
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.
Detailed description
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
Interventions
DRUGmFOLFIRINOX
mFOLFIRINOX: * 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.
DRUGRamucirumab
Ramucirumab 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.
OTHERPlacebo
Placebo infusion with volume calculated as if it were ramucirumab every 2 weeks.
Sponsors
Eli Lilly and Company
Hoosier Cancer Research Network
Walid Shaib, MD
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Site pharmacy staff will be unblinded to the study treatment. Subjects, site investigators, site analysis teams, and other site personnel will be blinded to the study treatment.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) at 9 Month | 9 months | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) \>= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions; Stable Disease (SD), not meet criteria for CR/PR/PD. PFS is defined as time of registration until disease progression met by RECIST 1.1 or death from any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Up to a maximum of 53 months | Overall survival is defined by the date of randomization to date of death from any cause. |
| Response Rate (RR) | Up to 44 months | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) \>= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions; Stable Disease (SD), not meet criteria for CR/PR/PD. Overall Response (OR) = CR + PR. |
| Number of Participants With Adverse Events | From date of first dose until 30 days after the last treatment, assessed up to 44 months | Adverse events will be assessed to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) version 4. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm A: Experimental Arm mFOLFIRINOX will be administered every 2 weeks, and consist of:
* 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 A will receive ramucirumab 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.
mFOLFIRINOX: mFOLFIRINOX:
* 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.
Ramucirumab: Ramucirumab 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. | 42 |
| Arm B: Placebo Arm mFOLFIRINOX will be administered every 2 weeks, and consist of:
* 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 ramucirumab
mFOLFIRINOX: mFOLFIRINOX:
* 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.
Placebo: Placebo infusion with volume calculated as if it were ramucirumab every 2 weeks. | 40 |
| Total | 82 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Eligibility Criteria Not Met | 0 | 1 |
| Overall Study | Screen Failure Before Therapy Start | 0 | 1 |
Baseline characteristics
| Characteristic | Arm A: Experimental Arm | Total | Arm B: Placebo Arm |
|---|---|---|---|
| Age, Continuous | 62 years | 63 years | 65 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 4 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 41 Participants | 76 Participants | 35 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 8 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 5 Participants | 4 Participants |
| Race (NIH/OMB) White | 35 Participants | 69 Participants | 34 Participants |
| Region of Enrollment United States | 42 participants | 82 participants | 40 participants |
| Sex: Female, Male Female | 19 Participants | 39 Participants | 20 Participants |
| Sex: Female, Male Male | 23 Participants | 43 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 33 / 42 | 35 / 40 |
| other Total, other adverse events | 41 / 42 | 39 / 40 |
| serious Total, serious adverse events | 19 / 42 | 17 / 40 |
Outcome results
Primary
Progression Free Survival (PFS) at 9 Month
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) \>= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions; Stable Disease (SD), not meet criteria for CR/PR/PD. PFS is defined as time of registration until disease progression met by RECIST 1.1 or death from any cause.
Time frame: 9 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Experimental Arm | Progression Free Survival (PFS) at 9 Month | 25.1 Percentage of participants |
| Arm B: Placebo Arm | Progression Free Survival (PFS) at 9 Month | 35 Percentage of participants |
Secondary
Number of Participants With Adverse Events
Adverse events will be assessed to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) version 4.
Time frame: From date of first dose until 30 days after the last treatment, assessed up to 44 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A: Experimental Arm | Number of Participants With Adverse Events | 42 Participants |
| Arm B: Placebo Arm | Number of Participants With Adverse Events | 40 Participants |
Secondary
Overall Survival (OS)
Overall survival is defined by the date of randomization to date of death from any cause.
Time frame: Up to a maximum of 53 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Experimental Arm | Overall Survival (OS) | 10.3 Months |
| Arm B: Placebo Arm | Overall Survival (OS) | 9.7 Months |
Secondary
Response Rate (RR)
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) \>= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions; Stable Disease (SD), not meet criteria for CR/PR/PD. Overall Response (OR) = CR + PR.
Time frame: Up to 44 months
Population: The analysis population for the endpoint Response Rate (RR) was defined as all participants with at least one post-baseline disease assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Experimental Arm | Response Rate (RR) | 17.7 Percentage of participants |
| Arm B: Placebo Arm | Response Rate (RR) | 22.6 Percentage of participants |