Pancreatic Cancer Non-resectable
Conditions
Keywords
locally advanced pancreatic cancer, unresectable pancreatic cancer
Brief summary
This is a Phase 3, randomized, double-blind trial to evaluate the efficacy and safety of neoadjuvant treatment with pamrevlumab or placebo in combination with either gemcitabine plus nab-paclitaxel (G/NP) or FOLFIRINOX in the treatment of participants with locally advanced, unresectable pancreatic cancer.
Detailed description
Participants will be randomized in a 1:1 ratio to one of the two study treatment arms; pamrevlumab with either G/NP or FOLFIRINOX, placebo with G/NP or FOLFIRINOX. Each participant may receive up to 6 cycles of treatment (each treatment cycle is 28 days). Tumor tissue will be collected during resection to determine surgical outcome and for biomarker analysis. Tumor response will be evaluated by changes in CT scan, FDG-PET, CA 19-9, and NCCN® guidelines. All participants randomized will have a safety follow-up visit approximately 28 days after the last dose of study treatment and a final safety follow-up phone call at approximately 60 days after the last dose. Participants who complete study treatment will be evaluated for surgical exploration for possible R0 or R1 resection. Surgery will occur at least 4 weeks after the last dose (allowing for a wash-out period from treatment) and only after receipt of the recommendation from the central review board with regards to surgical eligibility. Surgery will occur no longer than 8 weeks after the last dose. Participants who undergo surgery will be evaluated for surgical complications for at least an additional 90 days following discharge from surgery. Participants who are ineligible for surgical exploration (i.e. participants who did not complete study treatment or do not meet any of the protocol defined criteria or had a contraindication to surgery) will continue in the Follow-up period and receive treatment as per standard of care (SOC) for each institution. All participants will be followed for disease progression (if not previously detected) or recurrence following resection (local progression or metastatic disease). Participants will also be followed for any additional anti-cancer therapy received for their pancreatic cancer. All participants will be followed for survival (until death) or until the last participant to complete treatment reaches 18 months post-treatment.
Interventions
DRUGPamrevlumab + Gemcitabine + Nab-paclitaxel or Pamrevlumab + FOLFIRINOX
Drug: Pamrevlumab is administered on Days 1, 8 and 15 of Treatment Cycle 1 and on Day 1 and 15 of each subsequent treatment cycle via IV infusion. Drug: Gemcitabine is administered on Days 1, 8 and 15 of each 28 day treatment cycle via IV infusion. Drug: Nab-paclitaxel is administered on Days 1, 8 and 15 of each 28 day treatment cycle via IV infusion. Drug: FOLFIRINOX is a combination of several agents administered on Days 1 and 15 of each 28 day treatment cycle via IV infusion. The specific agents are Oxaliplatin, Folinic Acid, Irinotecan, and Fluorouracil.
DRUGPlacebo + Gemcitabine + Nab-paclitaxel or Placebo + FOLFIRINOX
Drug: Placebo is administered on Days 1, 8 and 15 of Treatment Cycle 1 and on Day 1 and 15 of each subsequent treatment cycle via IV infusion. Drug: Gemcitabine is administered on Days 1, 8 and 15 of each 28 day treatment cycle via IV infusion. Drug: Nab-paclitaxel is administered on Days 1, 8 and 15 of each 28 day treatment cycle via IV infusion. Drug: FOLFIRINOX is a combination of several agents administered on Days 1 and 15 of each 28 day treatment cycle via IV infusion. The specific agents are Oxaliplatin, Folinic Acid, Irinotecan, and Fluorouracil.
Sponsors
FibroGen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Double blind
Intervention model description
Participants will be randomized in a 1:1 ratio to one of the two study treatment arms; pamrevlumab with G/NP or FOLFIRINOX or placebo with G/NP or FOLFIRINOX.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Understand and sign informed consent; be willing to comply with study procedures, including surgery 2. Age ≥ 18 years 3. Be a male, or non-pregnant and non-lactating female 4. Negative serum B-hCG pregnancy test at screening for women of childbearing potential 5. Male participants with partners of childbearing potential and female participants of childbearing potential are required to use highly effective contraception methods during the conduct of the study and for 6 months after the last dose of study drug 6. Histologically or cytologically proven diagnosis of pancreatic ductal adenocarcinoma (PDAC) 7. Locally advanced pancreatic cancer considered unresectable according to NCCN Guidelines® Version 2.2018 as determined by central imaging 8. Measurable disease as defined by RECIST 1.1 criteria as determined by central imaging 9. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 10. Adequate liver function: aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \<2.5 x upper limit of normal (ULN), alkaline phosphatase \<2.5 x ULN, and bilirubin ≤1.5 x ULN or in participants with biliary stenting ≤2.0 x ULN 11. Adequate bone marrow function: platelets \>100,000 cells/mm3, hemoglobin \>9.0 g/dl and absolute neutrophil count (ANC) \>1,500 cells/mm3 12. Adequate renal function: creatinine \< 1.5 x ULN, creatinine clearance ≥ 30 mL/min 13. Less than grade 2 pre-existing peripheral neuropathy (per CTCAE)
Exclusion criteria
1. Prior chemotherapy or radiation for pancreatic cancer 2. Previous (within the past 3 years) or concurrent malignancy diagnosis except non-melanoma skin cancer and in situ carcinomas (excluding in situ breast cancer) 3. Major surgery within 4 weeks prior to signing informed consent form. Biliary stents are permitted. 4. History of allergy or hypersensitivity to human, humanized or chimeric monoclonal antibodies 5. History of allergy or hypersensitivity to any of the chemotherapy agents being prescribed or their excipients 6. Any medical or surgical condition that may place the participant at increased risk while on study 7. Any condition potentially decreasing compliance to study procedures 8. Exposure to another investigational drug within 28 days of first dosing visit, or 5 half-lives of the investigational drug (whichever is longer) 9. Uncontrolled intercurrent illness including, but not limited to, ongoing or active systemic infections, symptomatic congestive heart failure, unstable angina pectoris, clinically significant cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements 10. Documented history of drug or alcohol abuse within 6 months of signing informed consent 11. Any medical condition that, in the opinion of the investigator, may pose a safety risk to a participant in this trial, may confound the assessment of safety and efficacy, or may interfere with study participation 12. Participants with a history of interstitial pulmonary disease, hepatitis C virus (HCV), hepatitis B virus (HBV) or human immunodeficiency virus (HIV) infection 13. Participants who have been administered a live vaccine within 4 weeks prior to the first administration of therapy 14. Participants who cannot stop chronic medications that inhibit or induce cytochrome P (CYP) 2C8 or CYP3A4 15. Participants with poorly controlled comorbid conditions, including; congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), uncontrolled diabetes mellitus (DM) or neurologic disorders (not acutely related to pancreatic cancer) or limited function
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | Up to approximately 5 years | Overall survival was defined as the time from date of randomization to date of death due to any cause. Overall survival was calculated using the Kaplan-Meier method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Event-free Survival (EFS) | Up to approximately 5 years | The EFS endpoint was a composite time-to-event endpoint. The event being analyzed ('treatment failure') was defined as the earliest occurrence of: a) failure to achieve disease-free status locally after completion of neoadjuvant treatment and/or after surgery (that is, resection failure or progression that precludes surgery); b) local or distant recurrence, or c) death. The EFS was calculated using the Kaplan-Meier method. |
| Progression-free Survival (PFS) as Assessed Using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Up to approximately 5 years | The PFS was defined as time from date of randomization until disease progression or death due to any cause, whichever occurred first. PFS was calculated using the Kaplan-Meier method. Progression was defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 millimeters (mm). Unequivocal progression of existing non-target lesions and the appearance of one or more new lesions was also considered progression. |
| Number of Participants With Best Overall Objective Response as Assessed Using RECIST v1.1 | Up to approximately 5 years | Best overall objective response was defined as a complete response (CR) or partial response (PR). CR was defined as disappearance of all target or non-target lesions and normalization of tumor marker level (for non-target lesions), any pathological lymph nodes (whether target or non-target) must have reduced in short axis to \<10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. |
Countries
Austria, Belgium, Canada, China, France, Germany, Israel, Italy, South Korea, Spain, United Kingdom, United States
Participant flow
Pre-assignment details
Participants were randomized in a 1:1 ratio to one of the 2 study treatment arms: Pamrevlumab with Gemcitabine/Nab-paclitaxel or FOLFIRINOX or Placebo with Gemcitabine/Nab-paclitaxel or FOLFIRINOX.
Participants by arm
| Arm | Count |
|---|---|
| Pamrevlumab + Gemcitabine/Nab-paclitaxel or FOLFIRINOX Participants received pamrevlumab in combination with one chemotherapy treatment regimen (gemcitabine plus nab-paclitaxel or FOLFIRINOX) over a 28-day cycle, for up to 6 cycles. Pamrevlumab was administered on Days 1, 8 and 15 of Treatment Cycle 1 and on Day 1 and 15 of each subsequent treatment cycle via IV infusion. Nab-paclitaxel was administered on Days 1, 8 and 15 of each 28-day treatment cycle via IV infusion. Gemcitabine was administered on Days 1, 8 and 15 of each 28-day treatment cycle via IV infusion. FOLFIRINOX was a combination of several agents administered on Days 1 and 15 of each 28-day treatment cycle via IV infusion. The specific agents were oxaliplatin, folinic acid, irinotecan, and fluorouracil. | 143 |
| Placebo + Gemcitabine/Nab-paclitaxel or FOLFIRINOX Participants received pamrevlumab matched placebo in combination with one chemotherapy treatment regimen (gemcitabine plus nab-paclitaxel or FOLFIRINOX) over a 28-day cycle, for up to 6 cycles. Placebo was administered on Days 1, 8 and 15 of Treatment Cycle 1 and on Day 1 and 15 of each subsequent treatment cycle via IV infusion. Nab-paclitaxel was administered on Days 1, 8 and 15 of each 28-day treatment cycle via IV infusion. Gemcitabine was administered on Days 1, 8 and 15 of each 28-day treatment cycle via IV infusion. FOLFIRINOX was a combination of several agents administered on Days 1 and 15 of each 28-day treatment cycle via IV infusion. The specific agents were oxaliplatin, folinic acid, irinotecan, and fluorouracil. | 141 |
| Total | 284 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Withdrawal by Subject | 9 | 6 |
Baseline characteristics
| Characteristic | Placebo + Gemcitabine/Nab-paclitaxel or FOLFIRINOX | Total | Pamrevlumab + Gemcitabine/Nab-paclitaxel or FOLFIRINOX |
|---|---|---|---|
| Age, Continuous | 64.5 years STANDARD_DEVIATION 9.6 | 64.5 years STANDARD_DEVIATION 9.56 | 64.5 years STANDARD_DEVIATION 9.54 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 12 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 124 Participants | 246 Participants | 122 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 15 Participants | 26 Participants | 11 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 35 Participants | 60 Participants | 25 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 10 Participants | 5 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 | 20 Participants | 37 Participants | 17 Participants |
| Race (NIH/OMB) White | 79 Participants | 175 Participants | 96 Participants |
| Sex: Female, Male Female | 72 Participants | 133 Participants | 61 Participants |
| Sex: Female, Male Male | 69 Participants | 151 Participants | 82 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 118 / 143 | 112 / 141 |
| other Total, other adverse events | 139 / 142 | 140 / 141 |
| serious Total, serious adverse events | 75 / 142 | 62 / 141 |
Outcome results
Primary
Overall Survival
Overall survival was defined as the time from date of randomization to date of death due to any cause. Overall survival was calculated using the Kaplan-Meier method.
Time frame: Up to approximately 5 years
Population: The ITT population included all randomized participants regardless of whether or not study treatment was received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pamrevlumab + Gemcitabine/Nab-paclitaxel or FOLFIRINOX | Overall Survival | 17.25 months |
| Placebo + Gemcitabine/Nab-paclitaxel or FOLFIRINOX | Overall Survival | 17.94 months |
p-value: 0.548795% CI: [0.83, 1.41]Stratified Log Rank Test
Secondary
Event-free Survival (EFS)
The EFS endpoint was a composite time-to-event endpoint. The event being analyzed ('treatment failure') was defined as the earliest occurrence of: a) failure to achieve disease-free status locally after completion of neoadjuvant treatment and/or after surgery (that is, resection failure or progression that precludes surgery); b) local or distant recurrence, or c) death. The EFS was calculated using the Kaplan-Meier method.
Time frame: Up to approximately 5 years
Population: The ITT population included all randomized participants regardless of whether or not study treatment was received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pamrevlumab + Gemcitabine/Nab-paclitaxel or FOLFIRINOX | Event-free Survival (EFS) | 5.72 months |
| Placebo + Gemcitabine/Nab-paclitaxel or FOLFIRINOX | Event-free Survival (EFS) | 5.78 months |
Secondary
Number of Participants With Best Overall Objective Response as Assessed Using RECIST v1.1
Best overall objective response was defined as a complete response (CR) or partial response (PR). CR was defined as disappearance of all target or non-target lesions and normalization of tumor marker level (for non-target lesions), any pathological lymph nodes (whether target or non-target) must have reduced in short axis to \<10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: Up to approximately 5 years
Population: The ITT population included all randomized participants regardless of whether or not study treatment was received.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pamrevlumab + Gemcitabine/Nab-paclitaxel or FOLFIRINOX | Number of Participants With Best Overall Objective Response as Assessed Using RECIST v1.1 | 43 Participants |
| Placebo + Gemcitabine/Nab-paclitaxel or FOLFIRINOX | Number of Participants With Best Overall Objective Response as Assessed Using RECIST v1.1 | 64 Participants |
Secondary
Progression-free Survival (PFS) as Assessed Using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
The PFS was defined as time from date of randomization until disease progression or death due to any cause, whichever occurred first. PFS was calculated using the Kaplan-Meier method. Progression was defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 millimeters (mm). Unequivocal progression of existing non-target lesions and the appearance of one or more new lesions was also considered progression.
Time frame: Up to approximately 5 years
Population: The ITT population included all randomized participants regardless of whether or not study treatment was received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pamrevlumab + Gemcitabine/Nab-paclitaxel or FOLFIRINOX | Progression-free Survival (PFS) as Assessed Using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | 9.36 months |
| Placebo + Gemcitabine/Nab-paclitaxel or FOLFIRINOX | Progression-free Survival (PFS) as Assessed Using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | 9.40 months |