Pancreatic Adenocarcinoma
Conditions
Keywords
pancreatic, cancer, asparaginase, gemcitabine, Abraxane, asparagine depletion, onivyde, nab-paclitaxel, folinic acid, fluorouracil, irinotecan, leucovorin, amino acid, RECIST 1.1
Brief summary
This is an open-label, multicenter, randomized, Phase 3 study in patients with ductal adenocarcinoma of the pancreas who have failed only one prior line of systemic anti-cancer therapy for advanced pancreatic cancer and have measurable disease.
Detailed description
Patients who meet all inclusion and exclusion criteria will be randomized in a 1:1 ratio to one of the following treatment arms (see figure below): * Arm A (investigational arm): eryaspase in combination with either gemcitabine/Abraxane or irinotecan-based therapy (FOLFIRI \[FOLinic acid-Fluorouracil-IRInotecan regimen\] or Onivyde®/5 fluorouracil/leucovorin), or * Arm B (control arm): gemcitabine/Abraxane or irinotecan-based therapy (FOLFIRI or Onivyde/5-FU/leucovorin) The chemotherapy will be investigator's choice and based on what patient has received in first line treatment. Treatment will continue until disease progression, unacceptable toxicity, or the patient's withdrawal of consent. An End of Treatment visit should occur within approximately 30 days from last dose of eryaspase or chemotherapy regimen. A survival follow-up period will include the collection of survival, progression of disease if applicable, treatment updates, and quality of life assessments every 8 weeks.
Interventions
DRUGeryaspase
L-asparaginase encapsulated in erythrocytes (red blood cells)
DRUGGemcitabine plus Abraxane
gemcitabine, Abraxane
DRUGIrinotecan plus 5-FU plus leucovorin
irinotecan, 5-FU, leucovorin
Sponsors
ERYtech Pharma
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
A patient will be eligible for the study if all the following criteria are met: 1. Must be 18 years of age or older. 2. Must have histologically confirmed pancreatic adenocarcinoma. 3. Must have Stage III or IV disease. 4. Must have received one line of systemic chemotherapy in the advanced setting with or without targeted agents, immunotherapy, or radiotherapy for treatment of advanced pancreatic adenocarcinoma. 5. Must have radiological evidence of disease progression following most recent prior treatment, defined as appearance of any new lesion or increase of \>20% of one or more existing lesions. 6. Must have measurable lesion(s) per RECIST version 1.1 by CT scan with contrast (or MRI, if the patient is allergic to CT contrast media). NOTE: Bone disease consisting of blastic lesion only is not measurable. 7. Archival or fresh tumor tissue must be available for evaluating relevant biomarkers. Formalin-fixed paraffin-embedded \[FFPE\] block preferred, or a minimum of 10 unstained FFPE slides of one archived block is required. NOTE: Cytology samples from fine needle aspirates or brushing biopsies are not sufficient. If archival tissue is unavailable and an elective biopsy can't be scheduled due to COVID, this will be waived. 8. Must have adequate performance status: 1. ECOG Performance Status (PS) score of 0, or 2. ECOG PS score one and score ≥80 on Karnofsky Performance Status (KPS) scale. NOTE: Must have body mass index (BMI) ≥18.5 kg/m2 (obtained \<14 days prior to randomization. 9. Must have life expectancy of \>12 weeks according to the investigator's clinical judgment. 10. Females of childbearing potential must have a negative pregnancy test at screening and additional negative pregnancy test prior to first dose. Males and females of childbearing potential must agree to use a highly effective method of contraception during treatment and for at least 6 months after the last dose of study treatment. 11. Must have adequate laboratory parameters at baseline (obtained \<14 days prior to randomization). Laboratory parameters outside of these ranges that are deemed clinically insignificant should be discussed with the medical monitor: 1. Absolute neutrophil count ≥1.5 x 109/L. 2. Hemoglobin ≥9 g/dL. Patients with a baseline Hemoglobin ≥13 g/dL should be discussed with the medical monitor. 3. Platelet count ≥100,000/mm3 (100 x 109/L). 4. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 x upper limit of normal (ULN) (≤5 x ULN in presence of liver metastases). 5. Total bilirubin ≤ 1.5 x institutional ULN. 6. Serum creatinine within normal limits or calculated clearance \>60 mL/min/1.73 m2 for patients with serum creatinine levels above or below the institutional normal range. 7. Acceptable coagulation parameters: plasma antithrombin III \>70% and fibrinogen ≥1.5 g/L 8. Serum albumin ≥3.0 g/dL. 12. Patients requiring biliary stent placement must have the biliary stent placed \>7 days prior to screening and must have normalization of bilirubin level after stenting. 13. Must not be receiving therapy in a concurrent clinical study and must agree not to participate in any other interventional clinical studies during their participation in this trial while on study treatment. Patients taking part in surveys or observational studies are eligible to participate in this study. 14. Must be able to understand and comply with the conditions of the protocol and must have read and understood the consent form and provided written informed consent.
Exclusion criteria
A patient is not eligible to participate in the study if any of the following criteria are met: 1. Resectable or borderline resectable pancreatic adenocarcinoma at the time of signing the informed consent. 2. Histology other than pancreatic adenocarcinoma (for example, but not inclusive: neuroendocrine, adenosquamous, etc.). 3. More than one line of prior treatment in advanced or metastatic setting. 4. Patient has experienced medically significant acute decline in clinical status including 1. Decline in ECOG PS to \>1 (or KPS \<70) between baseline visit and within 72 hours prior to randomization. 2. Weight loss of ≥10% during screening. 5. Presence of active or symptomatic untreated central nervous system (CNS) metastases. NOTE: Patients with asymptomatic or stable CNS metastases are eligible, provided that the CNS metastases are radiologically and clinically stable, and the patient is off high-dose steroid treatment for at least one month prior to randomization. 6. Prior radiotherapy to the only area of measurable disease. NOTE: Patients must have completed treatment and recovered from all acute treatment-related toxicities prior to administration of the first dose of eryaspase or chemotherapy. 7. Bone as the only site of metastatic disease from pancreatic cancer (bone only disease). 8. History of recent clinical pancreatitis, according to revised Atlanta criteria, within 3 months of randomization. NOTE: The revised Atlanta classification \[1\] requires that two or more of the following criteria be met for the diagnosis of acute pancreatitis: (a) abdominal pain suggestive of pancreatitis, (b) serum amylase or lipase level ≥3 x ULN, or (c) characteristic imaging findings using CT or MRI. 9. Neurosensory neuropathy \> Grade 2 at baseline. 10. Pregnancy or breastfeeding. 11. History of infection with human immunodeficiency virus (HIV) and/or active infection with hepatitis B or hepatitis C. NOTE: Patients with unknown status of hepatitis B or C must be tested and declared negative before randomization. 12. Hypersensitivity to any of the components of the chemotherapy or ASNase. 13. Patients who have received live or live attenuated vaccines within 3 weeks of randomization. 14. History of other malignancies NOTE: Adequately treated non-melanoma skin cancer or curatively treated in-situ cancer of the cervix may be eligible. NOTE: Patients successfully treated for other malignancies and are disease-free for at least 5 years may be eligible. 15. Any other severe acute or chronic condition/treatments that may increase the risk of study participation including: 1. History of abdominal fistula, gastrointestinal perforation, peptic ulcer, or intra-abdominal abscess within 6 months prior to randomization. 2. Current or history within 6 months prior to randomization of medically significant cardiovascular disease including symptomatic congestive heart failure \>New York Heart Association (NYHA) Class II, unstable angina pectoris, clinically significant cardiac arrhythmia. 3. Patients with pre-existing coagulopathy (e.g. hemophilia). 4. Psychiatric illness/social situations or any other serious uncontrolled medical disorders in the opinion of the Investigator that would limit compliance with study requirements.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | ~12 months | To determine whether the addition of eryaspase to chemotherapy improves OS when compared to chemotherapy alone |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | ~24 weeks | To compare the ORR between the 2 treatment arms. ORR is defined as the proportion of patients who achieve objective tumor response (CR or PR) per modified RECIST 1.1: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions. |
| Duration of Response (DoR) | ~24 weeks | To compare the DoR between the 2 treatment arms |
| Progression Free Survival (PFS) | ~24 weeks | To compare PFS between the 2 treatment arm. Progression is determined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. |
| Incidence of Treatment Emergent Adverse Events as Assessed by CTCAE v5.0 | ~9 months | To evaluate the safety and tolerability of eryaspase in combination with chemotherapy versus chemotherapy alone by assessing the number of patients with with treatment emergent adverse events per CTCAE v5.0 |
| Time to Quality of Life Questionnaire EORTC QLQ-C30 First Worsening in Global Health Status Analysis | ~1 year | The time to first Worsening was defined as the date of randomization to the date of first Worsening occurred in patient score on their global health status. Patients who did not have any worsening were censored at date of last measurement or at baseline if no measurement is available post-baseline. |
| Disease Control Rate (DCR) | ~24 weeks | To compare the between the 2 treatment arms |
Countries
France, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Eryaspase Plus Chemotherapy eryaspase 100 U/kg dosed every 2 weeks in combination with
Gemcitabine plus abraxane (albumin-bound paclitaxel) administered on Days 1, 8, and 15 of each 4 week cycle as follows:
* Abraxane (125 mg/m2) IV
* Gemcitabine (1000 mg/m2) IV
Or
Irinotecan plus 5-FU plus leucovorin administered on Days 1 and 15 of each 4 week cycle as follows:
* Onivyde 70 mg/m2 (irinotecan freebase) IV (recommended dose in patients homozygous for UGT1A1\*28 is 50 mg/m2)
* Leucovorin 400 mg/m2 IV
* 5 FU 2400 mg/m2
Or
* FOLFIRI: Irinotecan 180 mg/m2 IV
* Leucovorin 400 mg/m² IV
* 5 FU 400 mg/m² IV bolus
* 5 FU 2400 mg/m² IV continuous infusion over 46 hours immediately following bolus 5 FU
eryaspase: L-asparaginase encapsulated in erythrocytes (red blood cells)
Gemcitabine plus Abraxane: gemcitabine, Abraxane
Irinotecan plus 5-FU plus leucovorin: irinotecan, 5-FU, leucovorin | 255 |
| Chemotherapy Alone Standard treatment: Gemcitabine plus abraxane (albumin-bound paclitaxel) administered on Days 1, 8, and 15 of each 4 week cycle Or Irinotecan plus 5-FU plus leucovorin administered on Days 1 and 15 of each 4 week cycle
Gemcitabine plus Abraxane: gemcitabine, Abraxane
Irinotecan plus 5-FU plus leucovorin: irinotecan, 5-FU, leucovorin | 257 |
| Total | 512 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Patients ongoing on treatment | 9 | 6 |
| Overall Study | Randomized but not treated | 7 | 11 |
| Overall Study | survival follow up ongoing | 23 | 0 |
Baseline characteristics
| Characteristic | Eryaspase Plus Chemotherapy | Total | Chemotherapy Alone |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 115 Participants | 230 Participants | 115 Participants |
| Age, Categorical Between 18 and 65 years | 140 Participants | 282 Participants | 142 Participants |
| Age, Continuous | 62.0 years STANDARD_DEVIATION 10.29 | 62.2 years STANDARD_DEVIATION 10 | 62.5 years STANDARD_DEVIATION 9.72 |
| ECOG PS ECOG 0 | 107 participants | 212 participants | 105 participants |
| ECOG PS ECOG 1 | 148 participants | 300 participants | 152 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 4 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 7 Participants | 1 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 | 12 Participants | 17 Participants | 5 Participants |
| Race (NIH/OMB) White | 235 Participants | 483 Participants | 248 Participants |
| Region of Enrollment Europe | 236 participants | 473 participants | 237 participants |
| Region of Enrollment United States | 19 participants | 39 participants | 20 participants |
| Sex: Female, Male Female | 121 Participants | 245 Participants | 124 Participants |
| Sex: Female, Male Male | 134 Participants | 267 Participants | 133 Participants |
| Time from initial diagnosis of advanced disease to randomization <6 months | 79 Participants | 153 Participants | 74 Participants |
| Time from initial diagnosis of advanced disease to randomization >=6 months | 176 Participants | 359 Participants | 183 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 209 / 248 | 211 / 246 |
| other Total, other adverse events | 248 / 248 | 244 / 246 |
| serious Total, serious adverse events | 122 / 248 | 105 / 246 |
Outcome results
Primary
Overall Survival (OS)
To determine whether the addition of eryaspase to chemotherapy improves OS when compared to chemotherapy alone
Time frame: ~12 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Eryaspase Plus Chemotherapy | Overall Survival (OS) | 7.5 months |
| Chemotherapy Alone | Overall Survival (OS) | 6.7 months |
Secondary
Disease Control Rate (DCR)
To compare the between the 2 treatment arms
Time frame: ~24 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Eryaspase Plus Chemotherapy | Disease Control Rate (DCR) | 147 Participants |
| Chemotherapy Alone | Disease Control Rate (DCR) | 126 Participants |
Secondary
Duration of Response (DoR)
To compare the DoR between the 2 treatment arms
Time frame: ~24 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Eryaspase Plus Chemotherapy | Duration of Response (DoR) | 5.7 months |
| Chemotherapy Alone | Duration of Response (DoR) | 6.8 months |
Secondary
Incidence of Treatment Emergent Adverse Events as Assessed by CTCAE v5.0
To evaluate the safety and tolerability of eryaspase in combination with chemotherapy versus chemotherapy alone by assessing the number of patients with with treatment emergent adverse events per CTCAE v5.0
Time frame: ~9 months
Population: Analysis set includes only patients who were treated on study (Safety Population). 7 patients in the eryaspase plus chemotherapy arm and 11 patients in the chemotherapy alone arm discontinued study prior to initiation of first dose.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Eryaspase Plus Chemotherapy | Incidence of Treatment Emergent Adverse Events as Assessed by CTCAE v5.0 | number of patients with TEAE >= Grade 3 | 195 participants |
| Eryaspase Plus Chemotherapy | Incidence of Treatment Emergent Adverse Events as Assessed by CTCAE v5.0 | Number of patients with TEAEs leading to study drug discontinuation | 46 participants |
| Eryaspase Plus Chemotherapy | Incidence of Treatment Emergent Adverse Events as Assessed by CTCAE v5.0 | Number of patients with TE SAE | 122 participants |
| Eryaspase Plus Chemotherapy | Incidence of Treatment Emergent Adverse Events as Assessed by CTCAE v5.0 | Number of patients with TE SAE with outcome of death | 14 participants |
| Eryaspase Plus Chemotherapy | Incidence of Treatment Emergent Adverse Events as Assessed by CTCAE v5.0 | Number of patients with treatment emergent adverse events (TEAE) | 248 participants |
| Chemotherapy Alone | Incidence of Treatment Emergent Adverse Events as Assessed by CTCAE v5.0 | Number of patients with TE SAE with outcome of death | 9 participants |
| Chemotherapy Alone | Incidence of Treatment Emergent Adverse Events as Assessed by CTCAE v5.0 | Number of patients with treatment emergent adverse events (TEAE) | 246 participants |
| Chemotherapy Alone | Incidence of Treatment Emergent Adverse Events as Assessed by CTCAE v5.0 | number of patients with TEAE >= Grade 3 | 176 participants |
| Chemotherapy Alone | Incidence of Treatment Emergent Adverse Events as Assessed by CTCAE v5.0 | Number of patients with TE SAE | 105 participants |
| Chemotherapy Alone | Incidence of Treatment Emergent Adverse Events as Assessed by CTCAE v5.0 | Number of patients with TEAEs leading to study drug discontinuation | 41 participants |
Secondary
Objective Response Rate (ORR)
To compare the ORR between the 2 treatment arms. ORR is defined as the proportion of patients who achieve objective tumor response (CR or PR) per modified RECIST 1.1: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions.
Time frame: ~24 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Eryaspase Plus Chemotherapy | Objective Response Rate (ORR) | 41 Participants |
| Chemotherapy Alone | Objective Response Rate (ORR) | 32 Participants |
Secondary
Progression Free Survival (PFS)
To compare PFS between the 2 treatment arm. Progression is determined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time frame: ~24 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Eryaspase Plus Chemotherapy | Progression Free Survival (PFS) | 3.7 months |
| Chemotherapy Alone | Progression Free Survival (PFS) | 3.4 months |
Secondary
Time to Quality of Life Questionnaire EORTC QLQ-C30 First Worsening in Global Health Status Analysis
The time to first Worsening was defined as the date of randomization to the date of first Worsening occurred in patient score on their global health status. Patients who did not have any worsening were censored at date of last measurement or at baseline if no measurement is available post-baseline.
Time frame: ~1 year
Population: The number of participants in this section consist of all patients who receive at least one dose of the study treatment and provide answers to at least some items of the EORTC QLQ-C30 at Cycle 1 Day 1 (i.e, baseline) and a time point after the date of first dose of study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Eryaspase Plus Chemotherapy | Time to Quality of Life Questionnaire EORTC QLQ-C30 First Worsening in Global Health Status Analysis | 4.0 months |
| Chemotherapy Alone | Time to Quality of Life Questionnaire EORTC QLQ-C30 First Worsening in Global Health Status Analysis | 3.6 months |