E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Pancreatic Adenocarcinoma |
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E.1.1.1 | Medical condition in easily understood language |
Pancreatic Adenocarcinoma |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10051971 |
E.1.2 | Term | Pancreatic adenocarcinoma |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this study is to determine whether the addition of eryaspase to chemotherapy improves overall survival (OS) in second-line treatment of pancreatic adenocarcinoma compared to chemotherapy alone. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study: To compare progression-free survival (PFS) between the 2 treatment arms. To compare the objective response rate (ORR) and duration of response (DoR) between the 2 treatment arms. To compare the disease control rate (DCR) between the 2 treatment arms.To evaluate the safety and tolerability of eryaspase in combination with chemotherapy versus chemotherapy alone. To assess the effect of eryaspase on quality of life using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). To determine the pharmacokinetics of eryaspase. To assess the immunogenicity of eryaspase in terms of the induction of anti-asparaginase antibodies and neutralizing antibodies. To evaluate the relationship of clinical outcome with relevant biomarkers and genetic changes present in tumor tissues and blood and/or serum samples. To investigate the predictive relationship between the patient’s DNA sequence variation. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 (see Appendix 1). 4. Must have received one line of systemic chemotherapy in advanced setting with or without targeted agents, immunotherapy, or radiotherapy for treatment of advanced pancreatic adenocarcinoma. NOTE: patients whose disease progresses on, or within 3 months, of neo(adjuvant) chemotherapy may be considered eligible 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). - Measurable disease may be in the field of prior irradiation; however, at least 4 weeks must have elapsed between the completion of radiation therapy and the baseline scan documenting disease status. - Bone disease is considered radiologically measurable only if there is at least a 50% lytic component. 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. NOTE: 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: - ECOG Performance Status (PS) score of 0, or - ECOG score 1 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. These include, but not limited to: a. combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: i. intravaginal ii. transdermal b. progestogen-only hormonal contraception associated with inhibition of ovulation: i. injectable ii. implantable c. intrauterine device (IUD) d. bilateral tubal occlusion e. vasectomised partner f. sexual abstinence (defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments) is intended. g. males with partners of childbearing potential must agree to use condoms NOTE: Since an indirect interaction between components of the oral contraceptives and ASNase cannot be ruled out, oral contraceptives are not considered acceptable as contraceptive methods in the current clinical trial. A method other than oral contraception should be used in women of childbearing potential. NOTE: All chemotherapeutic agents may be teratogenic and excreted in breast milk. Patients who are breast feeding should consider alternative methods. 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: a. Absolute neutrophil count ≥1.5 x 109/L. b. Hemoglobin ≥9 g/dL. Patients with a baseline Hemoglobin ≥13 g/dL should be discussed with the medical monitor. c. Platelet count ≥100,000/mm3 (100 x 109/L). d. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 x upper limit of normal (ULN) (≤5 x ULN in presence of liver metastases). e. Total bilirubin ≤1.5 x institutional ULN. f. 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. g. Acceptable coagulation parameters: plasma antithrombin III >70%, and fibrinogen ≥1.5 g/L. h. 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 CT and must agree not to participate in any other interventional CT during their participation in this trial while on study treatment. Patients taking part in surveys or observational CTs are eligible to participate in this study. 14. Be able to understand and comply with the conditions of the protocol and must have read and understood the ICF and provided written ICF |
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E.4 | Principal 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). 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 a. Decline in ECOG PS to >1 (or KPS <70) between baseline visit and within 72 hours prior to randomization. b. 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 treatmentrelated 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 asparaginase. NOTE: Patients known to be homozygous for UGT1A1*28 who are assigned to an irinotecan-containing regimen must have the initial irinotecan dose reduced unless they have previously tolerated full doses of irinotecan. Subjects whose UGT1A1 status is not known but are being considered for irinotecan-based chemotherapy must be screened for UGT1A1*28 allele unless they have previously tolerated full doses of irinotecan before enrollment into the trial and must have the initial irinotecan dose reduced if demonstrated to be homozygous for the UGT1A1*28 allele. NOTE: Patients assigned to the irinotecan/5 FU arms in the study should not have dihydropyridine dehydrogenase deficiency (DPD). Patients whose DPD status is unknown at time of screening should be tested before enrollment in the irinotecan/5 FU arm unless they have previously tolerated full doses of 5 FU. 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: a. History of abdominal fistula, gastrointestinal perforation, peptic ulcer, or intraabdominal abscess within 6 months prior to randomization. b. 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. c. Patients with pre-existing coagulopathy (e.g. hemophilia). d. Psychiatric illness/social situations or any other serious uncontrolled medical disorders in the opinion of the Investigator that would limit compliance with study requirements. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary objective of this study is to determine whether the addition of eryaspase to chemotherapy improves overall survival (OS) in second-line treatment of pancreatic adenocarcinoma compared to chemotherapy alone. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
To be measured from the date of randomization to the date of death from any cause. Patients who are not known to have died will be censored at the date of last contact, and this will apply as of the date of data cut-off for any particular analysis. |
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E.5.2 | Secondary end point(s) |
The secondary objectives of this study are: - To compare progression-free survival (PFS) between the 2 treatment arms. - To compare the objective response rate (ORR) and duration of response (DoR) between the 2 treatment arms. - To compare the disease control rate (DCR) between the 2 treatment arms. - To evaluate the safety and tolerability of eryaspase in combination with chemotherapy versus chemotherapy alone. - To assess the effect of eryaspase on quality of life using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). - To determine the pharmacokinetics of eryaspase. - To assess the immunogenicity of eryaspase in terms of the induction of anti-asparaginase antibodies and neutralizing antibodies. - To evaluate the relationship of clinical outcome with relevant biomarkers and genetic changes present in tumor tissues and blood and/or serum samples. - To investigate the predictive relationship between the patient’s DNA sequence variation, e.g. exploratory SNP genotyping and their response to combination treatment in terms of safety and tolerability (pharmacogenetics [PGx]). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
PFS will be compared between the 2 treatment arms using the same methods of analysis as for OS. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 85 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
United States |
Austria |
Belgium |
Finland |
France |
Germany |
Italy |
Netherlands |
Spain |
Sweden |
United Kingdom |
Czechia |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |