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    Summary
    EudraCT Number:2018-000572-15
    Sponsor's Protocol Code Number:GRASPANC-2018-01
    National Competent Authority:Sweden - MPA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2018-06-20
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSweden - MPA
    A.2EudraCT number2018-000572-15
    A.3Full title of the trial
    A Randomized, Phase 3 Study of Eryaspase in Combination with Chemotherapy versus Chemotherapy Alone as Second-Line Treatment in Patients with Pancreatic Adenocarcinoma
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Clinical study in subjects with pancreatic adenocarcinoma to assess safety and efficacy of investigational product (eryaspase) when added to standard chemotherapy
    A.3.2Name or abbreviated title of the trial where available
    TRYbeCA-1– TRial of erYaspase in pancreatic CAncer
    A.4.1Sponsor's protocol code numberGRASPANC-2018-01
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorERYTECH Pharma
    B.1.3.4CountryFrance
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportERYTECH Pharma
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationERYTECH Pharma
    B.5.2Functional name of contact pointIman El-Hariry
    B.5.3 Address:
    B.5.3.1Street Address60 avenue Rockefeller
    B.5.3.2Town/ cityLyon
    B.5.3.3Post code69008
    B.5.3.4CountryFrance
    B.5.4Telephone number33478744438
    B.5.5Fax number33478755629
    B.5.6E-mailvsemareg@erytech.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/09/633
    D.3 Description of the IMP
    D.3.1Product nameEryaspase
    D.3.4Pharmaceutical form Dispersion for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    Unknown use (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNL-asparaginase encapsulated in red blood cells
    D.3.9.3Other descriptive nameL-ASPARAGINASE ENCAPSULATED IN RED BLOOD CELLS
    D.3.9.4EV Substance CodeSUB181586
    D.3.10 Strength
    D.3.10.1Concentration unit IU/kg international unit(s)/kilogram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Pancreatic Adenocarcinoma
    E.1.1.1Medical condition in easily understood language
    Pancreatic Adenocarcinoma
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10051971
    E.1.2Term Pancreatic adenocarcinoma
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main 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.
    E.2.2Secondary 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.
    E.2.3Trial contains a sub-study No
    E.3Principal 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
    E.4Principal 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.
    E.5 End points
    E.5.1Primary 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.
    E.5.1.1Timepoint(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.
    E.5.2Secondary 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]).
    E.5.2.1Timepoint(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.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA85
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If 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
    E.8.7Trial 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
    Last Patient Last Visit
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months8
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months8
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 338
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 144
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 416
    F.4.2.2In the whole clinical trial 482
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-07-30
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-07-11
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2022-01-18
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