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    Summary
    EudraCT Number:2018-002211-10
    Sponsor's Protocol Code Number:GRASPA-TNBC-2018-02
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2018-08-29
    Trial 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 ConcernedUK - MHRA
    A.2EudraCT number2018-002211-10
    A.3Full title of the trial
    A Randomized Phase 2/3 Study of Eryaspase in Combination with Gemcitabine and Carboplatin Chemotherapy versus Chemotherapy Alone for the Treatment of Patients with Metastatic or Locally Recurrent Triple-Negative Breast Cancer.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to determine whether the addition of eryaspase to gemcitabine and carboplatin will reduce the tumor burden and stabilizate the tumor progression.
    A.3.2Name or abbreviated title of the trial where available
    TRYbeCA-2 – TRial of erYaspase in Breast CAncer
    A.4.1Sponsor's protocol code numberGRASPA-TNBC-2018-02
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03674242
    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 number+33478744438
    B.5.5Fax number+33478755629
    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 No
    D.2.5.1Orphan drug designation number
    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
    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
    Triple-Negative Breast Cancer
    E.1.1.1Medical condition in easily understood language
    Triple-Negative Breast Cancer
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10075566
    E.1.2Term Triple negative breast cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine whether the addition of eryaspase to gemcitabine and carboplatin improves the disease control rate (DCR) by modified Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as determined by an independent radiological review (IRR) in patients with locally recurrent or metastatic triple-negative breast cancer (TNBC) compared with chemotherapy alone.
    E.2.2Secondary objectives of the trial
    The secondary objectives of this study are:
    To compare DCR between the two treatment arms as determined by the
    Investigator's assessment; To compare ORR between the two treatment arms as determined by the IRR; To compare DoR between the two treatment arms; To compare PFS between the two treatment arms; To compare OS between the two treatment arms; To evaluate the safety and tolerability of eryaspase in combination with chemotherapy versus chemotherapy alone; To evaluate the change in F-18 fluorodeoxyglucose (FDG) tumor uptake as a predictor of clinical response following one cycle of treatment with eryaspase and chemotherapy; To determine the PK and pharmacodynamics of eryaspase; To assess the immunogenicity of eryaspase as determined by the induction of antiasparaginase antibodies and neutralizing antibodies; To evaluate the relationship of clinical outcome with relevant biomarkers and tumorspecific mutational changes present in tumor tissues and blood samples
    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. Female or male, 18 years of age or older.
    2. Histologically or cytologically confirmed diagnosis of invasive breast cancer.
    3. Metastatic or locally recurrent inoperable breast cancer with no more than one prior systemic therapy.
    4. Diagnosis (original primary tumour or subsequent relapse) of triple negative breast cancer, defined as the absence of expression of the following receptors in the primary and/or metastatic tumor tissue:
    - HER2 protein over-expression and/or gene amplification, defined as:
    a) fluorescent in situ hybridization (FISH)-negative: FISH ratio <2.2), or
    b) immunohistochemistry (IHC) 0-1+, or c) IHC 2+/3+ AND FISH-negative (FISH ratio <2.2) (1).
    - Estrogen receptor (ER), defined as <1% staining by IHC (2).
    - AND progesterone receptors (PgR), defined as <1% staining by IHC.
    5. Measurable lesion(s) per RECIST 1.1.
    6. Available archival or fresh tumor tissue. Formalin-fixed paraffin-embedded (FFPE) block is preferred, or a minimum of 10 unstained, consecutive FFPE slides of one archived block is required.
    7. Adequate performance status (PS) score (see Appendix 11.2):
    o Eastern Cooperative Oncology Group (ECOG) PS score of 0, or
    o ECOG PS score 1 and score ≥80 on Karnofsky Performance Status (KPS) scale.
    8. Life expectancy of >12 weeks according to the Investigator’s clinical judgment.
    9. Females of childbearing potential must have a negative pregnancy test at screening and an additional negative pregnancy test prior to first dose. 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: combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation:
    - intravaginal
    - transdermal; progestogen-only hormonal contraception associated with inhibition of ovulation: - injectable, - implantable intrauterine device (IUD)
    - bilateral tubal occlusion - vasectomy - condoms - sexual abstinence (defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments). The true abstinence is when this is in line with the preferred and usual lifestyle of the patient. [Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception]
    NOTE: A woman is considered of childbearing potential (i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.
    NOTE: Since an indirect interaction between components of the oral contraceptives and free ASNase cannot be ruled out (potential increase in the risk of a change in coagulation parameters and thrombosis), 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.
    10. 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.:
    - Absolute neutrophil count ≥1.5 x 109/L.
    - Hemoglobin ≥9 g/dL. Patients with a baseline haemoglobin ≥13 g/dL should be discussed with the medical monitor.
    - Platelet count ≥100,000/mm3 (100 x 109/L).
    - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT)
    ≤2.5 x upper limit of normal (ULN) (≤5 x ULN in presence of liver metastases).
    - Total bilirubin ≤ 1.5 x institutional ULN.
    - 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. Actual body weight should be used for calculating creatinine clearance (e.g., using the Cockcroft-Gault formula). For patients with a Body Mass Index (BMI) >30 Kg/m2, lean body weight should be used instead.
    - Acceptable coagulation parameters: plasma antithrombin III >70%, fibrinogen ≥1.5 g/L, international normalized ratio (INR) <1.5, and partial thromboplastin time (PTT) ≤ institutional ULN.
    - Serum albumin ≥3.0 g/dL.
    11. Patients 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.
    E.4Principal exclusion criteria
    A patient is not eligible to participate in the study if any of the following criteria are met:
    1. Pregnant or lactating females.
    2. Known BRCA1 or BRCA2 mutation carrier. NOTE: Patients with unknown BRCA1/2 mutation status may be included in the study, but are required to be tested during the study
    3. Bone as the only site of disease.
    4. Presence of untreated symptomatic central nervous system (CNS) metastases as determined by MRI or CT scan performed during screening.
    5. Prior radiotherapy to the only area of measurable disease.
    6. Prophylactic use of supportive bone-modifying therapy for skeletal related events (e.g., bisphosphonate, pamidronate, or denosumab), unless treatment is initiated prior to or within 7 days after randomization.
    7. History of recent clinical pancreatitis, according to revised Atlanta criteria, within 3 months of randomization.
    8. Neurosensory neuropathy >Grade 2 at baseline.
    9. Known history of infection with human immunodeficiency virus (HIV) and/or active infection with hepatitis B or hepatitis C.
    10. Known hypersensitivity to gemcitabine, platinum compounds, or asparaginase.
    11. Patients who have received live or live attenuated vaccines within 3 weeks of randomization.
    12. Pre-existing coagulopathy (e.g. hemophilia).
    13. History of other malignancies except: adequately treated nonmelanoma skin cancer, curatively treated in situ cancer of the cervix, or other solid tumors curatively treated with no evidence of disease for >2 years.
    14. Any other severe acute or chronic condition/treatments that may increase the risk of study participation, including:
    - 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.
    - Psychiatric illness/social situations or any other serious uncontrolled medical disorders that in the opinion of the Investigator would limit compliance with study requirements.
    15. Receiving therapy in a concurrent clinical study. Patients 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.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is DCR in PP population, assessed by independent radiological review.
    E.5.1.1Timepoint(s) of evaluation of this end point
    In light of the small sample size for Part 1, the one-sided p-value will be obtained using the stratified version of Fisher's Exact test with stratification defined by the factors used for randomization.
    E.5.2Secondary end point(s)
    To evaluate PFS, measured as the interval from randomization until objective tumor progression or death from any cause, whichever occurs first.
    To evaluate ORR defined as the proportion of patients who achieve complete and/or partial response (CR/PR).
    To evaluate BOR recorded from start of treatment until the EoT and will be determined based on evaluations of target, non-target, and new lesions.
    Evaluation of Duration of Treatment, defined as time from randomization to discontinuation of study treatment for any reason.
    To evaluate the Duration of Response measured from the time measurement criterias are first met for CR/PR (whichever is first recorded) per modified RECIST 1.1 until the first date that recurrent disease or PD is objectively documented.
    Overall survival is defined as the interval from the date of randomization to the date of death from any cause.
    E.5.2.1Timepoint(s) of evaluation of this end point
    To be measured from the date of randomization to the date of death
    from any cause compared between two treatment arms. 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.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 Yes
    E.6.13.1Other scope of the trial description
    Immunogenicity; Biomarker assessment;Radiological disease assessment
    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) Yes
    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 concerned10
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA50
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    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
    The end of the study is defined as completion of the last patient’s 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 months5
    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 months5
    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: 44
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 20
    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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 64
    F.4.2.2In the whole clinical trial 64
    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 Decision2018-10-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-03-20
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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