Efficacy And Safety Of L-asparaginase Encapsulated In RBC Combined With Gemcitabine Or FOLFOX In 2nd Line For Progressive Metastatic Pancreatic Carcinoma

Study Overview

Efficacy and Safety of L-asparaginase Encapsulated in RBC Combined With Gemcitabine or FOLFOX in 2nd Line for Progressive Metastatic Pancreatic Carcinoma

A new approach that aims to destroy pancreatic tumor cells through modification of the tumor environment. Asparagine synthetase (ASNS) is an enzyme wich synthetise asparagine. Asparagine is an essential nutriment for pancreatic cancer cells which have no or low level of ASNS. by L-asparaginase encapsulated in erythrocytes deplete (supress) Plasma asparagine. in selected patients having no or low ASNS, may provide a new therapeutic approach.

N/A

Pancreatic Adenocarcinoma Metastatic

DRUG: ERY001
DRUG: Gemcitabine
DRUG: 5-fluoro-uracil/oxaliplatin/leucovorin (folfox)

GRASPANC 2013-03
2013-004262-34 (EUDRACT_NUMBER Identifier) (EUDRACT_NUMBER: )

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates	Results Reporting Dates	Study Record Updates
First Submitted 2014-07-16	Results First Submitted N/A	Last Update Submitted that met QC Criteria 2018-07-25
First Submitted that Met QC Criteria 2014-07-17	Results First Submitted that Met QC Criteria N/A	Last Update Posted (ACTUAL) 2018-07-27
First Posted (ACTUAL) 2014-07-21	Results First Posted N/A	Last Verified 2017-11

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

Design Details

Primary Purpose:
Treatment

Allocation:
Randomized

Interventional Model:
Parallel

Masking:
None

Arms and Interventions

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: standard of care combined with ERY001 standard of care = Gemcitabine or folfox	DRUG: ERY001 DRUG: Gemcitabine DRUG: 5-fluoro-uracil/oxaliplatin/leucovorin (folfox) oxaliplatin 85 mg/m2 levo-leucovorin 200 mg/m2 5-FU 400 mg/m2
SHAM_COMPARATOR: standard of care alone standard of care = Gemcitabine or folfox	DRUG: Gemcitabine DRUG: 5-fluoro-uracil/oxaliplatin/leucovorin (folfox) oxaliplatin 85 mg/m2 levo-leucovorin 200 mg/m2 5-FU 400 mg/m2

Participant Group/Arm

Intervention/Treatment

EXPERIMENTAL: standard of care combined with ERY001

standard of care = Gemcitabine or folfox

DRUG: ERY001

DRUG: Gemcitabine

DRUG: 5-fluoro-uracil/oxaliplatin/leucovorin (folfox)

oxaliplatin 85 mg/m2 levo-leucovorin 200 mg/m2 5-FU 400 mg/m2

SHAM_COMPARATOR: standard of care alone

standard of care = Gemcitabine or folfox

DRUG: Gemcitabine

DRUG: 5-fluoro-uracil/oxaliplatin/leucovorin (folfox)

oxaliplatin 85 mg/m2 levo-leucovorin 200 mg/m2 5-FU 400 mg/m2

Primary Outcome Measures	Measure Description	Time Frame
Overall survival (OS)	Evaluate the effects of eryaspase when combined with chemotherapy for the second line treatment of patients with pancreatic adenocarcinoma in terms of OS, whose tumors has low or no ASNS expression (ASNS 0 or 1+)	From last study treatment assessment visit until patient's death, loss to follow up, or study closure, assessed up to 36 months.
Progression free survival (PFS)	Evaluate the effects of eryaspase when combined with chemotherapy for the second line treatment of patients with pancreatic adenocarcinoma in terms of PFS, whose tumors has low or no ASNS expression (ASNS 0 or 1+)	From date of randomization to first documented progression of disease, death for any cause or until start of new anti-cancer treatment, whcihever came first, assessed up to 24 months.

Secondary Outcome Measures	Measure Description	Time Frame
Incidence of Treatment Emergent Adverse Events (Safety and Tolerability)	Compare the safety profile in patients treated with eryaspase in combination with chemotherapy versus chemotherapy alone, including adverse events, vital signs and clinical laboratory assessments	collected from time of informed consent until 4 weeks after last study treatment
Overall survival	Evaluate the effects of eryaspase in combination with chemotherapy on investigator-assessed OS in all randomized patients (all patients) and in patients with ASNS 2+/3+ expressing tumors.	From last study treatment assessment visit until patient's death, loss to follow up, or study closure, assessed up to 36 months.
Progression free survival	Evaluate the effects of eryaspase in combination with chemotherapy on investigator-assessed PFS in all randomized patients (all patients) and in patients with ASNS 2+/3+ expressing tumors.	From date of randomization to first documented progression of disease, death for any cause or until start of new anti-cancer treatment, whcihever came first, assessed up to 24 months.
Objective response rate (ORR)	Evaluate the effect of eryaspase in combination with chemotherapy on the ORR, and the duration in all comers, patients with ASNS 0/1+ expressing tumors, and those with ASNS 2+/3+ expressing tumors.	From date of randomization to last tumor assessment data collected for each patient, assessed up to 24 months.
Disease control rate (DCR)	Evaluate the effect of eryaspase in combination with chemotherapy on the DCR in all comers, patients with ASNS 0/1+ expressing tumors, and those with ASNS 2+/3+ expressing tumors.	From date of randomization to 16 and 24 weeks.
Duration of response (DoR)	Evaluate the effect of eryaspase in combination with chemotherapy on the DoR in all comers, patients with ASNS 0/1+ expressing tumors, and those with ASNS 2+/3+ expressing tumors.	From date of first response of complete or partial response until tumor progression, assessed up to 24 months.
Evaluate the relationship of clinical outcomes with tumor markers	Evaluate the relationship of clinical outcome (i.e. OS, PFS, ORR, DCR and DoR) with tumor markers, namely cancer antigen (CA19-9), and carcinoembryonic antigen test (CEA).	From date of randomiztion to end of treatment visit, assessed up to 20 months.
Optical density reading	Assess the effect of eryaspase in combination with chemotherapy on PFS, OS, ORR, BOR, and other clinical outcomes in ASNS subsets, as determined by optical density reading.	From date of randomization to first documented progression of disease, death for any cause or until start of new anti-cancer treatment, whcihever came first, assessed up to 24 months.
Quality of Life status	Compare the 2 treatment arms with respect to change in quality of life status, the change of QOL relative to baseline	From date of randomiztion to end of treatment visit, assessed up to 20 months.

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person’s general health condition or prior treatments.

Ages Eligible for Study:
ALL

Sexes Eligible for Study:
18 Years

Accepts Healthy Volunteers:

Advanced or metastatic exocrine pancreatic adenocarcinoma, confirmed histologically
Available archival tumor tissue block with sufficient tissue either from primary tumor and/or from metastatic lesions for biomarker testing; alternatively, unstained slides with sufficient tissue may be substituted
Only 1 prior systemic therapy for advanced or metastatic disease. NOTE: Patient must be eligible to 2nd line gemcitabine or mFOLFOX6 treatment Documented disease progression during or following first-line therapy for advanced disease
Measurable lesion (>1cm) as assessed by CT scan or MRI (Magnetic Resonance Imaging) according to RECIST criteria (version 1.1)
Age 18 years and older
ECOG performance status 0 or 1
Ability to understand, and willingness to sign, a written informed consent and to comply with the scheduled visits, treatment plans, laboratory tests, and other study procedures.
Patient beneficiary of a Social Security Insurance if applicable

Patient who have received Oxaliplatin in first line will not be eligible in FOLFOX arm; Patient who received Gemcitabine in first line will not be eligible in Gemcitabine arm
Resectable pancreatic adenocarcinoma
Known hypersensitivity to L-asparaginase or have had prior exposure to any form of L-asparaginase
Anti-vitamin K treatment. Replacement with low molecular weight heparin treatment if required
Inadequate organ functions:

hemoglobin < 9.0 g/dl, neutrophil count < 1.5 x 109/L, platelets < 100 x 109/L.
Liver or pancreatic function abnormalities

AST or ALT > 3 x ULN, or
Total bilirubin > 1.5 x ULN, or
Lipase > 2 x ULN with suggestive clinical sign of pancreatitis or > 3N without suggestive clinical sign
Renal insufficiency: Renal clearance determined by the Cockroft and Gault Formula < 60 mL/min
Current or prior coagulopathy disorders in the last month

PT ≥1.5 fold the upper limit of normal value or
INR ≥1.5 fold the upper limit of normal value or
Fibrinogen ≤ 0.75 fold the lower limit of normal value
Known Infection: HIV, active hepatitis related to B or C virus
Concurrent active malignancies (with the exception of in situ carcinoma of the cervix and inactive non melanoma skin cancer
Other serious conditions than pancreatic cancer according to investigator's opinion
NYHA Grade ≥ 2 congestive heart failure
Systemic chemotherapy or radiation within the last 3 weeks or major surgery within 4 weeks NOTE: chemotherapy or radiation therapy given in less than 3 weeks is allowed, provided patient recovered from all related toxicities
History of grade 3 blood transfusion reaction (life threatening situation)
Presence of anti-erythrocyte antibodies (auto-antibodies or anti-public antibodies) preventing from getting a compatible packed Red Blood Cells for the patient
Participation in another concurrent clinical trial
Women of child-bearing potential and men with partners of childbearing potential without effective contraception as well as pregnant or breast feeding women
Other severe acute/chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the Investigator would make the patient inappropriate for entry into this study.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

PRINCIPAL_INVESTIGATOR: Pascal Hammel, Pr MD, Hopital Beaujon

Publications

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Bachet JB, Blons H, Hammel P, Hariry IE, Portales F, Mineur L, Metges JP, Mulot C, Bourreau C, Cain J, Cros J, Laurent-Puig P. Circulating Tumor DNA is Prognostic and Potentially Predictive of Eryaspase Efficacy in Second-line in Patients with Advanced Pancreatic Adenocarcinoma. Clin Cancer Res. 2020 Oct 1;26(19):5208-5216. doi: 10.1158/1078-0432.CCR-20-0950. Epub 2020 Jun 30.
Hammel P, Fabienne P, Mineur L, Metges JP, Andre T, De La Fouchardiere C, Louvet C, El Hajbi F, Faroux R, Guimbaud R, Tougeron D, Bouche O, Lecomte T, Rebischung C, Tournigand C, Cros J, Kay R, Hamm A, Gupta A, Bachet JB, El Hariry I. Erythrocyte-encapsulated asparaginase (eryaspase) combined with chemotherapy in second-line treatment of advanced pancreatic cancer: An open-label, randomized Phase IIb trial. Eur J Cancer. 2020 Jan;124:91-101. doi: 10.1016/j.ejca.2019.10.020. Epub 2019 Nov 21.

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