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Maintenance Therapy With OSE2101 Vaccine Alone or in Combination With Nivolumab, or FOLFIRI After Induction Therapy With FOLFIRINOX in Patients With Locally Advanced or Metastatic Pancreatic Ductal Adenocarcinoma (TEDOPAM)

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ClinicalTrials.gov Identifier: NCT03806309
Recruitment Status : Recruiting
First Posted : January 16, 2019
Last Update Posted : February 12, 2020
Sponsor:
Collaborators:
OSE Immunotherapeutics
Bristol-Myers Squibb
Information provided by (Responsible Party):
GERCOR - Multidisciplinary Oncology Cooperative Group

Brief Summary:
TEDOPAM is a randomized (1.1.1) non-comparative phase II study. This study will assess the efficacy and safety of OSE2101 alone or in combination with nivolumab followed by FOLFIRI reintroduction, versus FOLFIRI as maintenance therapy in patients with advanced PDAC after induction therapy with FOLFIRINOX.

Condition or disease Intervention/treatment Phase
Pancreatic Ductal Adenocarcinoma Locally Advanced Cancer Metastatic Cancer Drug: FOLFIRI Drug: OSE2101 Drug: Nivolumab Phase 2

Detailed Description:

Current standard of care for patients with advanced pancreatic ductal adenocarcinoma (PDAC) is chemotherapy, preferential regimen being FOLFIRINOX (5FU, leucovorin, irinotecan, and oxaliplatin) in fit patients (PS 0-1, bilirubin < 1.5 ULN). The question of how and when the FOLFIRINOX regimen and doses can be deescalated after a period of disease control (i.e. maintenance therapy) remains unanswered. In routine practice, oxaliplatin is usually stopped after 6-8 cycles due to limiting neuropathy, and the fluoropyrimidine is continued, either alone or, more frequently, in combination with irinotecan (FOLFIRI regimen), until disease progression.

Immune therapies have opened new opportunities in cancer therapy. However, results of immunotherapy in PDAC have been disappointing so far, with failure of checkpoint inhibitor monotherapies (anti-CTLA4 and anti-PD-L1 monoclonal antibodies [mAb]) in progressive advanced PDAC, while monovalent vaccines were demonstrated to be safe but with limited activity.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 156 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized Non-comparative Phase II Study of Maintenance Therapy With OSE2101 Vaccine Alone or in Combination With Nivolumab, or FOLFIRI After Induction Therapy With FOLFIRINOX in Patients With Locally Advanced or Metastatic Pancreatic Ductal Adenocarcinoma (TEDOPaM - D17-01 PRODIGE 63 Study).
Actual Study Start Date : February 7, 2019
Estimated Primary Completion Date : December 30, 2022
Estimated Study Completion Date : December 30, 2023

Resource links provided by the National Library of Medicine

Drug Information available for: Nivolumab

Arm Intervention/treatment
Active Comparator: Arm A : maintenance with FOLFIRI
FOLFIRI (IV; folinic acid 400 mg/m2, irinotecan 180 mg/m2, 5-FU bolus 400 mg/m2 and continuous infusion 2,400 mg/m2; in case of previous reduction in the dose of 5FU or irinotecan, dose adjustment will be accepted).
Drug: FOLFIRI
Intravenous (IV); folinic acid 400 mg/m2, irinotecan 180mg/m2, 5-FU bolus 400 mg/m2 and continuous infusion 2,400 mg/m2

Experimental: Arm B : maintenance with OSE2101 monotherapy

OSE2101 monotherapy - subcutaneous injection on day 1, every 3 weeks for 6 doses then every 8 weeks for the remainder of year one and then every 3 months during year 2, for a maximum treatment duration of 24 months, and reintroduction of FOLFIRI at disease progression or unacceptable toxicity.

OSE2101 vaccine is a preservative-free, sterile suspension of 10 synthetically manufactured peptides, an aqueous/DMSO (dimethylsulfoxide) buffer system, and emulsified before use with Montanide® ISA 51 adjuvant. When extemporaneously reconstituted, the product is formulated with 0.5 mg/mL of each peptide (5.0 mg/mL total peptide).

Drug: OSE2101
subcutaneous injection on day 1, every 3 weeks for 6 doses then every 8 weeks for the remainder of year one and then every 3 months during year 2 as monotherapy, for a maximum treatment duration of 24 months,

Experimental: Arm C: maintenance with OSE2101 plus nivolumab
OSE2101 (subcutaneous injection on day 2, every 3 weeks for 6 doses then every 8 weeks for the remainder of year one and then every 3 months during year 2) plus nivolumab (360 mg IV infusion on day 1 every 3 weeks for 6 doses, then 480 mg every 4 weeks), for a maximum treatment duration of 24 months, and reintroduction of FOLFIRI at disease progression or unacceptable toxicity
Drug: OSE2101
subcutaneous injection on day 1, every 3 weeks for 6 doses then every 8 weeks for the remainder of year one and then every 3 months during year 2 as monotherapy, for a maximum treatment duration of 24 months,

Drug: Nivolumab
360 mg IV infusion on day 1 every 3 weeks for 6 doses, then 480 mg every 4 weeks, f or a maximum treatment duration of 24 months




Primary Outcome Measures :
  1. Overall Survival (OS) [ Time Frame: At 12 months ]
    The OS is defined according to the DATECAN (Definition for the Assessment of Time-to-event Endpoints in CANcer trials) consensus as the time from randomization to death for any reason. In the absence of confirmation of death, survival time will be censored at the date of the last clinical assessment


Secondary Outcome Measures :
  1. Progression free survival (PFS) by centralized review of CT-scan imaging. [ Time Frame: assessed up to 60 months ]

    The PFS is defined according to the DATECAN consensus as the time from randomization to first progression or death for any reason, whichever occurs first. In the absence of event (confirmation of progression or death), PFS status will be censored at the date of the last radiological assessment.

    PFS according to RECIST (Response Evaluation Criteria In Solid Tumors) v1.1 in the FOLFIRI arm (Arm A) and iRECIST (immune Response Evaluation Criteria In Solid Tumors) in the immune therapy arms (Arm B and C) by centralized review of CT-scan imaging


  2. Rate of patients with success of the strategy (SSR) [ Time Frame: At 6 months ]
    The SSR is derived from the duration of disease control (DDC), which is defined as the PFS, or, if FOLFIRI is reintroduced and achieves partial response (PR) or stable disease (SD), as the addition of the initial PFS (PFS1) and the PFS of the reintroduction PFS (PFS2)

  3. Number of participants with treatment-related adverse events as assessed by National Cancer Institute-Common Terminology Criteria for Adverse Events [NCICTCAE] v5.0 [ Time Frame: from signature of informed consent to 28 days after the last administration of the investigational product in Arm A and B and 100 days after the last administration of the investigational product in Arm C. ]
    All grade and severe (grade 3-5) toxicities, according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0

  4. Objective response rate (ORR) [ Time Frame: assessed up to 60 months ]
    Response according to RECIST v1.1 in the FOLFIRI arm (Arm A) and iRECIST in the immune therapy arms (Arms B and C) (centralized review of CT-scan imaging); a comparative analysis of tumor response according to these two evaluation rules will be performed in Arm B and C

  5. Health-related Quality of life (HRQoL) evaluation assessed by EORTC QLQ (quality of life questionnaire) -C30 questionnaire [ Time Frame: Baseline, Month 2, Month 4, Month 6, Month 8, Month 10, Month 12, Month 14, Month 16, Month 18, Month 20, Month 22, Month 24 (until the date of first documented progression or date of death, assessed up 60 months) ]
    Rate of patients with an improvement of their quality of life score according to EORTC QLQ-C30. A quality of life score is obtained according to the answers to the 30 questions. The Minimal Clinically Important Difference (MCID) will be fixed to 10 points.

  6. Estimate the Quality-Adjusted Time Without Symptoms of Disease or Toxicity of Treatment (Q-Twist) for each participant [ Time Frame: assessed up to 60 months ]

    Q-TWiST analysis considers three health states, TOX (toxicity), TWiST, and REL (The duration of the relapse), and the duration of each state is calculated for every patient.

    The TOX state comprises the total number of days after randomisation and before strategy failure spent with toxicity, regardless of when the toxicity started or whether there were gaps between toxicities. All grade 3 or 4 toxicities attributable to the study drugs are included in the analysis, apart from those starting after strategy failure.

    The TWiST state is defined as DDC time minus time with toxicities.

    The duration of the relapse or REL state is defined as OS time minus DDC time, or the period of time from progression to death. Patients alive at the end of the study are censored for the OS endpoint.




Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Signed and dated informed consent document, willing and able to comply with protocol requirements
  2. Histologically or cytologically proven PDAC
  3. Age ≥ 18 years
  4. ECOG Performance Status (Eastern Cooperative Oncology Group) 0-1
  5. HLA-A2 genotype (Human Leukocyte Antigen)
  6. Recurrent or advanced disease not amenable to surgery with curative intent (previous resection of primary tumor allowed)
  7. Measurable or evaluable (radiologically detectable disease which does not fulfill RECIST criteria for measurable disease) lesions according to RECIST v1.1 criteria (CT-scan < 4 weeks)
  8. Stable disease or tumor response according to RECIST v1.1 after a 4-month (8 cycles) course of first-line FOLFIRINOX or modified FOLFIRINOX induction chemotherapy
  9. Have archival tissue sample that has been identified and confirmed as available for study, or newly obtained core or excisional biopsy of a tumor lesion
  10. Adequate organ function, as defined by the following:

    • Serum aspartate aminotransferase (AST) and serum alanine aminotransferase (ALT) < 3 x upper limit of normal (ULN)
    • Total serum bilirubin < 1.5 ULN
    • Prothrombin ratio > 70%
    • Serum albumin ≥ 2.8 g/dL
    • Hemoglobin ≥ 10,0 g/dl
    • White blood cell count (WBC) ≥ 3,000/μL
    • Absolute neutrophil count (ANC) ≥ 1,500/μL
    • Platelets ≥ 100,000/μL
    • Serum creatinine ≤ 1.5 ULN or creatinine clearance > 50 mL/min (MDRD)
  11. Life expectancy ≥ 3 months
  12. Women participants of childbearing potential must have a negative serum pregnancy test within the 3 days prior to the first treatment administration until 6 months after the last dose of FOLFIRI, and 90 days after the last dose of OSE2101. Both women participants of childbearing potential and men participants who are sexually active with women of childbearing potential must agree to use a reliable method of birth control (i.e. pregnancy rate < 1% per year); women of childbearing potential receiving nivolumab will be instructed to adhere to contraception for a period of 5 months after the last dose of nivolumab. Men receiving nivolumab and who are sexually active with women of childbearing potential will be instructed to adhere to contraception for a period of 7 months after the last dose of nivolumab.
  13. Registration in a national health care system (PUMA included).

Exclusion Criteria:

  1. Obstructive jaundice (bilirubin > 1.5 ULN) without adequate biliary drainage
  2. Any systemic steroid therapy (> 10 mg daily dose of prednisone or equivalent) whatever the duration of this corticotherapy
  3. Allograft recipient
  4. Active HBV (hepatitis B virus), HCV (hepatitis C virus ), or HIV infection Note: Patients with past HBV infection or resolved HBV infection (defined as having a negative HBsAg test and a positive HBc (hepatitis B core antigen) antibody test are eligible.

    Note: Patients positive for HCV antibody are eligible only if polymerase chain reaction testing is negative for HCV ribonucleic acid (RNA).

  5. Diagnosis of any second malignancy within the last 5 years, except for adequately treated basal cell or squamous cell skin cancer, or in situ carcinoma of the cervix uteri
  6. Any unresolved toxicity NCI CTCAE Grade ≥ 2 from previous anticancer therapy with the exception of neuropathy, alopecia, and the laboratory values defined in the inclusion criteria
  7. Prior treatment with any immune checkpoint inhibitor, including anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 (Cytotoxic T-lymphocyte-associated antigen-4) antibody
  8. Known active central nervous system metastases and/or carcinomatous meningitis; patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 4 weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids at a dose > 10 mg/day of prednisone or equivalent for at least 14 days prior to trial treatment
  9. Uncontrolled massive pleural effusion or massive ascites
  10. History of autoimmune disease including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis, that has required systemic treatment (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs) Note: Patients with vitiligo, alopecia, or any chronic skin condition that does not require systemic therapy are exception to this criterion.

    Note: History of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone may be eligible.

    Note: Controlled Type 1 diabetes mellitus on a stable insulin regimen may be eligible.

  11. Evidence of interstitial lung disease, any active, non-infectious pneumonitis, or known active tuberculosis
  12. Active uncontrolled infection, or current unstable or uncompensated respiratory or cardiac conditions, or bleeding
  13. Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study
  14. Live vaccine administration within 30 days prior to the first dose of study treatment
  15. History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with participation for the full duration of the trial, or is not in the best interest of the participant, in the opinion of the treating investigator
  16. Known or suspected drug hypersensitivity to OSE2101 vaccine or nivolumab
  17. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drug
  18. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of investigational product Note: Local surgery of isolated lesions for palliative intent is acceptable.
  19. Treatment with any investigational medicinal product within 28 days prior to study entry
  20. Prior intolerance/severe toxicity with 5FU or irinotecan (including DPD ( dihydropyrimidinedehydrogénase) and UGT1A1 deficiency)
  21. Pregnancy/lactation
  22. Tutelage or guardianship.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03806309


Contacts
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Contact: Cindy NEUZILLET, MD 0140298500 cindy.neuzillet@gmail.com
Contact: Marie-Line GARCIA LARNICOL, MD 0140298500 marie-line.garcia-larnicol@gercor.com.fr

Locations
Show Show 28 study locations
Sponsors and Collaborators
GERCOR - Multidisciplinary Oncology Cooperative Group
OSE Immunotherapeutics
Bristol-Myers Squibb
Investigators
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Principal Investigator: Cindy NEUZILLET, MD Institut Curie site de Saint Cloud

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Responsible Party: GERCOR - Multidisciplinary Oncology Cooperative Group
ClinicalTrials.gov Identifier: NCT03806309    
Other Study ID Numbers: TEDOPAM D17-01 PRODIGE 63
First Posted: January 16, 2019    Key Record Dates
Last Update Posted: February 12, 2020
Last Verified: February 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by GERCOR - Multidisciplinary Oncology Cooperative Group:
Immunotherapy
Chemotherapy
Additional relevant MeSH terms:
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Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Nivolumab
Folfirinox
Vaccines
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Immunological
Antineoplastic Agents