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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

NCT03806309

Description:

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.

Related Conditions:
  • Pancreatic Ductal Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 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
  • 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).

Clinical Trial IDs

  • ORG STUDY ID: TEDOPAM D17-01 PRODIGE 63
  • NCT ID: NCT03806309

Conditions

  • Pancreatic Ductal Adenocarcinoma
  • Locally Advanced Cancer
  • Metastatic Cancer

Interventions

DrugSynonymsArms
FOLFIRIArm A : maintenance with FOLFIRI
OSE2101Arm B : maintenance with OSE2101 monotherapy
NivolumabArm C: maintenance with OSE2101 plus nivolumab

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A : maintenance with FOLFIRIActive ComparatorFOLFIRI (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).
  • FOLFIRI
Arm B : maintenance with OSE2101 monotherapyExperimentalOSE2101 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).
  • OSE2101
Arm C: maintenance with OSE2101 plus nivolumabExperimentalOSE2101 (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
  • OSE2101
  • Nivolumab

Eligibility 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Survival (OS)
Time Frame:At 12 months
Safety Issue:
Description: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

Measure:Progression free survival (PFS) by centralized review of CT-scan imaging.
Time Frame:assessed up to 60 months
Safety Issue:
Description: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
Measure:Rate of patients with success of the strategy (SSR)
Time Frame:At 6 months
Safety Issue:
Description: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)
Measure: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.
Safety Issue:
Description:All grade and severe (grade 3-5) toxicities, according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0
Measure:Objective response rate (ORR)
Time Frame:assessed up to 60 months
Safety Issue:
Description: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
Measure: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)
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:GERCOR - Multidisciplinary Oncology Cooperative Group

Trial Keywords

  • Immunotherapy
  • Chemotherapy

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