| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| metastatic pancreatic adenocarcinoma |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10033599 |
| E.1.2 | Term | Pancreatic adenocarcinoma metastatic |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase I :
To identify the maximum tolerated dose (MTD) and the recommended phase II dose of first-line treatment combining gemcitabine plus nab-paclitaxel followed by Folfirinox in metastatic pancreatic adenocarcinoma.
Phase II :
To improve the objective response rate of patients treated with this new combination (according to the RECIST v1.1 (appendix 6) criteria). |
|
| E.2.2 | Secondary objectives of the trial |
Only for phase II is to evaluate:
- Safety profile assessed by NCI CTCAE v4.03
- Progression-free survival
- Overall survival
- Secreted protein acidic and rich in cysteine (SPARC) (optional study and centraly analyzed), and CA19-9 levels in relation to efficacy |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Secreted protein acidic and rich in cysteine (SPARC) (optional study and centraly analyzed), and CA19-9 levels in relation to efficacy |
|
| E.3 | Principal inclusion criteria |
1. Histologically or cytologically confirmed metastatic adenocarcinoma of the pancreas. The definitive diagnosis of metastatic pancreatic adenocarcinoma will be made by integrating the histopathological data within the context of the radiologic data.
2. Initial diagnosis of metastatic disease must have occurred ≤6 weeks prior to inclusion in the study.
3. One or more measurable metastatic lesions (Recist 1.1) by CT scan of the abdomen, pelvis and chest, or hepatic MRI and CT scan (abdomen, pelvis and chest) without injection, if patient is allergic to CT contrast media).
4. No previous radiotherapy, surgery, chemotherapy or investigational therapy for the treatment of metastatic disease.
5. Prior treatment with 5 FU or gemcitabine administered as a radiation sensitizer in the adjuvant setting is allowed, provided that at least 6 months have relapsed since completion of the last dose and no lingering toxicities are present.
6. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1.
7. Males or females aged 18 to 75 years at the time of signing the Informed Consent Form (ICF).
8. Adequate blood function at baseline (obtained within 14 days before start of study treatment) as defined by :
•Absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L;
•Platelets count ≥ 100,000/mm3 (100 × 10^9/L);
•Hemoglobin (Hgb) ≥ 9 g/dL.
9. Adequate liver and renal function at baseline (obtained within 14 days before start of study treatment) as defined by :
•AST and ALT ≤ 2.5 x upper limit of normal range (ULN), unless liver metastases are clearly present in which case AST and ALT ≤ 5 × ULN is allowed;
•Total bilirubin ≤ 1.5 x ULN;
•Serum creatinine within normal limits or calculated clearance ≥ 60mL/min for patients with serum creatinine levels above or below the institutional normal value (using the Cockroft-Gault formula).
10. Patient has no clinical significant abnormalities in urinalysis results (obtained ≤ 14 days before start of study treatment)
11. Patient has acceptable coagulation values (obtained ≤14 days prior to the first administration of study drug) as demonstrated by :
•Prothrombin time (PT) within normal limits (± 15%)
•Partial thromboplastin time (PTT) within normal limits (± 15%)
12. Patient should be asymptomatic for jaundice prior to the first administration of study drug (Day1). Significant or symptomatic amounts of ascites should be drained prior to Day 1.
13. Pain symptoms should be stable and should not require modifications in analgesic management prior to Day 1 of treatment.
14. Life expectancy ≥ 2 months
15. Non-pregnant and non-lactating female. If a female patient is of child-bearing potential, as evidenced by regular menstrual periods, she must have a negative serum pregnancy test (β-hCG) documented 72 hours prior to randomization.
16. If sexually active, the patient must agree to use contraception considered adequate and appropriate by the Investigator during the period of administration of study drug. In addition, male and female patients must utilize contraception after the end of treatment as recommended in the product's Summary of Product Characteristics or Prescribing Information provided in the study manual.
17. Informed consent signed prior to any study specific procedures.
18. Affiliated to the French National social security |
|
| E.4 | Principal exclusion criteria |
1. Known brain metastases.
2. Patient has only locally advanced disease.
3. History of other malignancy in the last 5 years. Patients with prior history of in situ cancer or basal or squamous cell skin cancer are eligible. Patients with other malignancies are eligible if they were cured by surgery alone or surgery plus radiotherapy and have been continuously disease-free for at least 5 years.
4. Patients having received cytotoxic doses of any other chemotherapy (than 5FU and gemcitabine) in the adjuvant setting.
5. Peripheral sensory neuropathy ≥ grade 2 at the time of signing the ICF.
6. Patients using AVKs (Coumadin…)
7. Active and uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy.
8. Known historical or active infection with HIV
9. Major surgery, other than diagnostic surgery (i.e. surgery done to obtain a biopsy for diagnosis without removal of an organ), within 4 weeks prior to Day 1 of treatment in this study.
10. History of allergy or hypersensitivity to any of the study drugs or any of their excipients, or the patient exhibits any of the events outlined in the Contraindications or Special Warnings and Precautions sections of the SmPCs or Prescribing Information.
11. History of connective tissue disorders (e.g., lupus, scleroderma, arteritis nodosa).
12. Patients with high cardiovascular risk, including, but not limited to, coronary stenting or myocardial infarction in the past year.
13. History of Peripheral Artery Disease (e.g. claudication, Leo Buerger's disease).
14. Serious medical risk factors involving any of the major organ systems, or serious psychiatric disorders, which could compromise the patient's safety or the study data integrity.
15. Enrollment in any other clinical protocol within 4 weeks of signing the ICF.
16. Patient is unwilling or unable to comply with study procedures, or is planning to take vacation for 7 or more consecutive days during the course of the study.
17. Legal incapacity or limited legal capacity. Medical or psychological conditions not allowing the subject to complete the study or sign the consent. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase I :
Dose limiting toxicities (DLT) during the first administered cycle :
-any grade ≥ 4 toxicity (except for vomiting in the absence of adequate prophylaxis),
-any symptomatic grade ≥ 3 thrombocytopenia
-any grade ≥ 3 febrile neutropenia
-any grade ≥ 3 neutropenia with infection grade ≥ 3
-any grade ≥ 3 peripheral sensory neuropathy
Phase II : Objective response rate is defined as the percentage of complete response (CR) or partial response (PR). |
|
| E.5.2 | Secondary end point(s) |
Phase II : Safety is evaluated according to the NCI CTC AE v 4.03 classifications (see appendix 4).
Progression free survival (PFS) is defined as the time from the date of inclusion to the date of the first documented progression or the date of death from any cause.
Overall Survival (OS) is defined as the time from the date of inclusion to the date of death from any cause.
SPAC will be analyzed in Spain (Madrid) for immunohistochemistry analysis.
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| SPARC and CA19-9 levels in relation to efficacy (optional study and centraly analyzed) |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| To identify the maximum tolerated dose |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Groups of dose level for phase I |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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