| 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 |
| metastatic pancreatic adenocarcinoma |
|
| 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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10033599 |
| E.1.2 | Term | Pancreatic adenocarcinoma metastatic |
| E.1.2 | System Organ Class | 100000016906 |
|
| 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 |
| The primary objective of the study is to evaluate the efficacy of ibrutinib in combination with nab-paclitaxel and gemcitabine versus placebo in combination with nab-paclitaxel and gemcitabine, based on investigator assessment of progression-free survival (PFS) and overall survival (OS), for the first line treatment of patients with metastatic pancreatic adenocarcinoma. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives are the following:
• Clinical benefit response (CBR) rate
• Overall response rate (ORR): complete response (CR) + partial response (PR), per investigator assessment
• Carbohydrate antigen 19-9 (CA19-9) response
• Patient-reported outcome (PRO) by EORTC QLQ-C30
• Rate of venous thromboembolic event (VTE)
• To evaluate the safety and tolerability of ibrutinib in combination with nab-paclitaxel and gemcitabine versus placebo in combination with nab-paclitaxel and gemcitabine |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
To be enrolled in the study, each potential subject must satisfy all of the following inclusion criteria.
1. Histologically or cytologically confirmed diagnosis of pancreatic adenocarcinoma.
2. Stage IV disease diagnosed within 6 weeks of randomization.
3. Disease which is evaluable according to RECIST 1.1, with at least one measurable metastatic lesion (not in a previously irradiated area).
4. Disease status for which, in the opinion of the investigator, nab-paclitaxel and gemcitabine is considered an appropriate treatment choice.
5. No previous radiotherapy, surgery, cytotoxic chemotherapy or investigational therapy for the treatment of metastatic pancreatic adenocarcinoma.
6. No prior neo-adjuvant, peri-operative or adjuvant chemotherapy for primary disease of pancreaatic adenocarcinoma. Prior treatment with 5-FU, gemcitabine or capecitabine administered as a radiation sensitizer (at non-cytotoxic doses) in the adjuvant setting is allowed, provided at least 6 months have elapsed since completion of the last dose.
7. No clinically significant third-space fluid accumulation (eg, ascites or pleural effusion).
effusion).
8. Male and female subjects of reproductive potential who agree to use highly effective methods of birth control (eg, implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], complete abstinence, or sterilized partner) and a barrier method (eg, condoms, cervical ring, sponge, etc)during the period of therapy and for 6 months for males and females after the last dose of study medication.
9. Ability to provide written informed consent and to understand and comply with the requirements of the study.
Laboratory
10. Adequate hematologic function independent of transfusion and growth factor support for at least 7 days prior to randomization:
• Absolute neutrophil count (ANC) ≥1.5 x 109/L
• Platelet count ≥100 x 109/L
• Hemoglobin ≥9 g/dL
• Serum aspartate transaminase (AST) and/or alanine transaminase (ALT) ≤5.0 x upper limit of normal (ULN) if liver metastases, or ≤3 x ULN without liver metastases
• Alkaline phosphatase <3.0 x ULN or ≤5.0 x ULN if liver or bone metastases present
• Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin, such as hemolysis)
• Estimated Creatinine Clearance ≥30 mL/min (Cockcroft-Gault)
12. PT/INR <1.5 x ULN and PTT (aPTT) <1.5 x ULN.
Demographic
13. Men and women ≥18 years of age.
14. Karnofsky performance status (KPS) ≥70. Two observers will be required to assess KPS at screening. If discrepant, the one with the lowest assessment will be accepted.
15.Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1 |
|
| E.4 | Principal exclusion criteria |
To be enrolled in the study, potential subjects must meet NONE of the following exclusion criteria:
Disease-related
1. Prior radiotherapy to any measurable lesion at any time.
2. Radiotherapy in the adjuvant setting, or earlier, within the last six months.
3. Previous cytotoxic chemotherapy for primary disease of pancreatic adenocarcinoma.
4. Neuroendocrine (carcinoid, islet cell) or acinar pancreatic carcinoma.
Concurrent Conditions
5. Known brain or leptomeningeal disease (CT or MRI scan of the brain required only in case of clinical suspicion of central nervous system involvement).
6. Prior exposure to BTK inhibitor.
7. A documented ≥10% decrease in KPS between screening visit and within 72 hours prior to randomization.
8. History of other malignancies, except:
• Malignancy treated with curative intent and with no known active disease present for ≥3 years before the first dose of study drug and felt to be at low risk for recurrence by investigator.
• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
• Adequately treated carcinoma in situ without current evidence of disease.
9. Known bleeding disorders (eg, von Willebrand’s disease or hemophilia).
10. Known history of human immunodeficiency virus (HIV) or active with hepatitis C virus (HCV) or hepatitis B virus (HBV). Subjects who are positive for hepatitis B core antibody, hepatitis B surface antigen, or hepatitis C antibody must have a negative polymerase chain reaction (PCR) result before enrollment. Those who are PCR positive will be excluded.
11. Live vaccination within 4 weeks prior to randomization.
12.Any uncontrolled active systemic infection including any infection requiring systemic IV treatment which was completed ≤7 days before randomization.
13. Major surgery within 4 weeks of first dose of study drug.
14. Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator’s opinion, could compromise the subject’s safety or put the study outcomes at undue risk.
15. History of stroke or intracranial hemorrhage within 6 months prior to enrollment.
16. Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomization.
17. History of interstitial lung disease, idiopathic pulmonary fibrosis, or pulmonary hypersensitivity pneumonitis.
18. Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction.
19. Concomitant use of warfarin or other Vitamin K antagonists.
20. Known hypersensitivity to any study drug (nab-paclitaxel, gemcitabine, or ibrutinib)
21. Requires treatment with a strong cytochrome P450 (CYP) 3A inhibitor.
22. Currently active, clinically significant hepatic impairment (Class B or C) according to the Child-Pugh classification
23. Lactating or pregnant.
24. Unwilling or unable to participate in all required study evaluations and procedures.
25. Unable to understand the purpose and risks of the study and to provide a signed and dated informed consent form (ICF) and authorization to use protected health information (in accordance with national and local subject privacy regulations)
26. Decline in serum albumin more or equal than 20% from Screening to study randomization (both labs at Screening and prior to randomization may be confirmed locally). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoints are progression free survival, as determined by investigator assessment, according to RECIST 1.1 criteria and overall survival. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• Clinical benefit response (CBR) rate
• Overall response rate (ORR): CR + PR, per investigator assessment
• Carbohydrate antigen 19-9 (CA19-9) response
• Patient-reported outcomes (PRO): global health status based on QLQ-C30
• Rate of venous thromboembolic events (VTE)
Other Secondary Endpoints: the safety and tolerability of ibrutinib/placebo in combination with nab-paclitaxel and gemcitabine versus the combination of placebo with nab-paclitaxel and gemcitabine |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 41 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Belgium |
| France |
| Germany |
| Italy |
| Korea, Republic of |
| Spain |
| United Kingdom |
| United States |
|
| 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 | 14 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 14 |
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