E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
histologically confirmed diagnosis of metastatic pancreatic adenocarcinoma |
|
E.1.1.1 | Medical condition in easily understood language |
Metastatic pancreatic cancer |
|
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 | 19.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10033575 |
E.1.2 | Term | Pancreas cancer |
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 |
- to demonstrate that the combination of afatinib plus gemcitabine is superior to gemcitabine alone in the treatment of metastatic pancreatic cancer |
|
E.2.2 | Secondary objectives of the trial |
- accompanying translational research program: to define parameters which may serve to provide prognostic information or predict treatment efficacy |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Written informed consent in advance of any study-specific procedure 2. Histologically (not cytologically) confirmed diagnosis of metastatic pancreatic adenocarcinoma (stage IV according to UICC 2009 classification: each T, each N, M1) 3. Availability of tumour samples 4. Informed consent that tumour- and blood samples are centrally collected and will serve for translational analyses according to the study protocol 5. Age ≥ 18 years 6. ECOG 0-1 7. Life expectancy at least 3 months 8. No option for surgical resection or radiation in curative intent 9. At least one measurable tumour lesion (CT-scan or MRI) according to RECIST Version 1.1 10. Possibility of long-term follow-up 11. Negative pregnancy test in fertile females 12. Given legal capacity of the patient 13. Adequate hepatic, renal and bone marrow function, defined as: - absolute neutrophil count > 1500/µl - hemoglobin > 9 g/dl - thrombocytes > 100 000/µl - serum bilirubin < 2 x ULN (liver metastasis < 5 x ULN) - serum creatinin < 1.5 x ULN - creatinin clearance > 30 ml/min (Cockroft/Gault) - transaminases < 2.5 x ULN (liver metastasis < 5 x ULN) - albumin > 25 g/L |
|
E.4 | Principal exclusion criteria |
1. Evidence of weight loss > 15 % within one month 2. Active brain metastases (stable for <28 days, symptomatic, or requiring concurrent steroids) or leptomeningeal disease. Patients who have received prior whole brain irradiation and whose brain metastases are stable according to the criteria above will not be excluded 3. Previous gemcitabine treatment is allowed only if applied as monotherapy in the adjuvant setting (after potential curative R0 or R1 resection), and if the adjuvant single-agent gemcitabine chemotherapy was terminated at least 6 months before study entry 4. Previous systemic treatment with chemotherapy or radiotherapy for locally advanced, non resectable or metastatic pancreatic cancer 5. Radiotherapy within four weeks prior to randomization or radiation of target lesions 6. Prior treatment with EGFR targeting therapies or treatment with EGFR- or HER2 inhibiting drugs within the past 4 weeks before start of therapy or concomitantly with this trial 7. Hypersensitivity to afatinib or to gemcitabine or to any of the excipients or to compounds with similar chemical or biologic composition 8. Contraindications against the use of gemcitabine 9. Severe renal insufficiency (baseline creatinine clearance < 30 ml/mi) 10. LDH elevated by >2.5 ULN 11. Severe hepatic dysfunction (bilirubin ≥ 2.0 x ULN, transaminases ≥ 2.5 x ULN or ≥ 5 x ULN in case of liver metastases) 12. Any disease e. g. active infection, uncontrolled hypertension, clinically significant cardiovascular disease for example CVA (≤ 6 months before study start), myocardial infarction (≤ 6 months before study start), unstable angina, NYHA ≥ grade 2 CHF, arrhythmia requiring medication, metabolic dysfunction giving reasonable suspicion of a disease or condition that contra-indicates the use of the study drugs or puts the patient at high risk for treatment-related complications 13. Significant or recent acute gastrointestinal disorders with diarrhoea as a major symptom e.g. Crohn’s disease, malabsorption or CTC grade ≥2 diarrhoea of any aetiology 14. Pregnant or lactating females, non-effective contraception in men and women of childbearing potential (an effective contraceptive measure has a Pearl Index <1) 15. Any major surgery within the last 2 weeks before study entry 16. Chemo- or immunotherapy within the past 4 weeks 17. Treatment with an investigational drug in another clinical study within the past 28 days prior to the start of therapy or concomitantly with this study 18. Any persisting toxicities which are deemed to be clinically significant from the previous therapy 19. Patients with pre-existing interstitital lung disease 20. Psychological, familial, social or geographic conditions that may prevent an adequate compliance with the study protocol 21. Known or suspected alcohol- or drug abuse 22. Patients unable to comply with the protocol 23. Known hepatitis B infection, known hepatitis C infection or HIV carrier 24. Requirement for treatment with any of the prohibited concomitant medications listed in section 4.3.2 25. Any other malignancies within the last 5 years before study start, except for adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
- During study treatment: weekly/biweekly assessment - during Follow Up: every 3 months for a total duration of 12 months after end of treatment |
|
E.5.2 | Secondary end point(s) |
- Progression free survival - Duration of response - 1-year survival - Biochemical tumour marker response (serum CA 19-9) - Quality of life (EORTC QLQ C-30) - Toxicity (NCI CTC-AE v4.0) - explorative endpoint of translational research program: focus on potential prognostic and predictive biomarkers associated with the EGFR pathway (e.g. EGFR, HER2-HER4, PTEN, KRAS, EGFR intron 1 polymorphism, epiregulin, amphiregulin, single nucleotide polymorphism) and gemcitabin metabolism/toxicity (e.g. hENT1, RRM1, CDA) |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
During study treatment: - response will be assessed every two cycles (8 weeks) - CA 19-9 and Quality of life: every cycle - toxicity: weekly/biweekly During Follow Up: - toxicity and survival will be assessed every 3 months for a total period of 12 months after end of treatment - translational program: tumour and blood samples will be collected once during screening |
|
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 | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
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) | 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 | Yes |
E.8.1.1 | Randomised | Yes |
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 | 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 | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
comparison of treatment schemes |
|
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 | 30 |
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 | No |
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 | 4 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |