| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic Pancreatic Cancer |
| Cancro del pancreas metastatico |
|
| 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 | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10033605 |
| E.1.2 | Term | Pancreatic cancer 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 |
| To determine, in patients who do not develop any rash, or develop only grade 1 rash, within 4 weeks of start of treatment with gemcitabine + erlotinib, if overall survival can be improved by increasing the dose of erlotinib compared to patients who continue on 100 mg erlotinib. |
| Determinare, nei pazienti che non sviluppano rash o che sviluppano solo rash di grado 1 entro 4 settimane dall inizio del trattamento con gemcitabina + erlotinib, se la sopravvivenza generale possa essere aumentata incrementando la dose di erlotinib rispetto ai pazienti che continuano a ricevere erlotinib a una dose di 100 mg. |
|
| E.2.2 | Secondary objectives of the trial |
| - To evaluate the safety and tolerability of increased doses of erlotinib in combination with gemcitabine. - To evaluate if increasing the dose of erlotinib increases the incidence of grade ≥2 rash vs those who continue on 100 mg erlotinib. - To compare PFS, response and disease control rates between patients with increased dose of erlotinib vs those who continue on 100 mg erlotinib. - To make a non randomized comparison of efficacy and safety between patients who do develop vs those who do not develop grade 2 or higher rash during the first 4 weeks of therapy. - To correlate biomarkers (EGFR expression, EGFR gene copy number, K-ras mutations, EGFR Intron 1 polymorphisms) with outcomes and response to treatment (ORR, PFS, OS). |
| - Sperimentare la sicurezza e la tollerabilita` di dosi piu` alte di erlotinib in associazione a gemcitabina.- Valutare se aumentando la dose di erlotinib si aumenta l`incidenza di rash di grado ≥ 2 rispetto ai pazienti che continuano con erlotinib 100 mg.- Confrontare la sopravvivenza senza progressione,le percentuali di risposta e i tassi di controllo della malattia tra i pazienti con la dose piu` alta di erlotinib e quelli che continuano con erlotinib 100 mg.- Fare un confronto non randomizzato di efficacia e sicurezza tra i pazienti che sviluppano e quelli che non sviluppano rash di grado 2 o superiore durante le prime 4 settimane di terapia.- Stabilire una relazione tra i biomarker (espressione dell`EGFR,numero di copie del gene EGFR,mutazioni di K-ras,polimorfismi dell`introne 1 dell`EGFR) e gli esiti e la risposta al trattamento (ORR,sopravvivenza senza progressione,sopravvivenza generale). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| Inclusion Criteria for initial 4 weeks run-in period. Disease specific inclusion criteria: 1. Histologically or cytologically confirmed pancreatic cancer (adenocarcinoma) with measurable or non-measurable metastatic disease (stage IV); 2. Life expectancy of ≥ 8 weeks. General inclusion criteria: 3. Age ≥ 18 years; 4. ECOG performance status of 0 - 1 (see section 5.3.2); 5. Able to comply with the protocol; 6. Written (signed) Informed Consent to participate in the study; 7. Adequate hematological function: ANC ≥ 1.5 x 109/L, platelet count ≥ 100 x 109/L and Hb ≥ 9 g/dL; 8. PT-INR ≤ 1.5 and PTT ≤ 1.5 x ULN within 7 days prior to start of study treatment; 9. Adequate liver function: serum (total) bilirubin ≤ 1.5 x ULN, SGOT (AST) and SGPT (ALT) < 2.0 x ULN; 10. Albumin > 3.0 g/dL; 11. Adequate renal function: serum creatinine < 1.5 ULN ;12. For all females of childbearing potential a negative pregnancy test must be obtained within 7 days before start of treatment. Inclusion criteria for randomization between day 29 and 35 (after 4 weeks run-in period): 1. Completion of 4 weeks run-in period, without clinical evidence of disease progression, as per investigators opinion; 2. Patients who have not developed rash grade ≥ 2 during the 4 weeks run-in period; 3.Patients who have not developed any other toxicity leading to dose adjustments / discontinuation (for either gemcitabine or erlotinib) during the 4 weeks run-in period. Patients who during the run-in period have had only one gemcitabine related dose reduction (75% of full dose) for hematological toxicity, are eligible for randomization provided they are stable and tolerating the 75% of full dose and no further reductions are anticipated; 4. ECOG performance status of 0 - 1 (see section 5.3.2); 5. Adequate hematological function: ANC ≥ 1.5 x 109/L, platelet count ≥ 100 x 109/L and Hb ≥ 9 g/dL; 6. Adequate liver function: serum (total) bilirubin ≤ 1.5 x ULN, SGOT (AST) and SGPT (ALT) < 2.0 x ULN; 7. Albumin > 3.0 g/dL ; Et al... |
| - |
|
| E.4 | Principal exclusion criteria |
| Disease specific exclusion criteria: 1. Local (Stage Ia to IIb) pancreatic cancer and locally advanced (stage III) pancreatic cancer. (Patients relapsing with metastatic disease, after initial diagnosis with local or locally advanced disease can be enrolled into this study) 2. Prior chemotherapy or treatment with another systemic anti-cancer agent for locally advanced-unresectable or metastatic pancreatic cancer 3. Less than (or equal to) 6 months since last adjuvant chemotherapy. Patient must have recovered from all treatment related toxicities prior to 4 weeks run-in period and must have documented evidence of disease progression (metastatic) following adjuvant chemotherapy 4. Prior treatment with an investigational or marketed agent which acts on the EGFR axis. EGFR inhibitors include (but are not limited to) erlotinib, gefitinib or other anti-EGFR or EGF monoclonal antibody therapy or dual TKI inhibitors 5. Prior adjuvant radiotherapy for pancreatic cancer, except for patients with progressive lesions outside the radiation port who completed the radiotherapy at least 6 months prior to study entry 6. 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 7. Evidence of spinal cord compression or current evidence of CNS metastases. CT/MRI of the brain is mandatory (within 4 weeks before study start) in case of clinical suspicion or evidence of brain metastases General exclusion criteria: 8. Any disease (including psychotic disorders, drug abuse, 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, hepatic, renal or metabolic disease, metabolic dysfunction), physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contra-indicates the use of an investigational drug or puts the patient at high risk for treatment-related complications 9. Patients who have had any major surgery within 2 weeks prior to study start 10. Any known significant ophthalmologic abnormalities of the surface of the eye (the use of contact lenses is not recommended) 11. Patients unable to take oral medication, requiring intravenous alimentation, who have mal-absorption syndrome or any other conditions affecting gastrointestinal absorption, or who have active peptic ulcer disease 12. Pregnant or lactating females 13. Men and women of childbearing potential (<2 years after last menstruation) not using effective means of contraception (e.g. oral contraceptives, intrauterine contraceptive device, sexual abstinence, or surgically sterile), effective meaning failure rate < 1%/year 14. Current or recent (within the 30 days prior to starting study treatment) treatment with another investigational drug or participation in another investigational study 15. Patients known to be HIV positive. Testing is not required in the absence of clinical signs and symptoms suggestive of HIV infection. 16. Hypersensitivity to erlotinib or to gemcitabine or to any of the excipients or to compounds with similar chemical or biologic composition |
| Criteri associati alla malattia: - Carcinoma pancreatico locale (stadio Ia -IIb) e localmente avanzato (stadio III). (I pazienti con ricaduta e malattia metastatica, dopo diagnosi iniziale di malattia locale o localmente avanzata, possono partecipare allo studio). - Chemioterapia precedente o trattamento anticancro con altro agente sistemico per il carcinoma pancreatico metastatico o localmente avanzato-inoperabile - Ultima chemioterapia adiuvante <6 mesi. Il paziente deve aver recuperato tutti i parametri indicatori di tossicita` prima delle 4 settimane di run-in e deve essere documentata la progressione (metastatica) della malattia dopo terapia adiuvante. - Trattamenti precedenti con farmaci sperimentali o commerciali che agiscono su EGFR. Gli inibitori EGFR comprendono (ma non sono limitati a) erlotinib, gefitinib o altre terapie con anticorpi monoclonali anti EGFR o inibitori TKI. - Precedente radioterapia adiuvante per il carcinoma pancreatico, eccetto pazienti con lesioni in progressione al di fuori del campo di radiazione che hanno completato la radioterapia almeno 6 mesi prima di partecipare allo studio. - Qualsiasi tumore entro 5 anni dall`inizio dello studio, eccetto carcinoma della cervice in situ adeguatamente trattato, carcinoma della pelle basale o squamoso. - Evidenza di sompressione midollare o di metastasi SNC. Obbligo di CT/MRI del cervello in caso di sospetto o evidenza di metastasi cerebrali. segue.. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Overall survival |
| Sopravvivenza generale |
|
| 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 | Yes |
| 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 | 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 | No |
| 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 |
| - Stesso farmaco ad altro dosaggio |
| - same IMP used at different dosage |
|
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 58 |
| 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
|
| In caso di pochi pazienti rimasti per un lungo periodo dopo la data di cut-off, lo studio potra` essere chiuso a quella data ed il trattamento proseguira` con il farmaco commerciale. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 57 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 57 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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