E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Pancreatic cancer |
Pancreascarcinoom |
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E.1.1.1 | Medical condition in easily understood language |
Pancreatic cancer |
Alvleesklierkanker |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
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 determine the toxicity and optimal dose of LDE225 when co-administered with fixed doses of gemcitabine and nab-paclitaxel in patients with advanced and metastasized pancreatic cancer. Phase II To determine the anti-tumor activity of LDE225 when co-administered with gemcitabine and nab-paclitaxel in patients with advanced and metastasized pancreatic cancer.
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fase I Het bepalen van de toxiciteit en de optimale dosis van LDE225 bij gelijktijdige toediening met een vaste doses gemcitabine en nab-paclitaxel bij patiënten met gevorderde en uitgezaaide alvleesklierkanker. fase II Het bepalen van de anti-tumor activiteit van LDE225 bij gelijktijdige toediening met gemcitabine en nab-paclitaxel bij patiënten met gevorderde en uitgezaaide alvleesklierkanker. |
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E.2.2 | Secondary objectives of the trial |
To determine survival and progression free survival of LDE 225 in combination with nab-paclitaxel and gemcitabine. |
Het bepalen van de overleving en progressie vrije overleving van LDE225 in combinatie met nab-paclitaxel en gemcitabine . |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients eligible for inclusion in this study have to fulfill all of the following criteria: 1.patients must provide written informed consent according to ICH/GCP, and national/local regulations prior to any screening procedures. 2. Male or female adult patients (> 18 years) 3. Patients with histologically/cytologically confirmed diagnosis of pancreatic ductal adenocarcinoma. 4. a. Phase I Patients with non resectable or metastasized pancreatic ductal adenocarcinoma 4b. Phase II Patients with non resectable or metastasized pancreatic ductal adenocarcinomanot pre-treated with chemotherapy or radiotherapy unless adjuvant treatment with gemcitabine >6 months 5. Measurable disease as assessed by RECIST 1.1 6. ECOG performance status 0-2 7. Patient has adequate bone marrow and organ function as defined by the following laboratory values: • Absolute Neutrophil Count > 1.5 x 109/L • Hemoglobin > 9.0 g/dL (5.6 mmol/L) • Platelets > 100 x 109/L • Serum total bilirubin within normal range (or ≤ 1.5 x ULN (upper limit of normal); or total bilirubin < 3.0 x ULN with direct bilirubin within normal range in patients with well documented Gilbert’s syndrome) • INR < 1.5 • Potassium, calcium, within normal limits for the institution • Serum creatinine < 1.5 x ULN or creatinine clearance >60 mL/min/1.73 m2 • Alanine aminotransferase (AST) and aspartate aminotransferase (ALT) within normal range or < 3.0 x ULN if liver metastases are present • Blood creatinine phosphokinase level < 1.5 ULN
8. Patient is able to swallow and retain oral medication 9. Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
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Patienten met een niet resectabel of gemetastaseerd ductaal adenocarcinoom van de pancreas |
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E.4 | Principal exclusion criteria |
1. Use of other investigational drugs within 30 days of enrollment or 5 half-lives of the study drug, whichever is longer. For investigational biologics enrollment can occur when the expected PD effect has returned to baseline. 2. History of hypersensitivity to LDE225, or to drugs of similar chemical classes. 3. Patient has received previous treatment with smoothened inhibitors. 4. Patients with known CNS metastases or a primary CNS malignancy 5. Patients who have neuromuscular disorders (e.g. inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis and spinal muscular atrophy) or are on concomitant treatment with drugs that are recognized to cause rhabdomyolysis, such as HMG CoA inhibitors (statins), clofibrate and gemfibrozil. If it is essential that the patient remains on a statin to control hyperlipidemia, only Pravastatin may be used with extra caution. 6. Patients who are planning on embarking on new physical activities, such as strenuous exercise, that can result in significant increases in plasma CK levels while on study treatment. 7. Patients who require the use of warfarin (substrate of CYP2C9) cannot be enrolled as LDE225 is a competitive inhibitors of CYP2C9 based on in-vitro data. 8. Patients who are not willing to avoid consumption of Seville oranges, grapefruit or grapefruit juice grapefruit hybrids, pommelos and exotic citrus fruits during the entire study and preferably 7 days before the first dose of study medications, due to potential CYP3A4 interaction with the study medications. 9. Patients who are not willing to stop taking herbal medications at least 7 days prior to the first dose of study treatment. 10. Patient is currently being treated with drugs known to be strong inhibitors or inducers of CYP3A4/5, which cannot be discontinued or switched to a different medication 7 days prior to starting study treatment and for the duration of the study.
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Patienten met een overgevoeligheid voor LDE225. Patienten met een neuromusculaire aandoening |
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E.5 End points |
E.5.1 | Primary end point(s) |
Phase I DLT and MTD of LDE225 co-administered with fixed doses of gemcitabine and nab-paclitaxel in patients with advanced or metastasized pancreatic cancer. Phase II Response rate according to RECIST 1.1
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Fase I: Bepalen van de DLT en MTD van LDE225 Fase II: respons evaluatie volgens recist |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Fase I: coninuously during treatment Fase II: every two months |
Fase I Continue tijdens behandeling
Fase II: Elke twee maanden |
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E.5.2 | Secondary end point(s) |
1. Adverse events (AEs ), serious adverse events (SAEs) according to NCI CTC version 4.0 2. Median survival and progression free survival • Changes in vascularity with DCE MRI: Observe the difference in Ktrans between baseline, after 8 weeks of treatment and at tumor progression. • Changes in tumor stroma density with DWI MRI : Observe the difference in AUC between baseline, after 8 weeks of treatment and at tumor progression. 3. Correlation of SPARC (matrix), SMO and Gli (tumor cells) expression in initial tumor biopsy material and CA19.9 (serum) levels during therapy with tumor response. |
1. Bijwerkingen (AE), ernstige ongewenste voorvallen (SAE's) volgens de NCI CTC versie 4.0 2. De mediane overleving en progressie vrije overleving • Veranderingen in vasculariteit met DCE MRI: Let op het verschil in Ktrans tussen basislijn, na 8 weken van de behandeling en bij progressie van de tumor. • Veranderingen in tumorstroma dichtheid met DWI MRI: Let op het verschil in AUC tussen basislijn, na 8 weken van de behandeling en bij progressie van de tumor. 3. Correlatie van SPARC (matrix), SMO en Gli (tumorcellen) expressie in de initiële tumor biopsie materiaal en CA19.9 (serum) niveaus tijdens de behandeling met tumor respons.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1.continuously during treatment 2. Every two months 3. Baseline |
1. Continue tijdens de behandeling 2. Elke twee maanden 3. Baseline |
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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) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | Yes |
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 | 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 | 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 | 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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 2 |
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
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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 | 0 |
E.8.9.1 | In the Member State concerned days | 0 |