| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| First line treatment of metastatic pancreas CA with MSC1936369B in combination with gemcitabine and / or after progression under gemcitabine monotherapy second line treatment with MSC1936369B. |
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| E.1.1.1 | Medical condition in easily understood language |
| treatment of pancreas cancer |
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| 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 | 17.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10033576 |
| E.1.2 | Term | Pancreas carcinoma |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10033577 |
| E.1.2 | Term | Pancreas carcinoma recurrent |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To evaluate the anti-tumor activity of MSC1936369B combined with gemcitabine compared to gemcitabine alone as first line treatment in subjects with metastatic pancreatic adenocarcinoma.
During the safety run-in the Maximum Tolerated Dose (MTD) and the recommended dose of MSC1936369B when combined with gemcitabine in subjects with metastatic pancreatic adenocarcinoma will be determined for each of the two treatment regimens.
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| E.2.2 | Secondary objectives of the trial |
• To determine the safety and tolerability of MSC1936369B combined to gemcitabine in subjects with metastatic pancreatic cancer.
• To evaluate the anti-tumor activity in each treatment arm in terms of response rate, clinical benefit, overall survival and time to progression.
• To assess the pharmacokinetics (PK) of MSC1936369B when given in combination, in subjects with metastatic pancreatic cancer
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subject has provided signed informed consent. Fully understands requirements of the trial and willing to comply with all trial visits and assessments.
2. Histologically or cytologically confirmed adenocarcinoma of the pancreas with documented distant metastases and availability of tumor sample.
3. Evidence of disease (not necessarily measurable disease). Complete tumor assessment including chest X ray, CT scan of abdomen and other scans as necessary to document all sites of disease performed within 28 days prior to trial entry/randomization.
4. Age ≥ 18 years.
5. Women of childbearing potential must have a negative blood pregnancy test at the screening visit. For the purposes of this trial, women of childbearing potential is defined as: “All female subjects after puberty unless they are post-menopausal for at least two years, or are surgically sterile.”
6. Female subjects of childbearing potential must be willing to avoid pregnancy by using an adequate method of contraception for 2 weeks prior to screening, during and four weeks after the last dose of trial medication. Male subjects with female partner of childbearing potential must be willing o avoid pregnancy of their partner by using an adequate method of contraception for 2 weeks prior to screening, during and up to 6 months after the last dose trial medication. Adequate contraception is defined as two barrier methods, or one barrier method with a spermicide, or intrauterine device. The use of oral contraception is not recommended because of nausea and vomiting potentially induced by the study drugs. |
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| E.4 | Principal exclusion criteria |
1. Bone marrow impairment as evidenced by hemoglobin < 9.0 g/dL, neutrophil count < 1.5 x 109/L, platelets < 100 x 109/L.
2. Renal impairment as evidenced by calculated creatinine clearance < 60 mL/min.
3. Liver function abnormality as defined by total bilirubin > 1.5 x ULN, or AST/ALT > 2.5 x ULN, for subjects with liver involvement AST/ALT > 5 x ULN.
4. Serum calcium > 1 x ULN.
5. History of central nervous system (CNS) metastases, unless subject has been previously treated for CNS metastases, is stable by CT scan without evidence of cerebral edema, and has no requirements for corticosteroids or anticonvulsants.
6. History of difficulty swallowing, malabsorption or other chronic gastro-intestinal disease or conditions that may hamper compliance and/or absorption of the tested product.
7. Eastern Cooperative Oncology Group Performance Status (ECOG PS) greater than 1.
8. Known HIV positivity, active hepatitis C, active hepatitis B or signs and symptoms suggestive of transmissible spongiform encephalopathy, or family members who suffer(ed) from such.
9. Prior chemotherapy for metastatic disease, however prior chemotherapy will be accepted in the following situations:
• Subjects who received gemcitabine with radiation therapy as a radiosensitizer for locally advanced disease
• Subjects who completed chemotherapy (5-FU or gemcitabine) in adjuvant setting for resectable disease 6 months or more prior to the study entry
10. Extensive prior radiotherapy on more than 30% of bone marrow reserves, or prior bone marrow/stem cell transplantation. Prior radiation for local disease management is allowed if last fraction was completed at least 4 weeks prior to trial entry/randomization.
11. History of any other significant medical disease such as major gastric or small bowel surgery, recent drainage of significant volumes of ascites or pleural effusion or has other significant disease or a psychiatric condition that might impair the subjects well being or preclude full participation in the trial.
12. Significant cardiac conduction abnormalities, including QTc prolongation of >480 ms and/or pacemaker.
13. Pregnant or nursing female subject.
14. Retinal degenerative disease (Hereditary retinal degeneration or age-related macular degeneration), history of uveitis or history of retinal vein occlusion.
15. Known hypersensitivity to the MSC1936369B or gemcitabine.
16. Participation in another clinical trial within the past 28 days.
17. Has CPK level at baseline NCI CTCAE Grade ≥2 (i.e., > 2.5 x ULN), and/or has a previous history of myositis or rhabdomyolysis. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Progression-Free Survival (PFS), defined as time (in months) from randomization date to date of progression prior to the start of subsequent MSC1936369B monotherapy, as reported and documented by the Investigator (i.e. radiological progression per RECIST criteria).
• To determine the safety and tolerability of MSC1936369B combined to gemcitabine in subjects with metastatic pancreatic cancer.
• To evaluate the anti-tumor activity in each treatment arm in terms of response rate, clinical benefit, overall survival and time to progression.
• To assess the pharmacokinetics (PK) of MSC1936369B when given in combination with gemcitabine , in subjects with metastatic pancreatic cancer.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
time from randomization date to date of progression
During the safety run-in: when the DLT will be reached |
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| E.5.2 | Secondary end point(s) |
• Grade 3 or 4 toxicity using the NCI-CTCAE v4.0 during the trial period, judged to be related to the trial medication.
• Treatment-emergent adverse events (TEAEs).
• Clinically significant change in a laboratory parameter and/or vital signs judged to be related to the trial medication.
• Best overall response: presence of at least one Complete Response (CR) or Partial Response (PR) (using the Response Evaluation Criteria in Solid Tumors [RECIST] v1.0) during treatment.
• Clinical Benefit: presence of at least one CR, PR or Stable Disease (SD) (using RECIST v1.0) during treatment.
• Time to progression (TTP).
• Overall survival (OS) time.
• Population PK parameter estimates of MSC1936369B (absorption rate constant ka, clearance from central compartment CL/f, volume of central compartment V1/f, intercompartmental clearance Q/f, and volume of peripheral compartment V2/f)
• PK MSC1936369B derived from sparse sampling.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
any time during the study and maximum 6 months after last patient has been randomized
During the safety run-in: any time till the DLT being reached |
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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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| 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 | 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| open during the safety run-in part |
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| 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 | 39 |
| 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 |
| Russian Federation |
| Serbia |
| Spain |
| United Kingdom |
| United States |
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| 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
|
| End of trial is defined as the date of the last dose + 28 days or when at least 2/3 events for survival have been observed, which ever comes last. |
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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 | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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