| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients suffering from advanced, recurrent or metastatic gastrointestinal adenocarcinoma. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients suffering from advanced, recurrent or metastatic cancer of the gastrointestinal tract. |
|
| 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 | 18.0 |
| E.1.2 | Level | HLGT |
| E.1.2 | Classification code | 10017991 |
| E.1.2 | Term | Gastrointestinal neoplasms malignant and unspecified |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
| Safety and tolerability of MSC_apceth_111 in combination with Ganciclovir. |
|
| E.2.2 | Secondary objectives of the trial |
- Dose finding.
- Hints of efficacy based on RECIST criteria 1.1.
- Tumor / serum markers.
- Quality of Life.
- Overall survival (OS).
- Immunological monitoring of potential allo-immunization after repeated administration of allogeneic MSC_apceth_111.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Age ≥ 18 years.
2. Patients with advanced or recurrent or metastatic gastrointestinal adenocarcinoma.
Target indication:
- Gastric cancer (cTNM: T3NxMx or T4NxMx) (including gastro-esophageal junction) or
- Pancreatic cancer (cTNM: T3NxMx) or
- Metastatic colorectal cancer (cTNM: TxNxM1) or
- Cholangiocellular carcinoma (cTNM: T3NxMx or T4NxMx)
The TNM classification should not be older than 4 months.
3. Premature or scheduled termination of standard therapy (including possible preoperative therapy; for details see CTP section 7) due to intolerability / progress / inefficacy or no acceptance by the patient, if relapses/metastases are measurable by means of imaging techniques.
4. No relapse and no single metastasis should exceed 5 cm in its maximal diameter.
5. In case of metastases due to colorectal cancer:
- Metastases are unresectable
- The total volume of the liver metastases does not exceed 30 % of the total liver volume
- In addition to liver metastases lung metastases (as assessed by a radiologists with a minimum diameter of at least 0,5 cm) are allowed, however, not more than 10 with the largest one not exceeding 2,0 cm in diameter
- Lymph node metastases are permitted
- Brain metastases: As long as only one organ is affected by extra-cranial metastases due to colorectal cancer no radiological investigation for brain metastases is needed if there are no signs or symptoms suspicious for brain metastases. In case of liver and lung metastases the patient has to be excluded unless a cranial image verifies absence of brain metastases.
6. Progressive disease as clinically assessed by the investigator.
7. Adequate organ function:
- Hb > 9.0 g/dl
- WBC > 3,000 cells/µl and Neutrophils >500 /μl
- Platelets > 100,000 cells/µl
- ALT/AST ≤ 5 ULN
- total bilirubin ≤ 3 ULN
- Creatinine ≤ 2.0 mg/dl and creatinine clearance ≥ 50 ml/min
8. General condition ECOG 0-1.
9. Anticipated minimal life expectancy of at least 3 months.
10. Men and women of reproductive potential must agree to follow accepted contraception methods during treatment and for 3 months after completion of treatment. Medically acceptable methods of birth control are methods with a low failure rate of less than 1% per year; e.g. hormonal contraceptives for at least 7 days before trial enrollment or an intrauterine device, or double barrier method (male or female condom or diaphragm, in combination with a spermicidal gel). All women, including those with tubal ligation, are considered to be of childbearing potential unless they have been postmenopausal for at least 2 years. Hysterectomized women are considered surgically sterile and are not required to use any contraception.
Males should not participate in a sperm donation program.
11. Ability of patient to understand character and individual consequences of clinical trial.
12. Written informed consent must be available before any study specific procedure is performed. |
|
| E.4 | Principal exclusion criteria |
1. Patients with severe heart diseases: NYHA stage III and IV; unstable angina pectoris, or myocardial infarction during the last 8 weeks before Visit 1 (Baseline).
2. Clinical significant ischemic disease during the last 4 weeks before Visit 1 (Baseline).
3. Severe lung disease: COPD Grade III, Asthma bronchiale Grade IV, lung fibrosis.
4. Clinically relevant ascites / peritoneal carcinomatosis.
5. Symptomatic pleural or pericardial effusion.
6. Serious uncontrolled acute infections less than 3 weeks before Visit 1 (Baseline).
7. Patients with HCV infection as defined by anti-HCV pos and HCV RNA pos and / or HBV infection as defined by anti-Hbc pos and/ or HBV DNA pos.
8. Patients with HIV infection as minimally demonstrated by HIV RNA.
9. Immunodeficiencies or systemic autoimmune diseases (e.g. M. Crohn, Colitis ulcerosa) or known malformations of the gastrointestinal tract.
10. Active infection with HSV (by IgM pos).
11. Patient with detection of anti-HLA Abs (pos) at screening prior to MSC_apceth_111 infusion.
12. Second carcinoma in addition to the underlying carcinoma unless the second carcinoma was curatively and successfully resected more than 5 years ago before Visit 1 (Baseline) (exception: basal cell carcinoma, precancerous conditions).
13. Use of any immunomodulators.
14. Need for any standard anti-tumor therapy like chemo-, targeted immuno-, cytokine and radiotherapy in the time interval 2 weeks before infusion of MSC_apceth_111 or anticipation of chemo- or radiotherapy during treatment with MSC_apceth_111 and GCV until 2 days after the last administration of GCV.
15. Known dependency on alcohol or other drugs.
16. Committed to an institution by way of official or judicial order.
17. Patients requiring corticoids in doses above the Cushing threshold.
18. Known liver fibrosis or liver cirrhosis.
19. Any concomitant severe disease which could compromise the objectives of this study in the judgment of the investigator.
20. Pregnant or breast feeding female patient
21. Any surgery in the last four weeks before the administration of MSC_apceth_111.
22. History of hypersensitivity to the investigational product or to Ganciclovir, Valganciclovir, Aciclovir or Valaciclovir.
23. Any contraindication to Ganciclovir (see current SmPC) or the need for the following drugs interacting with Ganciclovir: Probenecid; combination of Imipenem-Cilastatin; Dapson, Pentamidin; Flucystosin; Vincristin, Vinblastin, Adriamycin, Amphotericin B; combination of Trimethoprim and Sulfonamides, Nucleosideanaloga or Hydroxy-urea.This is confined to the time period 14 days prior to Ganciclovir and up to 7 days after termination of Ganciclovir treatment
24. Participation in another clinical trial, respectively, during the last 4 weeks prior to the first MSC_apceth_111 dose. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety and tolerability of allogeneic MSC_apceth_111 evaluated via three (3) different doses as indicated by:
- Adverse events
- Common Toxicity Criteria (CTC-AE) of the National Cancer Institute |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Two (2) months after first treatment with MSC_apceth_111 (day 56) |
|
| E.5.2 | Secondary end point(s) |
Efficacy as indicated by
1) Tumor response (according to the RECIST criteria 1.1) assessed by CT or MRT (if medically indicated )
2) Optional: PET activity, if PET positive at baseline
3) Change of tumor / serum markers
4) Change of Quality of Life assessment
5) Overall survival (OS)
6) Testing for the presence of HLA-antibodies |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Endpoints 1 - 4: Two (2) months after first infusion of MSC_apceth_111 (day 56).
Endpoint 5: Up to twelve (12) months after first infusion of MSC_apceth_111 (day 336).
Endpoint 6: Two (2) months after first infusion of MSC_apceth_111 (day 56). |
|
| 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 | 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) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| 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 | 5 |
| 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 | 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 | 1 |
| 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 | 1 |
| 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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