| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| advanced or metastatic adenocarcinoma of the esophagogastric junction or the stomach |
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| E.1.1.1 | Medical condition in easily understood language |
| advanced or metastatic gastric 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 | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10062878 |
| E.1.2 | Term | Gastrooesophageal cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| 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 compare rate of Progression Free Survival acc. to RECIST v1.1 in patients treated with nivolumab and ipilimumab plus modified FOLFOX versus patients treated with modified FOLFOX alone for Arms A and B as well as the progression-free survival rate (PFS@6) for Arms A2 and C (FLOT plus Nivolumab).
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| E.2.2 | Secondary objectives of the trial |
To determine efficacy in terms of objective response rate (acc. to RECIST v1.1) and overall survival, as well as tolerability (acc. to NCI CTC AE v4.03) of the experimental regimen. In addition, histopathological types and molecular parameters such as immune cell composition and PD-L1 expression as determined by quantitative mRNA (RT-PCR) will be correlated with efficacy in an exploratory analysis. Subgroup analysis including PFS and OS by PD-L1 expression status.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. All subjects must have inoperable, advanced or metastatic GC or GEJ adenocarcinoma.
2. Subjects must have HER2-negative disease defined as either IHC 0 or I+ or IHC 2+, the latter in combination with ISH-, as assessed locally on a primary or metastatic tumour.
3. Subject must be previously untreated with systemic treatment given as primary therapy for advanced or metastatic disease.
4. Prior adjuvant or neoadjuvant chemotherapy, radiotherapy and/or chemoradiotherapy are permitted as long as the last administration of the last regimen (whichever was given last) occurred at least 6 months prior to randomization/enrolment.
5. Palliative radiotherapy is allowed and must be completed 2 weeks prior to randomization/enrolment.
6. Subjects must have measurable or evaluable non-measurable disease as assessed by the investigator, according to RECIST v1.1 (Appendix D).
7. ECOG performance status score of 0 or 1 (Appendix B).
8. Life expectancy > 12 weeks
9. Screening laboratory values must meet the following criteria (using NCI CTCAE v.4.03 ):
a. WBC ≥ 2000/uL
b. Neutrophils ≥ 1500/µL
c. Platelets ≥ 100x103/µL
d. Hemoglobin ≥ 9.0 g/dL
e. Serum creatinine ≤ 1.5 x ULN
f. AST ≤ 3.0 x ULN (or ≤ 5.0X ULN if liver metastates are present)
g. ALT ≤ 3.0 x ULN (or ≤ 5.0X ULN if liver metastates are present)
h. Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome who must have a total bilirubin level of < 3.0 x ULN)
10. Males and Females* ≥ 18 years of age
* There are no data that indicate special gender distribution. Therefore patients will be enrolled in the study gender-independently.
11. Subjects must have signed and dated an IRB/IEC approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol-related procedures that are not part of normal subject care.
12. Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests and other requirements of the study.
13. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study drug. Women must not be breastfeeding.
14. WOCBP must agree to follow instructions for method(s) of contraception for a period of 30 days (duration of ovulatory cycle) plus the time required for the investigational drug to undergo 5 half-lives. The terminal half-lives of nivolumab and ipilimumab are approximately 25 days and 15 days, respectively. WOCBP should use an adequate method to avoid pregnancy for approximately 5 months (30 days plus the time required for nivolumab to undergo 5 half-lives) after the last dose of investigational drug.
15. Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for a period of 90 days (duration of sperm turnover) plus the time required for the investigational drug to undergo 5 half-lives. The terminal half-lives of nivolumab and ipilimumab are approximately 25 days and 15 days, respectively. Males who are sexually active with WOCBP must continue contraception for approximately 7 months (90 days plus the time required for nivolumab to undergo 5 half-lives) after the last dose of investigational drug. In addition, male subjects must be willing to refrain from sperm donation during this time.
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| E.4 | Principal exclusion criteria |
1. Malignancies other than disease under study within 5 years prior to inclusion, with the exception of those with a negligible risk of metastasis or death (e.g., expected 5-year OS > 90%) treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated surgically with curative intent, ductal carcinoma in situ treated surgically with curative intent)
2. Subjects with untreated symptomatic CNS metastases. Subjects are eligible if CNS metastases are asymptomatic (this includes patients with unknown CNS metastatic status who have no clinical signs of CNS metastases) or those with asymptomatic or symptomatic CNS who are adequately treated and are neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment) for at least 2 weeks prior to randomization/enrolment. In addition, subjects must be either off corticosteroids, or on a stable or decreasing dose of < 10 mg daily prednisone (or equivalent) for at least 2 weeks prior to randomization/enrolment. Patients with unknown CNS metastatic status and any clinical signs indicative of CNS metastases are eligible if CNS metastases are excluded using CT and/or MRI scans, or CNS metastases are confirmed but adequately treated as described above.
3. Subjects with active, known, or suspected autoimmune disease. Subjects with Type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement, or skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment are permitted to enroll. For any cases of uncertainty, it is recommended that the medical monitor be consulted prior to signing informed consent.
4. Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids, and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
5. Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.
6. All toxicities attributed to prior anti-cancer therapy other than hearing loss, alopecia and fatigue must have resolved to Grade 1 (NCI CTCAE version 4.03) or baseline before administration of study drug.
7. > Grade 1 peripheral neuropathy according to CTCAE version 4.0
8. Known Dihydropyrimidine dehydrogenase (DPD) deficiency
9. Any serious or uncontrolled medical disorder or active infection that, in the opinion of the investigator, may increase the risk associated with study participation, study drug administration, or would impair the ability of the subject to receive study drug.
10. Ascites which cannot be controlled with appropriate interventions.
11. Unstable cardiac disease despite treatment, myocardial infarction within 6 months prior to study entry; congestive heart failure NYHA grade 3 and 4
12. Significant acute or chronic infections including, among others:
a. Positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
b. Any positive test result for hepatitis B virus or hepatitis C virus indicating acute or chronic infection.
13. History of allergy or hypersensitivity to study drugs or any constituent of the products
14. Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities § 40 Abs. 1 S. 3 Nr. 4 AMG.
15. Patients who are unable to consent because they do not understand the nature, significance and implications of the clinical trial and therefore cannot form a rational intention in the light of the facts [§ 40 Abs. 1 S.3 Nr. 3a AMG].
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| E.5 End points |
| E.5.1 | Primary end point(s) |
For Arm A and B: Progression Free Survival acc. to RECIST v1.1 based on the ITT population for patients treated with mFOLFOX plus Nivolumab plus Ipilimumab (Arm A) vs. patients treated with mFOLFOX alone (Arm B).
For Arm A2 and C: Progression Free Survival rate (PFS@6). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| tumor assessment every 8 weeks (±7 days) until EOT, afterwards every 3 months; date of first observed disease progression (acc. to RECIST v1.1 ) or death from any cause |
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| E.5.2 | Secondary end point(s) |
- Progression Free Survival acc. to RECIST v1.1 for Arms A1, A2 and C
- Progression Free Survival rate at 6 months (PFS@6) for Arms A and B
- Response Rate (ORR) according to RECIST v1.1
- Duration of response and disease stabilization
- Overall survival (OS)
- Subgroup analysis including PFS and OS by PD-L1 expression status
- Safety (according to NCI-CTCAE V 4.03) and tolerability
- Quality of life. The QoL analyses will include QoL mean values, QoL response and time to symptom deterioration (TTSD)
- Translational research: correlation of biomarkers potentially associated with clinical efficacy (OS, PFS and ORR) from nivolumab plus/minus ipilimumab
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
-Response Rate (ORR): every 8 weeks (±7 days)
-Duration of response and disease stabilization: continuously
- Overall survival (OS): continuously
- Safety and tolerability: continuously
- Quality of life: every 8 weeks (±7 days) until EOT, afterwards every 3 months
-Translational research: continuously
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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 | No |
| 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) | 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | 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
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| Database closure is defined as the end of the trial: Sites need to collect survival data of patients and are involved in the data cleaning process actively (e.g. additional source data may be requested and additonal monitoring visits may be neccessary). Therefore, database closure is considered the end of 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 | 5 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
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