| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| metastatic gastro-oesophageal cancer |
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| E.1.1.1 | Medical condition in easily understood language |
Cancer of the stomach or lower gullet
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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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10066354 |
| E.1.2 | Term | Adenocarcinoma of the gastroesophageal junction |
| E.1.2 | System Organ Class | 100000004864 |
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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 |
| The primary clinical objective is to determine the efficacy of a standard second-line regimen (paclitaxel + ramucirumab) with avelumab in patients with metastatic gastro-oesophageal cancer in terms of overall survival rate (OSR) at 6 months (according to RECIST v1.1). |
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| E.2.2 | Secondary objectives of the trial |
The main secondary objective is to determine safety and tolerability, according to NCI CTC AE v5.0 and to the obtained data on vital signs, clinical parameters and feasibility of the regimen. Further secondary objectives are to determine the efficacy of the therapy in terms of objective response rate (acc. to RECIST v1.1) including the duration of response, overall survival (OS), OSR at 12 month, progression free survival (PFS) and progression free survival rate (PFSR) at 6 months and at 12 months.
For efficacy parameters (PFS and ORR) an exploratory analysis according to modified RECIST will be performed.
The primary translational objective is the determination of an efficacy predictive immune signature (diversification pattern and TiL clone expansion in peripheral blood) and the subgroup analyses of all primary and secondary endpoints in view of PD-L1 status.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed written informed consent
2. Male or female ≥ 18 years of age
3. Histologically proven gastric adenocarcinoma including adenocarcinoma of the esophagogastric junction
4. Metastatic or locally advanced disease, not amenable to potentially curative resection
5. Documented objective radiological or clinical disease progression during or within 6 months of the last dose of first-line platinum and fluoropyrimidine doublet with or without anthracycline, docetaxel or trastuzumab. Neoadjuvant/adjuvant treatment is not counted unless progression occurs <6 months after completion of the treatment. In these cases neoadjuvant/adjuvant treatment is counted as first line.
6. Measurable or non-measurable but evaluable disease determined using guidelines RECIST 1.1
7. ECOG performance status 0-1
8. Life expectancy > 12 weeks
9. Adequate hematological, hepatic and renal functions:
a) Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
b) Platelet count ≥ 100 x 109/L
c) Hemoglobin ≥ 9 g/dl (may have been transfused)
d) Total bilirubin ≤ 1.5 times the upper limit of normal (ULN) and AST and ALT ≤ 2.5 x ULN in absence of liver metastases, or ≤ 5 x ULN in presence of liver metastases; AP ≤ 5 x ULN
e) Estimated creatinine clearance ≥ 30 mL/min according to the Cockcroft-Gault formula (or local institutional standard method)
f) Urinary protein ≤ 1+ on dipstick or routine urinalysis (UA; if urinedipstick or routine analysis is ≥ 2+, a 24-hour urine collection for protein must demonstrate < 1000 mg of protein in 24 hours to allow participation in this protocol)
g) Adequate coagulation function as defined by International Normalized Ratio (INR) ≤ 1,5 ULN, and a partial thromboplastin time (PTT) ≤ 5 seconds above the ULN (unless receiving anticoagulation therapy). Patients receiving warfarin/phenprocomon must be switched to low molecular weight heparin and have achieved stable coagulation profile prior to first dose of protocol therapy.
10. Women of child-bearing potential must have a negative urine or serum pregnancy test
11. Highly effective contraception for both male and female subjects throughout the study and for at least 30 days after last avelumab and at least 3 months after last ramucirumab treatment administration if the risk of conception exists
12. Ability to comply with scheduled assessments and with management of toxicities.
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| E.4 | Principal exclusion criteria |
1.Other tumor type than adenocarcinoma (e.g. leiomyosarcoma, lymphoma) or a second cancer except in patients with squamous or basal cell carcinoma of the skin or carcinoma in situ of the cervix that has been effectively treated. Patients curatively treated for any other malignancy and disease-free for at least 5 years will be discussed with the sponsor before inclusion
2.Concurrent chronic systemic immune therapy, chemotherapy, or hormone therapy not indicated in the protocol
3.Previous therapy with, paclitaxel or ramucirumab or pretreatment with a PD-1, PD-L1 inhibitor
4.Current treatment with any anti-cancer therapy ≤ 2 weeks prior to study treatment start unless rapidly progressing disease is measured
5.Previous exposure to a VEGF or VEGFR inhibitor or any antiangiogenic agent, or prior enrolment in the study
6.Major surgical procedure, open biopsy or significant traumatic injury within 4 weeks prior to start of study treatment;
7.Grade 3-4 GI bleeding within 3 months prior to enrollment
8.History of deep vein thrombosis, pulmonary embolism or any other significant thromboembolism during the 3 months prior to first dose of protocol therapy
9.Cirrhosis at a level of Child-Pugh B (or worse) or cirrhosis (any degree) and a history of hepatic encephalopathy or clinically meaningful ascites resulting from cirrhosis.
10.Known brain or leptomeningeal metastases
11.Known prior severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies
12.Other serious illness or medical conditions prior to study drug administration
a)Clinically significant cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication
b)Uncontrolled or poorly controlled hypertension despite optimal medical therapy
c)Current history of chronic diarrhea
d)Active disseminated intravascular coagulation
e)History of gastrointestinal perforation, fistulae or any clinically relevant arterial thromboembolic event within 6 months
f)Active infection
g)Hepatitis B virus or hepatitis C virus infection at screening (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive)
h)Active autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent
i)Serious or non-healing wound, ulcer, or bone fracture within 28 days prior to first dose
j)Prior organ transplantation incl. allogenic stem-cell transplantation
k)Other severe acute or chronic medical conditions incl. immune colitis, inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study
13.Current use of immunosuppressive medication, EXCEPT for the following:
a)intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection);
b)steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication
c)short term steroids to prevent chemotherapy induced nausea
14.The patient is receiving chronic antiplatelet therapy, including aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs, including ibuprofen, naproxen, and others), dipyridamole or clopidogrel, or similar agents. Once-daily aspirin use (max. dose 325 mg/day) is permitted
15.Vaccination within 4 weeks of the first dose of avelumab and while on trial is prohibited except for administration of inactivated vaccines
16.Subjects with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity
17.Concurrent treatment with other experimental drugs or participation in another clinical trial with any investigational drug within 30 days but at least 5 half-lives of the investigational drug prior to treatment start
18.Known drug abuse/ alcohol abuse
19.Persisting toxicity related to prior therapy
20.Subject pregnant or breast feeding,
21.Subject (male or female) is not willing to use highly effective methods of contraception (per institutional standard) during treatment and for 30 days after the end of treatment with avelumab and 3 months after the end of treatment with ramucirumab
22.Patients known to have a HER2 positive cancer who have not been treated already with a HER2 targeting agent
23.Patients with a psychiatric illness or patients imprisoned or working in the Institution of the treating physician.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Overall Survival Rate at 6 months |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The study population will be analyzed for the primary endpoint when the last patient included has passed the 6 months assessnment. When the last patient has passed the 3 months safety assessment the final safety analyses will be conducted. Further follow up for survival will be performed. The completion of the overall survival follow up will be the end of the trial.
To allow the option of earlier stopping for futility in case of unfavorable results, a standard two-stage phase II design is applied. In the first stage, n = 33 patients with the endpoint (OS at 6 months) available are analyzed, and the trial is stopped if the number of „successes“ is only 16 or lower. Otherwise, the study is continued until a total of 53 patients evaluable for the primary endpoint have been recruited.
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| E.5.2 | Secondary end point(s) |
• Overall Survival
• OSR at 12 month
• Progression Free Survival
• Progression Free Survival Rate at 6 and 12 month according to RECIST v1.1
• Safety and tolerability (acc. to NCI CTC AE v5.0 and to the obtained data on vital signs, clinical parameters and feasibility of the regimen)
• Best response according to RECIST v1.1
• Confirmed response rate according to RECIST v1.1
• Duration of response
• Translational research (correlation of efficacy parameters with immunoprofiling (TCRβ & IgH); tumor-infiltrating lymphocytes (TiL) repertoire determination, quantitative ctDNA and clonal dynamics)
• Subgroup analyses of all primary and secondary endpoints in view of PD-L1 status
• Efficacy parameters (PFS and ORR) according to modified RECIST
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
All secondary endpoints (except of the second) will be analyzed at the end of trial (after 40 months).
The secondary endpoint "OSR at 12 month" will be analyzed when the last patient included has passed the 12 months assessment. |
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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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| Translational research (correlation of efficacy parameters with immunoprofiling (TCRβ & IgH); tumor-infiltrating lymphocytes (TiL) repertoire determination, quantitative ctDNA and clonal dynamics) |
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| 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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| 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 | 19 |
| 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
|
The completion of the overall survival follow up (LVLS) will be 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 | 3 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | |
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