| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| locally advanced resectable adenocarcinoma of the esophagogastric junction or the stomach |
|
| E.1.1.1 | Medical condition in easily understood language |
| locally advanced resectable 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) |
|
| 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 pathological complete response in patients treated with ramucirumab plus FLOT versus patients treated with FLOT alone (Phase II)
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|
| E.2.2 | Secondary objectives of the trial |
To determine R0 resection rates, progression-free survival (PFS), overall survival (OS), safety and tolerability of ramucirumab , perioperative morbidity and mortality (Phase II)
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Histologically confirmed, resectable adenocarcinoma of the gastroesophageal junction (AEG/GEJ-type II-III) or the stomach (uT2, uT3, uT4, any N category, M0), or any T N+ M0 patient, with the following specifications:
a. Medical and technical operability, according to the techniques described in Chapter 12 Surgical Therapy that are subtotal, total or transhiatal extended gastrectomy (patients planned to receive transthoracic esophagectomy are not eligible for the study)
b. Participating sites in PETRARCA study: Negative HER-2 detection (score IHC HER-2 0 or IHC HER-2 1+ ); IHC HER-2 2+ and negative by FISH, SISH or CISH
2. No preceding cytotoxic or targeted therapy
3. No prior partial or complete tumor resection
4. Female and male patients ≥ 18 and ≤ 70 years. Patients in reproductive age must be willing to use adequate contraception during the study and for 7 months after the end of ramucirumab treatment (Appropriate contraception is defined as surgical sterilization (e.g., bilateral tubal ligation, vasectomy), hormonal contraception (implantable, patch, oral), and double-barrier methods (any double combination of: IUD, male or female condom with spermicidal gel, diaphragm, sponge, cervical cap)). Female patients with childbearing potential need to have a negative pregnancy test within 7 days before study start
5. ECOG ≤ 1
6. Exclusion of distant metastases by CT or MRI of abdomen, pelvis, and thorax, bone scan or MRI (if bone metastases are suspected due to clinical signs). Exclusion of the infiltration of any adjacent organs or structures by CT or MRI
7. Laparoscopic exclusion of peritoneal carcinomatosis in case of ascites, peritoneal masses, or if otherwise suspected clinically.
8. Adequate hematological, hepatic and renal function parameters:
a. Leukocytes ≥ 3000/mm³, platelets ≥ 100,000/mm³, neutrophil count (ANC) ≥1000/µL, hemoglobin ≥9 g/dL (5.58 mmol/L),
b. Adequate coagulation function as defined by International Normalized Ratio (INR) ≤ 1.5, and a partial thromboplastin time (PTT) ≤ 5 seconds above the ULN (unless receiving anticoagulation therapy). Patients receiving warfarin/ phenprocoumon must be switched to low molecular weight heparin and have achieved stable coagulation profile prior to randomization.
c. Serum creatinine ≤ 1.5 x upper limit of normal
d. Urinary protein ≤1+ on dipstick or routine urinalysis (UA; if urine dipstick 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).
e. Bilirubin ≤ 1.5 x upper limit of normal, AST and ALT ≤ 3.0 x upper limit of normal, alkaline phosphatase ≤ 6 x upper limit of normal
9. Patient able and willing to provide written informed consent and to comply with the study protocol and with the planned surgical procedures |
|
| E.4 | Principal exclusion criteria |
1. Known hypersensitivity against ramucirumab, 5-FU, leucovorin, oxaliplatin, or docetaxel
2. Other known contraindications against ramucirumab, 5-FU, leucovorin, oxaliplatin, or docetaxel
3. Patients with esophageal cancer and those with adenocarcinoma of GEJ type I and all patients who are planned to have transthoracic esophagectomy.
4. Clinically significant active coronary heart disease, clinically active cardiomyopathy or congestive heart failure, peripheral artery occlusive disease (PAOD, German pAVK), or any history of aortic aneurysm
5. Any arterial thromboembolic events, including but not limited to myocardial infarction, transient ischemic attack, cerebrovascular accident, or unstable angina.
6. Uncontrolled or poorly-controlled hypertension (>160 mmHg systolic or > 100 mmHg diastolic for >4 weeks) despite standard medical management.
7. Clinically significant valvular defect
8. Past or current history of other malignancies not curatively treated and without evidence of disease for more than 5 years, except for curatively treated basal cell carcinoma of the skin and in situ carcinoma of the cervix
9. Criteria of unresectability, e.g.:
• Radiologically documented evidence of major blood vessel invasion or encasement by cancer.
• Patients with involved retroperitoneal (e.g. para-aortal, paracaval or interaortocaval lymph nodes) or mesenterial lymph nodes (distant metastases!)
10. Known brain metastases
11. Other severe internal disease or acute infection
12. Peripheral polyneuropathy ≥ NCI Grade II
13. Chronic inflammatory bowel disease
14. Grade 3-4 GI bleeding within 3 months prior to enrollment.
15. History of gastric perforation or fistulae in past 6 months
16. Serious or nonhealing wound, ulcer, or bone fracture within 28 days prior to enrollment.
17. The patient has undergone major surgery within 28 days prior to enrollment except staging laparoscopy.
18. Receiving chronic antiplatelet therapy, including aspirin (Once-daily aspirin use (maximum dose 325 mg/day) is permitted), nonsteroidal anti-inflammatory drugs (including ibuprofen, naproxen, and others), dipyridamole or clopidogrel, or similar agents.
19. History of deep vein thrombosis, pulmonary embolism, or any other significant thromboembolism (venous port or catheter thrombosis or superficial venous thrombosis are not considered “significant”) during the 3 months prior to randomization.
20. Cirrhosis at a level of Child-Pugh B (or worse) or cirrhosis (any degree) and a history of hepatic encephalopathy or ascites.
21. On-treatment participation in another clinical study in the period 30 days prior to inclusion and during the study
22. Subject pregnant or breast feeding, or planning to become pregnant within 7 months after the end of treatment.
23. Patients in a closed institution according to an authority or court decision (AMG § 40, Abs. 1 No. 4)
24. Any other concurrent antineoplastic treatment including irradiation
25. Current chronic alcohol, nicotine or drug abuse or history of chronic alcohol abuse during last 12 months. Nicotine abuse is defined as ≥ 25 pack-years (Willigendael et al., 2004). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Rate of pathological complete or subtotal responses (pCR/pSR) (Phase II)
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Phase II
- R0 resection rate
- PFS
- OS
- pCR/pSR, OS and PFS (medians and rates) according to subgroup (intestinal vs. diffuse/mixed or unknown and GEJ vs. gastric)
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- R0 resection rate: after surgery
- Median DFS/OS: continuously
- Subgroup analyses: after study completion
|
|
| 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) | Yes |
| 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 | 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 | 50 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 63 |
| 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
|
| 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. |
|
| 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 | |
| E.8.9.1 | In the Member State concerned days | |
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