| Eligibility |
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:
1. 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)
2. 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 CISH1
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 metastasis 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:
1. Leukocytes = 3000/mm³, platelets = 100,000/mm³, neutrophil count (ANC) =1000/µL,
hemoglobin =9 g/dL (5.58 mmol/L),
2. 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.
3. Serum creatinine = 1.5 x upper limit of normal
4. 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).
5. 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
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, 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).
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