Neoadjuvant RCT Versus CT for Patients With Locally Advanced, Potentially Resectable Adenocarcinoma of the GEJ
Neoadjuvant RCT Versus CT for Patients With Locally Advanced, Potentially Resectable Adenocarcinoma of the GEJ
This is a multicenter, prospective, randomized, stratified, controlled, open-label study
 comparing neoadjuvant radiochemotherapy with FLOT versus FLOT chemotherapy alone für patients
 with locally advanced, potentially resectable adenocarcinoma of the gastroesophageal junction
 (GEJ)
The RACE trial seeks to demonstrate superiority of preoperative FLOT induction chemotherapy
 followed by preoperative radiochemotherapy and postoperative FLOT chemotherapy over
 perioperative FLOT chemotherapy without radiotherapy in patients with adenocarcinoma of the
 gastroesophageal junction undergoing adequate oncological surgery.

 Eligible patients will be randomly allocated to one of two treatment groups, i.e.
 preoperative chemotherapy (Arm A) or preoperative chemotherapy with subsequent preoperative
 radiochemotherapy (arm B), both followed by resection and postoperative completion of
 chemotherapy. Randomization will occur in a 1:1 ratio with stratification by primary tumor
 site (Siewert I vs. Siewert II/III).

 Arm A:

 Patients randomized to Arm A (control arm) will be treated with four preoperative cycles of
 FLOT. Cycles will be repeated every two weeks. The preoperative chemotherapy duration in Arm
 A is eight weeks. Surgical resection will follow 4-6 weeks after day 1 of the last cycle of
 neoadjuvant therapy. Postoperative chemotherapy will start 6-12 weeks after surgery and
 consists of another four cycles of FLOT every two weeks. The total treatment period is 25-32
 weeks.

 Arm B:

 Patients randomized in Arm B (experimental arm) will be treated with two cycles of FLOT every
 two weeks. Radiochemotherapy will start three weeks after day 1 of the second cycle and
 consists of oxaliplatin and infusional 5-fluorouracil plus concurrent radiotherapy given to a
 dose of 45 Gy (25 daily fractions with 1.8 Gy) over five weeks. The preoperative treatment
 duration is 10 weeks. Surgical resection will follow 4-6 weeks after last treatment with
 chemotherapy / radiation. Postoperative chemotherapy will start 6-12 weeks after surgery and
 consists of four cycles of FLOT every two weeks. The total treatment period is 26-33 weeks.
Inclusion Criteria:

 1. Histologically proven, locally advanced and potentially resectable adenocarcinoma of
 the gastroesophageal junction (GEJ) (Siewert I- III) that is: cT3-4, any N, M0 or cT2
 N+, M0 according to AJCC 8th edition

 2. Patients* must be candidates for potential curative resection as determined by the
 treating surgeon

 3. ECOG performance status 0-1

 4. Age 18 years or above

 5. Adequate hematologic function with absolute neutrophil count (ANC) ≥ 1.5 x 10^9/l,
 platelets ≥ 100 x 10^9/l and hemoglobin ≥ 9.0 mg/dl

 6. INR <1.5 and aPTT<1.5 x upper limit of normal (ULN) within 7 days prior to starting
 study treatment

 7. Adequate liver function as measured by serum transaminases (ASAT, ALAT) ≤ 2.5 x ULN
 and total bilirubin ≤ 1.5 x ULN

 8. Adequate renal function with serum creatinine ≤ 1.5 x ULN

 9. QTc interval (Bazett*) ≤ 440 ms

 10. Written informed consent obtained before randomization

 11. Negative pregnancy test for women of childbearing potential within 7 days of
 commencing study treatment. Males and females of reproductive potential must agree to
 practice highly effective*** contraceptive measures during the study and for 6 months
 after the end of study treatment. Male patients must also agree to refrain from father
 a child during treatment and up to 6 months afterwards and additionally to use a
 condom during treatment period. Their female partner of childbearing potential must
 also agree to use an adequate contraceptive measure.

 -  *There are no data that indicate special gender distribution. Therefore, patients
 will be enrolled in the study gender-independently.

 -  ** formula for QTc interval calculation (Bazett): QTc= ((QT) ̅" (ms)" )/√(RR
 (sec))= ((QT) ̅" (ms)" )/√(60/(Frequence (1/min)))

 -  *** highly effective (i.e. failure rate of <1% per year when used consistently
 and correctly) methods: intravaginal and transdermal combined (estrogen and
 progestogen containing) hormonal contraception; injectable and implantable
 progestogen-only hormonal contraception; intrauterine device (IUD); intrauterine
 hormone-releasing system (IUS); bilateral tubal occlusion; vasectomised partner;
 sexual abstinence (complete abstinence is defined as refraining from heterosexual
 intercourse during the entire period of risk associated with the study
 treatments).

 Exclusion Criteria:

 1. Evidence of metastatic disease (exclusion of distant metastasis by CT of thorax and
 abdomen, bone scan or MRI [if osseous lesions are suspected due to clinical signs])

 2. Past or current history (within the last 5 years prior to treatment start) of other
 malignancies. Patients with curatively treated basal and squamous cell carcinoma of
 the skin or in situ carcinoma of the cervix are eligible

 3. Evidence of peripheral sensory neuropathy > grade 1 according to CTCAE version 4.03

 4. Patients with other significant underlying medical conditions that may be aggravated
 by the study treatment or are not controlled

 5. Pregnant or lactating females

 6. Patients medically unfit for chemotherapy and radiotherapy

 7. Patients receiving any immunotherapy, cytotoxic chemotherapy or radiotherapy other
 than defined by the protocol. The participation in another clinical trial with the use
 of investigational agents, chemotherapy or radiotherapy during the trial is not
 permitted

 8. Known hypersensitivity against 5-FU, leucovorin, oxaliplatin or docetaxel

 9. Other known contraindications against 5-FU, leucovorin, oxaliplatin, or docetaxel

 10. Clinically significant active coronary heart disease, cardiomyopathy or congestive
 heart failure, NYHA III-IV

 11. Clinically significant valvular defect

 12. Other severe internal disease or acute infection

 13. Peripheral polyneuropathy > NCI Grade II according to CTCAE version 4.03

 14. Chronic inflammatory bowel disease