Clinical trial NCT04375605: Neoadjuvant RCT Versus CT for Patients With Locally Advanced, Potentially Resectable Adenocarcinoma of the GEJ
Official title: RACE-trial: Neoadjuvant Radiochemotherapy Versus Chemotherapy for Patients With Locally Advanced, Potentially Resectable Adenocarcinoma of the Gastroesophageal Junction (GEJ) A Randomized Phase III Joint Study of the AIO, ARO and DGAV
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Gastroesophageal Junction Adenocarcinoma
Lead sponsor: Universitätsmedizin Mannheim
Sponsor class: OTHER
Collaborators: name: Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest
name: Deutsche Krebshilfe e.V., Bonn (Germany)
First posted: 2020-05-05
Enrollment: 342
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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)

Detailed description: 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.

Eligibility criteria: 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 randomization
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, folinc acid, oxaliplatin or docetaxel
9. Other known contraindications against 5-FU, folinic acid, 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

Primary outcomes:
measure: Comparison of PFS between arms
timeFrame: up to 5 years
Secondary outcomes:
measure: Overall survival (OS)
timeFrame: up to 5 years
measure: R0 resection rate
timeFrame: after surgery, approx. 12 weeks after randomization
measure: Number of harvested lymph nodes
timeFrame: after surgery, approx. 12 weeks after randomization
measure: Site of tumor relapse
timeFrame: 5 years
measure: Overall survival rate at 1, 3 and 5 years
timeFrame: 1 year, 3 years, 5 years
measure: Patient reported outcomes: quality of life according to questionnaire EORTC-QLQ-C30
timeFrame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to approximately 68 months
measure: Patient reported outcomes: quality of life according to questionnaire EORTC module OG25
timeFrame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to approximately 68 months
Other outcomes:
Locations:
city: Mannheim
country: Germany
facility: Unversity Hospital Mannheim
Study officials:
affiliation: Universitätsmedizin Mannheim
name: Ralf-Dieter Hofheinz, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Lorenzen S, Biederstadt A, Ronellenfitsch U, Reissfelder C, Monig S, Wenz F, Pauligk C, Walker M, Al-Batran SE, Haller B, Hofheinz RD. RACE-trial: neoadjuvant radiochemotherapy versus chemotherapy for patients with locally advanced, potentially resectable adenocarcinoma of the gastroesophageal junction - a randomized phase III joint study of the AIO, ARO and DGAV. BMC Cancer. 2020 Sep 15;20(1):886. doi: 10.1186/s12885-020-07388-x.