Pre-Operative Or Peri-Operative Dox Regimen In Patients With Locally Advanced Resectable Gastric Cancer

Phase 2

Completed

• Conditions: Gastric Cancer; Locally Advanced Malignant Neoplasm
• Interventions: Other: DOX 4 cycles - Surgery; Other: DOX 2 cycles - Surgery - DOX 2 cycles

• Registration Number: NCT01876927
• Lead Sponsor: Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori

Brief Summary

Study design:

Multicenter, randomized, open label phase II study Arm A: DOX 4 cycles - Surgery - Follow-up Arm B: DOX 2 cycles - Surgery - DOX 2 cycles - Follow-up

Population:

Male or female, 18-75 years of age, with a diagnosis of histologically confirmed, potentially resectable adenocarcinoma of the stomach.

Sample Size: Planned sample size is 90 patients, 45 patients for each arm (p0=50%, p1=80%, alpha=0.05 (two sides), beta=0.2)

Treatment Plan:

Treatment will be administered for 4 and 2 cycles before surgery in arm A and B, respectively, and in arm B for a further 2 cycles after surgery unless progression or unacceptable toxicity occurs, or a patient refuses treatment. In such cases patients will go off treatment. 3-6 weeks after the end of the fourth (arm A) or second (arm B) preoperative cycle, patients will undergo surgery.

After surgery 3-6 weeks from surgery patients in arm B will receive 2 more cycles.

DOX: Docetaxel 35 mg/m2 day 1 and 8 Oxaliplatin 80 mg/m2 day 1 Capecitabine 750 mg/m2 x 2 daily for 2 weeks

Cycles repeated every 3 weeks

Evaluation criteria: Tumor assessment will be performed according to the RECIST criteria (version 1.1).

Duration of Study:

Overall study duration: 07/2010- 03/2017 Planned study duration per patient: 5 years

Detailed Description

Title: A randomised phase II study of pre-operative or peri-operative docetaxel, oxaliplatin, capecitabine (DOX) regimen in patients with locally advanced resectable gastric cancer.

Clinical Phase: II

Study Objectives:

Primary:

The percentage of patients receiving all the planned chemotherapeutic cycles.

Secondary:

* Downstaging according to Recist criteria

* pT1-3 vs pT0.

* Safety: number of patients with grade 3-4 toxicity

* The role of PET Scan as predictor of response

* Curative vs palliative surgery

* TTP

* OS

* Diagnostic correlation between the various staging methods

* Possible correlations between CT scan, CT/PET, laparoscopy;

* Molecular markers related to toxicity: DPYD, MTHFR, TS, XPD, ERCC1, XRCC1;

* Molecular markers related to prognosis: TYMS, GSTP1, COX-2, RUNX3, methylation profile (Cox2, hMLH1, MGMT);

* Molecular markers related to therapy response: TYMS, DPYD, MTHFR, OPRT, ERCC1, XRCC1/2/3, GSTP1, GSTM1, GSTT1, ABCB1, methylation profile (Cox2, hMLH1, MGMT), whole genome arrayCGH.

Study design:

Multicenter, randomized, open label phase II study Arm A: DOX 4 cycles - Surgery - Follow-up Arm B: DOX 2 cycles - Surgery - DOX 2 cycles - Follow-up

Population:

Male or female, 18-75 years of age, with a diagnosis of histologically confirmed, potentially resectable adenocarcinoma of the stomach.

Sample Size: Planned sample size is 90 patients, 45 patients for each arm (p0=50%, p1=80%, alpha=0.05 (two sides), beta=0.2)

Treatment Plan:

Treatment will be administered for 4 and 2 cycles before surgery in arm A and B, respectively, and in arm B for a further 2 cycles after surgery unless progression or unacceptable toxicity occurs, or a patient refuses treatment. In such cases patients will go off treatment. 3-6 weeks after the end of the fourth (arm A) or second (arm B) preoperative cycle, patients will undergo surgery.

After surgery 3-6 weeks from surgery patients in arm B will receive 2 more cycles.

DOX: Docetaxel 35 mg/m2 day 1 and 8 Oxaliplatin 80 mg/m2 day 1 Capecitabine 750 mg/m2 x 2 daily for 2 weeks

Cycles repeated every 3 weeks

Evaluation criteria: Tumor assessment will be performed according to the RECIST criteria (version 1.1).

Duration of Study:

Overall study duration: 07/2010- 03/2017 Planned study duration per patient: 5 years

Study Timeline

• Study Start: 2010-09
• Study First Submitted: 2013-06-07
• Study First Submitted QC: 2013-06-11
• Study First Posted: 2013-06-13
• Primary Completion: 2017-03
• Study Completion: 2022-09-15
• Status Verified: 2025-01
• Last Update Submitted: 2025-01-08
• Last Update Posted: 2025-01-09

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 106

Inclusion Criteria

1. Signed written informed consents

2. Male or female 18-75 years of age

3. Diagnosis of histologically confirmed, potentially resectable adenocarcinoma of the stomach

4. cT3 subserosal - cT4a - cT4b (7th edition UICC TNM) or bulky lymph node metastases independently of T

5. ECOG performance status of 0-1 at study entry

6. Laboratory requirements (≤ 7 days prior chemotherapy start):

   1. Hematology:

      I) Neutrophils > 1.5 x 109 /L II) Platelets > 100 x 109 /L III) Hemoglobin > 10g/dL

   2. Hepatic function I) Total bilirubin < 1.25 UNL II) AST (SGOT) and ALT (SGPT) < 2.5xUNL III) Alkaline phosphatase < 2.5xUNL

   3. Renal function I) Creatinine <1.5 UNL In the event of border-line values, the calculated creatinine clearance should be > 60 mL/min;

      • Written informed consent signed and dated before randomization procedures, including expected cooperation of patients for treatment and follow-up, must be obtained and documented according to local regulatory requirements.
      • Effective contraception for both male and female patients if the risk of conception exists

Exclusion Criteria

1. Early gastric cancer (if N0)
2. T2 (according to 7th edition of UICC TNM) if N0
3. Linitis plastica
4. Positive peritoneal cytology
5. Distant metastases
6. Neoplasm involving the gastro-esophageal junction
7. Pertoneal involvement
8. Concurrent chronic systemic immune therapy
9. Any investigational agent(s) administered 4 weeks prior to entry
10. Clinically relevant coronary artery disease, a history of myocardial infarction or of hypertension not controlled by therapy within the last 12 months
11. Known grade 3 or 4 allergic reaction to any of the components of the treatment
12. Known drug abuse/alcohol abuse
13. Legal incapacity or limited legal capacity
14. Medical or psychological condition which, in the opinion of the investigator, would not permit the patient to complete the study or sign meaningful informed consent
15. Women who are pregnant or breastfeeding
16. Acute or subacute intestinal occlusion
17. Any concurrent malignancy other than non-melanoma skin cancer, or carcinoma in situ of the cervix. (Patients with a previous malignancy but without evidence of disease for ≥ 5 years will be allowed to enter the trial)

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm A	DOX 4 cycles - Surgery	DOX 4 cycles - Surgery - Follow-up DOX: Docetaxel 35 mg/m2 day 1 and 8 by one hour infusion; Oxaliplatin 80 mg/m2 day 1 by two hours infusion; Capecitabine 750 mg/m2 x 2 daily for 2 weeks, per OS. Treatment should be administered for 4 cycles before surgery. Each cycle will be repeated every 3 weeks.
Arm B	DOX 2 cycles - Surgery - DOX 2 cycles	DOX 2 cycles - Surgery - DOX 2 cycles - Follow-up DOX: Docetaxel 35 mg/m2 day 1 and 8 by one hour infusion; Oxaliplatin 80 mg/m2 day 1 by two hours infusion; Capecitabine 750 mg/m2 x 2 daily for 2 weeks, per OS. Treatment should be administered for 2 cycles before surgery and for further 2 cycles after surgery, unless progression of disease or unacceptable toxicity occurs, or patient refusal. In these cases patients will go off treatment. Each cycle will be repeated every 3 weeks.

Primary Outcome Measures

Name	Time	Method
the difference in percentage of patients receiving all the planned chemotherapeutic cycles between the two arms.	7 years

Secondary Outcome Measures

Name	Time	Method
The percentage of tumors downstaged at the diagnosis	7 years	To determine the percentage of tumors downstaged at the diagnosis, compared with the pathological stage detected at the time of surgery (according to Recist criteria)
Treatment tolerability and safety and tumor response in patients with pathological stage pT1-3 vs pT0	7 years	Comparation of treatment tolerability and safety and tumor response between patients with pathological stage pT1-3 vs pT0 (detected at the time of surgery)
Efficacy comparation between curative vs palliative surgery	7 years
Diagnostic capability of PET	7 years	Evaluation of the role of PET as a tool to detect tumor response
Diagnostic capability of CT scan, CT/PET and laparoscopy	7 years	Evaluation of possible correlations between the diagnostic techniques CT scan, CT/PET and laparoscopy
Biological profile of treatment toxicity	7 years	Biological detection of molecular markers related to treatment toxicity (DPYD, MTHFR, TS, XPD, ERCC1, XRCC1)
Biologcal profile of treatment response	7 years	Biological detection of molecular markers related to therapy response (TYMS, DPYD, MTHFR, OPRT, ERCC1, XRCC1/2/3, GSTP1, GSTM1, GSTT1, ABCB1, methylation profile (Cox2, hMLH1, MGMT), whole genome arrayCGH)
Number of patients with adverse events of grade 3-4 as a measure of safety and tolerability	7 years
Time to progression	7 years
Overall survival	7 years
Biological profile of treatment prognosis	7 years	Biological detection of molecular markers related to treatment prognosis (TYMS, GSTP1, COX-2, RUNX3, methylation profile (Cox2, hMLH1, MGMT))

Trial Locations

Locations (20)

Azienda Ospedaliero - Universitaria Ospedali Riuniti Umberto I - GM Lancisi; 🇮🇹 Ancona, AN, Italy

USL 8 Arezzo - Presidio Ospedaliero Zona Casentino - Ospedale di Bibbiena; 🇮🇹 Bibbiena, AR, Italy

USL 8 Arezzo - Ospedale "Santa Maria alla Gruccia"; 🇮🇹 Montevarchi, AR, Italy

UO Oncologia , Spedali Civili di Brescia; 🇮🇹 Brescia, BS, Italy

Ospedale Bufalini; 🇮🇹 Cesena, FC, Italy

UO oncologia medica IRCCS IRST; 🇮🇹 Meldola (FC), FC, Italy

UOC Oncologia , Azienda USL 11; 🇮🇹 Empoli, FI, Italy

Ospedale Careggi; 🇮🇹 Firenze, FI, Italy

UO ONCOLOGIA , Istituto Europeo di Oncologia; 🇮🇹 Milano, MI, Italy

Istituto Clinico Humanitas; 🇮🇹 Rozzano, MI, Italy

Azienda Ospedaliera Universitaria Pisana; 🇮🇹 Pisa, PI, Italy

UO Oncologia, Fondazione Policlinico San Matteo; 🇮🇹 Pavia, PV, Italy

UO Oncologia Medica, PO Rimini, AUSL della Romagna; 🇮🇹 Rimini, RI, Italy

UO Oncologia , Casa di Cura Tortorella; 🇮🇹 Salerno, SA, Italy

Policlinico Le Scotte; 🇮🇹 Siena, SI, Italy

UO Oncologia, Azienda Ospedaliero Treviglio; 🇮🇹 Treviglio, TV, Italy

UO Oncologia Medica, azienda Ospedaliera di Varese; 🇮🇹 Varese, VA, Italy

Azienda Ospedaliera di Perugia - Ospedale S. Maria della Misericordia; 🇮🇹 Perugia, Italy

Ospedale San Filippo Neri; 🇮🇹 Roma, Italy

Ospedale Borgo Trento; 🇮🇹 Verona, Italy