Gemcitabine, Cisplatin, Epirubicin, and Capecitabine in Treating Patients With Stage I-II Resectable Pancreatic Cancer (PACT-15)

Randomized Phase II-III Trial of Peri- or Post-Operative Chemotherapy in Resectable Pancreatic Adenocarcinoma

RATIONALE: Drugs used in chemotherapy, such as gemcitabine hydrochloride, cisplatin, epirubicin hydrochloride, and capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving gemcitabine hydrochloride, with or without cisplatin, epirubicin hydrochloride, and capecitabine before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving these drugs after surgery may kill any tumor cells that remain after surgery.

PURPOSE: This randomized phase II/III trial is studying how well gemcitabine hydrochloride, with or without cisplatin, epirubicin hydrochloride, and capecitabine, works when given before and/or after surgery in treating patients with stage I or stage II pancreatic cancer that can be removed by surgery.

Study Overview

• Status: Completed
• Conditions: Pancreatic Cancer
• Intervention / Treatment: Drug: capecitabine; Drug: cisplatin; Drug: epirubicin; Drug: gemcitabine

Detailed Description

OBJECTIVES:

Primary

• To assess the proportion of patients who are event-free (defined as disease progression, local recurrence, distant metastasis, new tumor, or death) at 1 year after neoadjuvant therapy comprising gemcitabine hydrochloride with cisplatin, epirubicin hydrochloride, and capecitabine (PEXG), and adjuvant chemotherapy comprising gemcitabine hydrochloride or PEXG regimen in patients with resectable stage I or II adenocarcinoma of the pancreas. (phase II)
• To assess whether the best experimental regimen, which will be selected on the basis of the phase II part of the trial, is able to improve overall survival when compared to standard adjuvant gemcitabine in these patients. (phase III)

Secondary

• To assess radiological, biochemical, and pathological response rate (neoadjuvant arm only) in these patients.
• To assess surgical resection rate, surgical mortality and morbidity, and proportion of patients with negative surgical margins.
• To assess lymph node status in these patients.
• To determine tolerability of these regimens in these patients.

OUTLINE: This is a multicenter study. Patients are stratified according to center. Patients are randomized to 1 of 3 treatment arms.

• Arm I (adjuvant gemcitabine hydrochloride) : Patients receive gemcitabine hydrochloride IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days for 6 months in the absence of disease progression or unacceptable toxicity.
• Arm II (adjuvant cisplatin, epirubicin hydrochloride, gemcitabine hydrochloride, and capecitabine [PEXG regimen]): Patients receive cisplatin IV over 1 hour on days 1-5, epirubicin hydrochloride IV on days 1 and 8, gemcitabine hydrochloride IV over 1 hour on days 1 and 8, and oral capecitabine on days 1-14. Treatment repeats every 14 days for 6 months in the absence of disease progression or unacceptable toxicity.
• Arm III (neoadjuvant and adjuvant PEXG regimen): Patients receive neoadjuvant cisplatin IV over 1 hour on days 1-5, epirubicin hydrochloride IV on days 1 and 8, gemcitabine hydrochloride IV over 1 hour on days 1 and 8, and oral capecitabine on days 1-14. Treatment repeats every 14 days for up to 3 months. Patients then undergo surgery for pancreatic cancer followed by adjuvant (within 2 months of surgery) PEXG given as in neoadjuvant therapy. Treatment with adjuvant PEXG repeats every 14 days for 3 months in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year, every 4 months for 2 years, and then every 6 months thereafter.

• Study Type: Interventional
• Enrollment (Actual): 98
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • Milan, Italy, 20132
    • Istituto Scientifico H. San Raffaele

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Histologically or cytologically* confirmed adenocarcinoma of pancreas

  • Stage I-II disease
  • Resectable disease
• No superior mesenteric vein or artery, portal vein, celiac trunk, or hepatic artery infiltration
• No symptomatic duodenal stenosis
• NOTE: Patients without histological or cytological results may be allowed provided ≥ 1 attempt has been made by needle aspiration with negative imaging and clinical signs suggestive of adenocarcinoma.

PATIENT CHARACTERISTICS:

• Karnofsky performance status 70-100%
• WBC ≥ 3,500/mm³
• ANC ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Hemoglobin ≥ 10 g/dL
• Creatinine ≤ 1.5 mg/dL
• ALT and AST ≤ 3 times upper limit of normal
• Bilirubin ≤ 3 mg/dL
• No prior or concurrent malignancy within the past 5 years except for surgically cured carcinoma in situ of the cervix or basal cell or squamous cell carcinoma of the skin
• Not pregnant or nursing
• No psychological, familial, sociological, or geographical condition that would potentially hinder study compliance or follow-up schedule

PRIOR CONCURRENT THERAPY:

• No prior chemotherapy or radiotherapy for pancreatic adenocarcinoma
• No other concurrent experimental drugs

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: adjuvant PEXG; cisplatin and epirubicin at 30 mg/mq, gemcitabine at 800 mg/mq and capecitabine at 1250 mg/mq/day per os for 14 days every 14 days for 6 months	Drug: capecitabine; 1250 mg/mq/day per os for 14 days every 14 days for 6 months; Other Names: XELODA; Drug: cisplatin; 30 mg/mq every 14 days for 6 months; Other Names: cisplatino TEVA; Drug: epirubicin; 30 mg/mq every 14 days for 6 months; Other Names: farmorubicina; Drug: gemcitabine; ARM A: 1000 mg/mq for 3 weekly infusions every 4 weeks for 6 months ARM B and C: 800 mg/mq every 14 days for 6 months; Other Names: GEMZAR
EXPERIMENTAL: perioperative PEXG; cisplatin and epirubicin at 30 mg/mq, gemcitabine at 800 mg/mq and capecitabine at 1250 mg/mq/day per os for 14 days every 14 days for 3 months before surgery and 3 months after surgery	Drug: capecitabine; 1250 mg/mq/day per os for 14 days every 14 days for 6 months; Other Names: XELODA; Drug: cisplatin; 30 mg/mq every 14 days for 6 months; Other Names: cisplatino TEVA; Drug: epirubicin; 30 mg/mq every 14 days for 6 months; Other Names: farmorubicina; Drug: gemcitabine; ARM A: 1000 mg/mq for 3 weekly infusions every 4 weeks for 6 months ARM B and C: 800 mg/mq every 14 days for 6 months; Other Names: GEMZAR
ACTIVE_COMPARATOR: Adjuvant Gemcitabine; Adjuvant Gemcitabine at 1000 mg/mq for 3 weeks every 4 weeks for 6 months	Drug: gemcitabine; ARM A: 1000 mg/mq for 3 weekly infusions every 4 weeks for 6 months ARM B and C: 800 mg/mq every 14 days for 6 months; Other Names: GEMZAR

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event-free survival at 1 year (phase II)	CT scan	every 3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Radiological, biochemical, and pathological response rate (neoadjuvant arm only)	CT scan, CA19.9 serology; pathology report	after 3 months of induction therapy
Surgical resection rate	surgeon report	immediately after surgery
Surgical mortality and morbidity	surgeon report	immediately after surgery
Tolerability	outpatient visit; laboratory report	every 2 weeks during therapy
Proportion of patients with negative surgical margins	pathology report	immediately after surgery
Lymph node status	pathology report	immediately after surgery

Collaborators and Investigators

• Sponsor: IRCCS San Raffaele

Publications and helpful links

General Publications

• Reni M, Balzano G, Zanon S, Zerbi A, Rimassa L, Castoldi R, Pinelli D, Mosconi S, Doglioni C, Chiaravalli M, Pircher C, Arcidiacono PG, Torri V, Maggiora P, Ceraulo D, Falconi M, Gianni L. Safety and efficacy of preoperative or postoperative chemotherapy for resectable pancreatic adenocarcinoma (PACT-15): a randomised, open-label, phase 2-3 trial. Lancet Gastroenterol Hepatol. 2018 Jun;3(6):413-423. doi: 10.1016/S2468-1253(18)30081-5. Epub 2018 Apr 4.

Study record dates

Study Major Dates

• Study Start: May 1, 2010
• Primary Completion (ACTUAL): April 1, 2017
• Study Completion (ACTUAL): August 1, 2017

Study Registration Dates

• First Submitted: June 24, 2010
• First Submitted That Met QC Criteria: June 24, 2010
• First Posted (ESTIMATE): June 25, 2010

Study Record Updates

• Last Update Posted (ACTUAL): September 1, 2017
• Last Update Submitted That Met QC Criteria: August 31, 2017
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Keywords: adenocarcinoma of the pancreas; stage I pancreatic cancer; stage II pancreatic cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Endocrine System Diseases; Digestive System Neoplasms; Endocrine Gland Neoplasms; Pancreatic Diseases; Pancreatic Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Gemcitabine; Cisplatin; Capecitabine; Epirubicin
• Other Study ID Numbers: CDR0000675485; PACT-15 (OTHER: IRCCS San Raffaele); 2010-019942-23 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO