Short-course Versus Long-course Pre-operative Chemotherapy With mFOLFIRINOX or PAXG (CASSANDRA TRIAL)

NCT04793932 | Active Not Recruiting Phase 3

• 1 other identifier: PACT21
• Study Type: interventional
• Target: 261
• Locations: 1 country
• Sites: 22

Brief Summary

The main aim of this study is to compare the efficacy of short-course versus long-course pre-operative chemotherapy with PAXG or mFOLFIRINOX in patients who receive a diagnosis of pancreatic ductal adenocarcinoma (PDAC) resectable or borderline resectable.

Conditions

Pancreas Ductal Adenocarcinoma

Keywords

neoadjuvant chemotherapy; PAXG; mFOLFIRINOX; resectable; borderline resectable

Outcome Measures

Primary Outcomes (2)

• Event-free survival

  to compare in terms of event free survival (EFS) the efficacy of PAXG to that of mFOLFIRINOX. EFS is defined as the time from randomization to: RECIST 1.1 progression \[At least a 20 percent increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20 percent, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression\]; CA19.9 failure (defined as 2 consecutive increases of serum level ≥20 percent, separated by at least 4 weeks); recurrence; preoperative or intraoperative unresectability; intraoperative evidence of metastases; death for any cause; whichever occurs first. R1 resections will NOT be considered as events whereas R2 resections will be.

  12 weeks

• Event-free survival

  to compare in terms of event free survival (EFS) the efficacy of 4 months pre-operative and 2 months postoperative chemotherapy to that of 6 months of pre-operative chemotherapy . EFS is defined as the time from randomization to: RECIST 1.1 progression \[At least a 20 percent increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20 percent, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression\]; CA19.9 failure (defined as 2 consecutive increases of serum level ≥20 percent, separated by at least 4 weeks); recurrence; preoperative or intraoperative unresectability; intraoperative evidence of metastases; death for any cause; whichever occurs first. R1 resections will NOT be considered as events whereas R2 resections will be.

  12 weeks

Secondary Outcomes (10)

• Overall survival

  36 months

• RECIST 1.1 radiological response

  4-6 months

• Ca19.9 response rate

  4-6 months

• Surgery outcome

  4-6 months after chemotherapy

• Surgery outcome

  4-6 months after chemotherapy

Study Arms (4)

PAXG Arm A

ACTIVE COMPARATOR

cisplatin 30 mg/m2 every 2 weeks, nab-paclitaxel 150 mg/m2 every 2 weeks, gemcitabine 800 mg/m2 every 2 weeks, capecitabine 1250 mg/m2/day (for 28 consecutive days) in 28-day cycles administered for 4 cycles (4 months).

Drug: PAXG

mFOLFIRINOX Arm B

ACTIVE COMPARATOR

irinotecan 150 mg/m2 day 1, oxaliplatin 85 mg/m2 day 1, folinic acid at a fixed dose of 400 mg/m2, fluorouracil continuous IV infusion 2.4 g/m2 over 46 hours in 14-day cycles administered for 8 cycles (4 months).

Drug: mFOLFIRINOX

short-course chemotherapy

ACTIVE COMPARATOR

Allocated by second randomization after 4 months of chemotherapy to receive immediate surgery followed by 2 further months of the same chemotherapy

Drug: short-course chemotherapy

long-course chemotherapy

ACTIVE COMPARATOR

Allocated by second randomization after 4 months of chemotherapy to receive 2 further months of the same chemotherapy followed by surgery

Drug: long-course chemotherapy

Interventions

PAXG DRUG

Nab-paclitaxel, cisplatin and gemcitabine drugs will be administered on day 1 and 15 every 28 days. Capecitabine tablets will be taken orally on days 1 to 28, every 28 days

PAXG Arm A

mFOLFIRINOX DRUG

Oxaliplatin, folinic acid, irinotecan and 5-Fluoruracil will be administered on day 1 and 15 every 28 days

mFOLFIRINOX Arm B

short-course chemotherapy DRUG

other two months of chemotherapy after surgery

short-course chemotherapy

long-course chemotherapy DRUG

other two months of chemotherapy before surgery

long-course chemotherapy

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Cyto/histological diagnosis of pancreatic ductal adenocarcinoma\*;
• Clinical stage I-III disease according to TNM 8th Ed. 2017 \[appendix 1\];
• Resectable or borderline resectable disease, as anatomically defined according to NCCN Guidelines Version 1.2020 - Pancreatic Adenocarcinoma \[appendix 2\] and biologically defined according to the International consensus on definition and criteria of borderline resectable pancreatic ductal adenocarcinoma 2017 (CA 19.9 \> 500 IU/ml) (Isaji et al., 2018);
• Karnofsky Performance Status \> 60% \[appendix 3\];
• Age \> 18 and ≤ 75 years;
• Adequate bone marrow function (GB ≥ 3500/mm3, neutrophils ≥1500/mm3, platelets ≥ 100000/mm3, Hb ≥10 g/dl);
• Adequate kidney function (serum creatinine \< 1.5 mg/dL);
• Adequate liver function:
• ALT and AST \< 3 ULN
• Serum total bilirubin ≤ 1.5 ULN or in subjects with biliary stenting ≤ 2 ULN;
• No prior treatment (chemotherapy, radiotherapy and/or surgery) for pancreatic cancer;
• Women must not be on pregnancy or lactation;
• Patient of child-bearing potential must agree to use two medically acceptable methods of contraception (one for the patient and one for the partner) during the study and for a minimum of the following 6 months; this applies to patients of both sexes. \[appendix 4\];
• Patient information and signed written informed consent.

You may not qualify if:

• Other types of non-ductal tumor of the pancreas, including endocrine tumors or acinar cell adenocarcinoma, cystadenocarcinoma and other periampullary malignancies.
• Prior (within 1 year) or concurrent malignancies at other sites with the exception of surgically cured carcinoma in-situ of the cervix and basal or squamous cell carcinoma of the skin
• Symptomatic duodenal stenosis;
• Active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy, defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment
• Known infection with hepatitis B or C, or history of human immunodeficiency virus (HIV) infection, or subject receiving immunosuppressive or myelosuppressive medications that would in the opinion of the investigator, increase the risk of serious neutropenic complications
• Clinical stage IV (including ascites or malignant pleural effusion) disease according to TNM 8th Ed. 2017 \[appendix 1\];
• Locally advanced disease according to NCCN Guidelines Version 1.2020 - Pancreatic Adenocarcinoma \[appendix 2\];
• Serious medical risk factors involving any of the major organ systems, or serious psychiatric disorders, which could compromise the subject's safety or the study data integrity. These include, but are not limited to:
• History of connective tissue disorders (eg, lupus, scleroderma, arteritis nodosa)
• History of interstitial lung disease, slowly progressive dyspnea and unproductive cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, pulmonary hypersensitivity pneumonitis or multiple allergies
• History of the following within 6 months prior to Cycle 1 Day 1: a myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, New York Heart Association (NYHA) Class III-IV heart failure, uncontrolled hypertension, clinically significant cardiac dysrhythmia or ECG abnormality, cerebrovascular accident, transient ischemic attack, or seizure disorder
• Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study
• Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study
• Any condition that confounds the ability to interpret data from the study
• Any familiar, sociologic or geographic conditions that can potentially interfere with the adhesion to the protocol or to the follow-up;

Sponsors & Collaborators

• Associazione Italiana per lo Studio del Pancreas: lead
• High Research srl: collaborator
• Gruppo Italiano per lo studio dei Carcinomi dell'Apparato Digerente: collaborator

Study Sites (22)

Oncologia Medica e Prevenzione Oncologica Centro di riferimento oncologico (CRO), IRCCS

Aviano, 33081, Italy

Location

Oncologia Medica Az. Ospedaliera Istituto Tumori "Giovanni Paolo II"

Bari, 70124, Italy

Location

Oncologia ASST pg23

Bergamo, 24127, Italy

Location

Oncologia Medica Azienda Universitaria Ospedaliera Policlinico Sant'Orsola-Malpighi

Bologna, 40138, Italy

Location

Oncologia Medica dell'Az.Ospedaliera Fondazione Poliambulanza Istituto Ospedaliero

Brescia, 25124, Italy

Location

Oncologia Medica AOU Careggi

Florence, 50134, Italy

Location

Oncologia Ospedale Generale Provinciale

Macerata, 62100, Italy

Location

Oncologia Medica dell'Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori

Meldola, 47014, Italy

Location

Oncologia dell'Istituto Clinico Humanitas

Milan, 20089, Italy

Location

IRCCS San Raffaele

Milan, 20132, Italy

Location

Oncologia Medica Falck Niguarda

Milan, 20162, Italy

Location

Oncologia Medica Az Ospedaliera AOU Cagliari Policlinico Universitario Dullio Casula

Monserrato, 09042, Italy

Location

Oncologia Medica AOU FEDERICO II

Naples, 80131, Italy

Location

Oncologia Medica 1 Ospedaliera Istituto Oncologico Veneto IRCCS

Padua, 35128, Italy

Location

Oncologia Medica Arnas Civico

Palermo, 90121, Italy

Location

Oncologia Medica 2 Az. Ospedaliera Universitaria Pisana

Pisa, 56126, Italy

Location

Oncologia Medica Az. Ospedaliera Fondazione Policlinico Universitario A. Gemelli IRCCS

Rome, 00168, Italy

Location

Chirurgia Generale e Oncologica dell'AZ. Ospedaliera Ordine Mauriziano

Torino, 10028, Italy

Location

Divisione Chirurgica Az. Ospedaliera AULSS2

Treviso, 31100, Italy

Location

SOC di Oncologia Az. Ospedaliera Sanitaria Universitaria Friuli Centrale-P.O. "S. Maria della Misericordia"

Udine, 33100, Italy

Location

Chirurgia generale e del Pancreas Azienda Ospedaliera Universitaria Integrata

Verona, 37136, Italy

Location

Oncologia ULSS8 Berica

Vicenza, 36100, Italy

Location

Related Publications (7)

• Reni M, Cereda S, Mazza E, Passoni P, Nicoletti R, Balzano G, Zerbi A, Arcidiacono PG, Staudacher C, Di Carlo V. PEFG (cisplatin, epirubicin, 5-fluorouracil, gemcitabine) regimen as second-line therapy in patients with progressive or recurrent pancreatic cancer after gemcitabine-containing chemotherapy. Am J Clin Oncol. 2008 Apr;31(2):145-50. doi: 10.1097/COC.0b013e31814688f7.

  PMID: 18391598 BACKGROUND

• Reni M, Balzano G, Aprile G, Cereda S, Passoni P, Zerbi A, Tronconi MC, Milandri C, Saletti P, Rognone A, Fugazza C, Magli A, Di Muzio N, Di Carlo V, Villa E. Adjuvant PEFG (cisplatin, epirubicin, 5-fluorouracil, gemcitabine) or gemcitabine followed by chemoradiation in pancreatic cancer: a randomized phase II trial. Ann Surg Oncol. 2012 Jul;19(7):2256-63. doi: 10.1245/s10434-011-2205-2. Epub 2012 Jan 12.

  PMID: 22237835 BACKGROUND

• Reni M, Balzano G, Zanon S, Passoni P, Nicoletti R, Arcidiacono PG, Pepe G, Doglioni C, Fugazza C, Ceraulo D, Falconi M, Gianni L. Phase 1B trial of Nab-paclitaxel plus gemcitabine, capecitabine, and cisplatin (PAXG regimen) in patients with unresectable or borderline resectable pancreatic adenocarcinoma. Br J Cancer. 2016 Jul 26;115(3):290-6. doi: 10.1038/bjc.2016.209. Epub 2016 Jul 12.

  PMID: 27404453 BACKGROUND

• 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.

  PMID: 29625841 BACKGROUND

• Reni M, Zanon S, Balzano G, Passoni P, Pircher C, Chiaravalli M, Fugazza C, Ceraulo D, Nicoletti R, Arcidiacono PG, Macchini M, Peretti U, Castoldi R, Doglioni C, Falconi M, Partelli S, Gianni L. A randomised phase 2 trial of nab-paclitaxel plus gemcitabine with or without capecitabine and cisplatin in locally advanced or borderline resectable pancreatic adenocarcinoma. Eur J Cancer. 2018 Oct;102:95-102. doi: 10.1016/j.ejca.2018.07.007. Epub 2018 Aug 24.

  PMID: 30149366 BACKGROUND

• Reni M, Zanon S, Peretti U, Chiaravalli M, Barone D, Pircher C, Balzano G, Macchini M, Romi S, Gritti E, Mazza E, Nicoletti R, Doglioni C, Falconi M, Gianni L. Nab-paclitaxel plus gemcitabine with or without capecitabine and cisplatin in metastatic pancreatic adenocarcinoma (PACT-19): a randomised phase 2 trial. Lancet Gastroenterol Hepatol. 2018 Oct;3(10):691-697. doi: 10.1016/S2468-1253(18)30196-1. Epub 2018 Jul 7.

  PMID: 30220407 BACKGROUND

• Reni M, Macchini M, Orsi G, Procaccio L, Malleo G, Carconi C, Rapposelli IG, Bencardino K, Scartozzi M, Balzano G, Tamburrino D, Merelli B, Sperti E, Belfiori G, Liscia N, Bozzarelli S, Di Marco M, Tamburini E, Milella M, Lonardi S, Ercolani G, Mazzola M, Palumbo D, Torri V, Falconi M. Preoperative mFOLFIRINOX versus PAXG for stage I-III resectable and borderline resectable pancreatic ductal adenocarcinoma (PACT-21 CASSANDRA): results of the first randomisation analysis of a randomised, open-label, 2 x 2 factorial phase 3 trial. Lancet. 2026 Dec 20;406(10522):2945-2956. doi: 10.1016/S0140-6736(25)01685-X. Epub 2025 Nov 20.

  PMID: 41275879 DERIVED

Study Officials

• Michele Reni, MD

  IRCCS San Raffaele

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 2 by 2

Study Record Dates

• First Submitted: February 28, 2021
• First Posted: March 11, 2021
• Study Start: November 3, 2020
• Primary Completion: March 15, 2025
• Study Completion: January 31, 2026
• Last Updated: April 9, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will not share

Locations

IT (22)