Phase III Randomized Trial of Short vs. Long-Course Preoperative Chemotherapy with mFOLFIRINOX or PAXG in Stage I-III Pancreatic Ductal Adenocarcinoma
- Trial ID
- 2024-519031-42-00
- Protocol
- PACT-21/CASSANDRA
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this randomized phase III trial is to compare the efficacy of the **PAXG** regimen to that of **mFOLFIRINOX** in terms of event-free survival (EFS) in patients with stage I-III **pancreatic ductal adenocarcinoma**. This comparison is clinically relevant as it aims to determine the most effective chemotherapy regimen for improving patient outcomes in this aggressive cancer type.
Secondary objectives include:
- Comparing the efficacy in terms of EFS of 4 months of pre-operative and 2 months of postoperative chemotherapy to that of 6 months of pre-operative chemotherapy.
Participants
The clinical trial involves participants diagnosed with **pancreatic ductal adenocarcinoma**. The study population includes both male and female subjects, aged between 18 and 75 years, who are not considered part of a vulnerable population. Participants are required to have a Karnofsky Performance Status greater than 60% and must demonstrate adequate bone marrow, kidney, and liver function. The trial excludes individuals who have previously undergone treatment for pancreatic cancer. The sponsor has not provided information regarding the total number of participants. Lifestyle factors such as diet, physical activity, or habits are not specified as part of the trial's considerations. Participants must not be pregnant or lactating, and those of child-bearing potential are required to use two medically acceptable methods of contraception during the study and for at least six months thereafter. The selection criteria ensure that participants have resectable or borderline resectable disease, as defined by established guidelines, and have not received prior chemotherapy, radiotherapy, or surgery for pancreatic cancer.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy of two chemotherapy regimens, mFOLFIRINOX and PAXG, in patients with stage I-III **pancreatic ductal adenocarcinoma**. The primary objective is to compare event-free survival (EFS) between the two treatment groups. Secondary endpoints include overall survival (OS), response rates according to RECIST 1.1, CA19.9 response rate, complete pathologic response, resectability rate, surgical mortality and morbidity rate, intra- and post-operative metastasis rate, N0 and R0 resections rate, patient-reported outcomes, and treatment toxicity. The trial is expected to conclude by December 31, 2025, with recruitment having commenced on November 3, 2020.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a cyto/histological diagnosis of pancreatic ductal adenocarcinoma, age between 18 and 75 years, and adequate organ function. Following randomization, participants will receive either the mFOLFIRINOX or PAXG regimen. The treatment period is set for a maximum of six months, with regular follow-up visits to monitor treatment response and adverse events. The end-of-study visit will assess the final outcomes and collect data on the primary and secondary endpoints.
The expected length of participant involvement is approximately six months, with conditions for early termination including significant disease progression, unacceptable toxicity, or withdrawal of consent. Participants must adhere to the study protocol, including the use of two medically acceptable methods of contraception for those of child-bearing potential. The trial is conducted in accordance with ethical standards, and informed consent is obtained from all participants prior to enrollment.
Treatment
The clinical trial involves the administration of several **chemotherapy agents**. The first experimental medication is **Abraxane**, which contains the active substance **paclitaxel albumin-bound**. It is provided as a 5 mg/ml powder for dispersion for infusion. The pharmaceutical form is a dispersion for infusion, and it is administered via the **intravenous route**. The maximum daily dose is 150 mg/m², with a total maximum dose of 1800 mg/m² over a treatment period of up to 6 months.
**Leucovorin**, containing **calcium folinate pentahydrate**, is another treatment used in the study. It is available as a 10 mg/ml solution for injection or infusion. This medication is also administered intravenously. The maximum daily dose is 400 mg/m², with a total maximum dose of 4800 mg/m² over a 6-month period.
**Gemcitabine Accord** is administered as a 100 mg/ml solution for infusion, containing the active substance **gemcitabine**. This medication is delivered intravenously, with a maximum daily dose of 800 mg/m² and a total maximum dose of 9600 mg/m² over the course of 6 months.
**CAPECITABINE VIATRIS** is provided in two dosages: 500 mg and 150 mg film-coated tablets, containing the active substance **capecitabine**. This medication is administered orally, with a maximum daily dose of 1250 mg/m² and a total maximum dose of 210,000 mg/m² over a 6-month period.
**IRINOTECAN VIATRIS** is a concentrate for solution for infusion, containing **irinotecan hydrochloride trihydrate**. It is administered intravenously, with a maximum daily dose of 150 mg/m² and a total maximum dose of 1800 mg/m² over 6 months.
**Oxaliplatino Aurovit** is a 5 mg/ml concentrate for solution for infusion, containing **oxaliplatin**. This medication is administered intravenously, with a maximum daily dose of 85 mg/m² and a total maximum dose of 1020 mg/m² over a 6-month period.
**Cisplatino Sandoz** is a 0.5 mg/ml concentrate for solution for infusion, containing **cisplatin**. It is administered intravenously, with a maximum daily dose of 30 mg/m² and a total maximum dose of 360 mg/m² over 6 months.
**Fluorouracil/Anabiosis** is a 50 mg/ml solution for injection or infusion, containing **fluorouracil**. This medication is administered intravenously, with a maximum daily dose of 240 mg/m² and a total maximum dose of 2880 mg/m² over a 6-month period.
All medications are administered according to the specified dosing schedules, and participant compliance is monitored throughout the trial. The trial aims to compare the efficacy of the PAXG regimen to that of mFOLFIRINOX in terms of event-free survival in patients with stage I-III pancreatic ductal adenocarcinoma.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the measurement of **Event-Free Survival (EFS)**, which is defined as the time from randomization to progression according to RECIST 1.1 criteria. This involves at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. Secondary endpoints include Overall Survival (OS), RECIST 1.1 response rate, CA19.9 response rate, complete pathologic response, resectability rate, surgical mortality and morbidity rate, intra- and post-operative metastasis rate, N0 and R0 resections rate, patient-reported outcomes, and treatment toxicity.
The trial is designed to compare the efficacy of the PAXG regimen to that of mFOLFIRINOX in patients with stage I-III pancreatic ductal adenocarcinoma. The efficacy parameters will be collected and analyzed at various timepoints throughout the study, with the estimated end date set for December 31, 2025. The trial will utilize validated scales and laboratory tests to ensure accurate and reliable measurement of the endpoints. The study will adhere to rigorous clinical trial protocols to maintain the integrity and validity of the efficacy assessments.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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%
- 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
Exclusion Criteria
- 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: a. History of connective tissue disorders (eg, lupus, scleroderma, arteritis nodosa) b. History of interstitial lung disease, slowly progressive dyspnea and unproductive cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, pulmonary hypersensitivity pneumonitis or multiple allergies c. 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;
- Pre-existing neuropathy
- c.1679GG, c.1905+1AA, c.2846TT mutations in homozygous in DPYD gene. Dose modification according to DPYD and UGT1A1 mutations are reported in Table 1 (https://www.aiom.it/wp-content/uploads/2019/10/2019_Racc-analisi-farmacogenetiche.pdf.)
- Inflammatory disease of the colon or rectum, or occlusion or sub-occlusion of the intestine
- Concurrent treatment with other experimental drugs
- Fructose intolerance.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Not Yet Recruiting | 03 Nov 2020 | 261 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Abraxane 5 mg/ml powder for dispersion for infusion. | Test | POWDER FOR DISPERSION FOR INFUSION | INTRAVENOUS USE | 150 | 6 | PRD9254301 |
CAPECITABINE VIATRIS 150 mg, comprimé pelliculé | Test | COMPRIMÉ PELLICULÉ | ORAL USE | 1250 | 6 | PRD10074003 |
CAPECITABINE VIATRIS 500 mg, comprimé pelliculé | Test | COMPRIMÉ PELLICULÉ | ORAL USE | 1250 | 6 | PRD10074004 |
IRINOTECAN VIATRIS 20 mg/ml, solution à diluer pour perfusion | Comparator | SOLUTION À DILUER POUR PERFUSION | INTRAVENOUS USE | 150 | 6 | PRD10036294 |
Fluorouracil/Anabiosis 50 mg/ml διάλυμα για ένεση ή έγχυση | Comparator | ΔΙΆΛΥΜΑ ΓΙΑ ΈΝΕΣΗ Ή ΈΓΧΥΣΗ | INTRAVENOUS USE | 240 | 6 | PRD10152491 |
Oxaliplatino Aurovit 5 mg/ml concentrado para solución para perfusión EFG | Comparator | CONCENTRADO PARA SOLUCIÓN PARA PERFUSIÓN | INTRAVENOUS USE | 85 | 6 | PRD10183849 |
Leucovorin 10 mg/ml Lösung zur Injektion/ Infusion | Comparator | LÖSUNG ZUR INJEKTION/ INFUSION | INTRAVENOUS USE | 400 | 6 | PRD4259228 |
Gemcitabine Accord 100 mg/ml koncentratas infuziniam tirpalui | Test | KONCENTRATAS INFUZINIAM TIRPALUI | INTRAVENOUS USE | 800 | 6 | PRD10050563 |
Cisplatino Sandoz 0,5 mg/ml – Concentrato per soluzione per infusione | Test | CONCENTRATO PER SOLUZIONE PER INFUSIONE | INTRAVENOUS USE | 30 | 6 | PRD10787621 |