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

Study Overview
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Brief Summary
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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.

Detailed Description
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Pancreatic cancer is the seventh cause of death in cancer patients and more than 94% of affected patients die of cancer disease. In the majority of cases, the diagnosis is done at an advanced stage and only 10-20% of patients can be treated with a surgical resection. For this neoplasia, a radical resection may be an effective treatment. Nevertheless, results obtained with surgery alone are rather inadequate, showing a median survival of 12-14 months and 2-year survival of almost 20%: it seems evident the necessity to use complementary treatments in order to improve survival rate in this group of patients. Pancreatic cancer can relapse locally, at the level of tumoral bed, of the regional lymph nodes, on the immediately adjacent peritoneal surface or on contiguous organs. Also, distant metastases are quite frequent, mainly to the liver, at the entire peritoneal surface and, rarely, to the extra-abdominal organs. The rapid appearance of these metastases after surgical resection strongly suggests the presence of subclinical metastatic diffusion at an early phase of the disease. Currently, combination chemotherapy based on the mFOLFIRINOX regimen is considered the therapeutic standard in the adjuvant setting, in young and fit patients. Unfortunately, mFOLFIRINOX is burdened with strong haematological and extra-haematologic toxicity and just 2/3 of patients are able to complete the treatment. Recently, PAXG regimen [(Cisplatin (P), Abraxane (A), Capecitabine (X), Gemcitabine (G)] when compared to AG in randomized studies, showed an improvement in terms of progression-free survival (PFS) and overall survival in borderline resectable, locally advanced and metastatic patients. To date, several ongoing randomized trials are investigating the efficacy of perioperative or neoadjuvant strategies in early stage PDAC. Only few studies are available regarding neoadjuvant treatment: some are outdated, numerically inconsistent, retrospective, or not randomized. In this scenario, it aims to better investigate pre-operative therapeutic strategy. For this purpose, two randomizations are planned. FIRST RANDOMIZATION. Eligible patients will be randomized (1:1), stratifying by basal CA19.9 level (<5 ULN vs ≥ 5ULN) and centre to receive: PAXG or mFOLFIRINOX for 4 months SECOND RANDOMIZATION. Patients without progression or limiting toxicity after 4 months of the assigned chemotherapy in the study, will be randomized (1:1), stratifying by treatment assigned by the first randomization, to receive 2 further months of the same chemotherapy either BEFORE or AFTER surgery.

Official Title
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A Randomized Phase II Trial of Short-course Versus Long-course Pre-operative Chemotherapy With mFOLFIRINOX or PAXG Regimen for Stage I-III Pancreatic Ductal Adenocarcinoma (PDAC)

Conditions
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Pancreas Ductal Adenocarcinoma

Intervention / Treatment
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* Drug: PAXG
* Drug: mFOLFIRINOX
* Drug: short-course chemotherapy
* Drug: long-course chemotherapy


Participation Criteria
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Eligibility Criteria
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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% [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 and Serum total bilirubin ≤ 1.5 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 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 and of other neoplasms without evidence of disease at least from 5 years; 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; Pre-existing neuropathy, Gilbert's disease or genotype UGT1A1 * 28 / * 28. mutation in DPYD Inflammatory disease of the colon or rectum, or occlusion or sub-occlusion of the intestine. Concurrent treatment with other experimental drugs; Fructose intolerance.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Interventional Model Description: 2 by 2
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: PAXG Arm A<br>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<br>* 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<br>|
| Active Comparator: mFOLFIRINOX Arm B<br>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<br>* Oxaliplatin, folinic acid, irinotecan and 5-Fluoruracil will be administered on day 1 and 15 every 28 days<br>|
| Active Comparator: short-course chemotherapy<br>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<br>* other two months of chemotherapy after surgery<br>|
| Active Comparator: long-course chemotherapy<br>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<br>* other two months of chemotherapy before surgery<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The efficacy of PAXG versus mFOLFIRINOX in terms of EFS | 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 | 
| The efficacy of short-course versus long-course therapy in terms of EFS | 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | the time between the date of the patient's enrollment and the death of the patient for any cause or the last time the patient was seen alive | 36 months | 
| RECIST 1.1 radiological response | Radiological response evaluation during the treatment by using RECIST 1.1 criteria | 4-6 months | 
| Ca19.9 response rate | Biochemical response evaluation during the treatment by using this specific marker | 4-6 months | 
| Surgery outcome | The evaluation of resectability rate. | 4-6 months after chemotherapy | 
| Surgery outcome | The evaluation of surgical mortality and morbidity rate. | 4-6 months after chemotherapy | 
| Surgery outcome | The evaluation of intra- and post-operative metastasis rate. | 4-6 months after chemotherapy | 
| Surgery outcome | The evaluation of N0 and R0 resections rate. | 4-6 months after chemotherapy | 
| Incidence of Treatment Adverse Events | The evaluation of drugs safety and tolerability by SAE report | 4-6 months | 
| Quality of life | Impact of treatment on quality of life assessed by the latest version of the European Organization for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ-C30) | 4-6 months | 
| Quality of life | Impact of treatment on quality of life assessed by the European Organization for Research and Treatment of Cancer Quality of Life scale for pancreatic cancer (EORTC QLQ - PAN26) | 4-6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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neoadjuvant chemotherapy, PAXG, mFOLFIRINOX, resectable, borderline resectable