A Phase I-II Study of PAXG in Stage III-IV Pancreatic Adenocarcinoma

Study Overview
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Brief Summary
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Four-drug combo yielded a statistically significant improvement in progression-free survival and overall survival compared to gemcitabine in patients with advanced pancreatic adenocarcinoma. Nab-Paclitaxel showed promising antitumor activity in patients with pancreatic cancer. Given the synergism of taxanes with gemcitabine, fluoropyrimidines and platinating agents the role of nab-Paclitaxel in a 4-drug regimen will be explored. The aim of this trial is to determine the recommended dose of nab-paclitaxel in combination with cisplatin, capecitabine, and gemcitabine, PAXG regimen (Phase I), and to evaluate the feasibility and the activity of the PAXG regimen in patients with stage III and IV pancreatic cancer.

Detailed Description
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OBJECTIVES: PHASE I: to determine the recommended phase 2 dose of nab-paclitaxel in combination with cisplatin, capecitabine, and gemcitabine. PHASE II: to evaluate the feasibility and the activity of the PAXG regimen in terms of 6-months progression-free survival in patients with stage III and IV pancreatic cancer. OUTLINE Phase I - dose finding single institution trial, followed by a randomized open label multicenter phase II trial. Phase II: Patients will be stratified by stage (III vs IV) and CA19.9 level (< 10 x ULN versus >10 x ULN); Patients will be randomly assigned to receive PAXG (arm A) or gemcitabine-nab-paclitaxel regimen (arm B). Treatment plan (phase II): Arm A: PAXG every 4 weeks (1 cycle): cisplatin at 30 mg/m2 on days 1 and 15, nab-paclitaxel at the RP2D on days 1 and 15, capecitabine at 1250 mg/ m2 days 1-28, gemcitabine at 800 mg/ m2 on days 1 and 15. Arm B: Gemcitabine + nab-paclitaxel every 4 weeks (1 cycle): gemcitabine at 1000 mg/m2 on days 1, 8 and 15; nab-paclitaxel at 125 mg/mq on days 1, 8 and 15. Treatment will be administered for a maximum of 6 cycles or until there is a clinical benefit.

Official Title
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A Phase I-II Study of PAXG in Stage III-IV Pancreatic Adenocarcinoma

Conditions
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Pancreatic Cancer

Intervention / Treatment
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* Drug: cisplatin
* Drug: capecitabine
* Drug: gemcitabine
* Drug: nab-paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathologic diagnosis of pancreatic adenocarcinoma Stage III or IV disease Age > 17 < 76 years Karnofsky Performance Status > 50 Measurable disease (only for phase II part) Adequate bone marrow (GB > 3500/mm3, neutrophils > 1500/mm3; platelets > 100000/mm3; hemoglobin > 10 g/dl), liver (total bilirubin < 2 mg/dL; SGOT e SGPT < 3 UNL) and kidney function (serum creatinin < 1.5 mg/dL;) Written informed consent Exclusion Criteria: previous chemotherapy concurrent treatment with other experimental drugs previous or concurrent malignancies at other sites with the exception of surgically cured carcinoma in-site 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 brain metastases history of interstitial lung disease presence of serious disease which can compromise safety (cardiac failure, previous myocardial infarction within the prior 6 months, cardiac arrhythmia, history of psychiatric disabilities) pregnancy and lactating History of connective tissue disorders (eg, lupus, scleroderma, arteritis nodosa).

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PAXG regimen<br>cisplatin at 30 mg/m2 on days 1 and 15, nab-paclitaxel at the RP2D on days 1 and 15, capecitabine at 1250 mg/ m2 days 1-28, gemcitabine at 800 mg/ m2 on days 1 and 15 every 4 weeks | Drug: cisplatin<br>* cisplatin at 30 mg/m2 on days 1 and 15<br>* Other names: cisplatino TEVA;Drug: capecitabine<br>* capecitabine at 1250 mg/ m2 days 1-28<br>* Other names: XELODA;Drug: gemcitabine<br>* gemcitabine at 800 mg/ m2 on days 1 and 15 in arm A; at 1000 mg/m2 on days 1, 8 and 15 in arm B<br>* Other names: Gemzar;Drug: nab-paclitaxel<br>* nab-paclitaxel at the recommended phase II dose day 1 and 15 in arm A; at 125 mg/m2 on days 1, 8 and 15 in arm B<br>* Other names: abraxane;|
| Active Comparator: gemcitabine + nab-paclitaxel<br>gemcitabine at 1000 mg/ m2 on days 1, 8 and 15 every 4 weeks + nab-paclitaxel at 125 mg/ m2 on days 1, 8 and 15 every 4 weeks | Drug: gemcitabine<br>* gemcitabine at 800 mg/ m2 on days 1 and 15 in arm A; at 1000 mg/m2 on days 1, 8 and 15 in arm B<br>* Other names: Gemzar;Drug: nab-paclitaxel<br>* nab-paclitaxel at the recommended phase II dose day 1 and 15 in arm A; at 125 mg/m2 on days 1, 8 and 15 in arm B<br>* Other names: abraxane;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| first cycle toxicity for phase I part | Dose Limiting Toxicity definition: DLT will be defined as any of the following events attributable to the administered study drugs: Hematologic toxicity Grade ≥ 4 neutropenia lasting 7 days or more Grade ≥ 3 febrile neutropenia or fever of unknown origin ≥ 38.5°C Grade 4 thrombocytopenia Grade 3 thrombocytopenia which required transfusions Nausea or vomiting Grade ≥ 3 nausea or vomiting despite maximal antiemetic therapy Diarrhea Grade ≥ 3 diarrhea despite optimal management of the event Neurological toxicity Any Grade ≥ 2 neurological toxicity Other non-hematologic toxicity Any grade ≥ 3 toxicities or representing a shift by 2 grades from baseline (in case of abnormal baseline) Failure to recover Failure to recover to grade ≤ 1 toxicity (except alopecia) or to baseline values after delaying the initiation of next cycle by > 2 weeks. | after one month from treatment start | 
| progression-free survival for phase II part, stage IV patients | rate of progression-free patients at 6 months from randomization | after 6 months from randomization | 
| resectability rate for phase II part, stage III patients | rate of resectable patients at at time of CT evaluation and multidisciplinary assessment after 4 and 6 months from treatment start | after 4 and 6 months from treatment start | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| response rate | contrast enhanced CT scan tumor assessment | every two months up to 6 months during treatment; every 2-3 months afterwards until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 60 months | 
| biochemical response rate | blood sample for CA19.9 assessment | every month up to 6 months during treatment; every 2-3 months afterwards until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 60 months | 
| toxicity | outpatients visits; laboratory | every two weeks up to 26 weeks during treatment | 
| overall survival | outpatients visit; phone interviews | From date of trial enrolment until the date of death from any cause, assessed every two weeks up to 26 weeks during treatment; every 2-3 months afterwards up to 60 months | 
| Progression-free survival | contrast enhanced CT scan | From date of trial enrolment until the date of documented progression or date of death from any cause, whichever came first, assessed every two months up to 6 months during treatment; every 2-3 months afterwards up to 60 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pancreatic adenocarcinoma, stage III disease, stage IV disease, chemotherapy