A Phase I-II Study of PAXG in Stage III-IV Pancreatic Adenocarcinoma (PACT-19)

• first cycle toxicity for phase I part [ Time Frame: after one month from treatment start ] [ Designated as safety issue: Yes ]

  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.
  
  
• progression-free survival for phase II part, stage IV patients [ Time Frame: after 6 months from randomization ] [ Designated as safety issue: No ]
  rate of progression-free patients at 6 months from randomization
  
  
• resectability rate for phase II part, stage III patients [ Time Frame: after 4 and 6 months from treatment start ] [ Designated as safety issue: No ]
  rate of resectable patients at at time of CT evaluation and multidisciplinary assessment after 4 and 6 months from treatment start
  
  

• response rate [ Time Frame: 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 ] [ Designated as safety issue: No ]
  contrast enhanced CT scan tumor assessment
  
  
• biochemical response rate [ Time Frame: 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 ] [ Designated as safety issue: No ]
  blood sample for CA19.9 assessment
  
  
• toxicity [ Time Frame: every two weeks up to 26 weeks during treatment ] [ Designated as safety issue: Yes ]
  outpatients visits; laboratory
  
  
• overall survival [ Time Frame: 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 ] [ Designated as safety issue: Yes ]
  outpatients visit; phone interviews
  
  
• Progression-free survival [ Time Frame: 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 ] [ Designated as safety issue: No ]
  contrast enhanced CT scan
  
  

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.