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

• 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
• resectability rate [ Time Frame: participants will be assessed for resectability at time of every CT evaluation, an expected average of 2 months ] [ Designated as safety issue: No ]
  surgical evaluation for patients with stage III disease
• 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

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.

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 PEXG 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: PEXG every 4 weeks (1 cycle): same as above for cisplatin, gemcitabine and capecitabine, plus epirubicin at 30 mg/m2 on days 1 and 15.

Treatment will be administered for a maximum of 6 cycles or until there is a clinical benefit.

• Drug: cisplatin
  cisplatin at 30 mg/m2 on days 1 and 15
  Other Name: cisplatino TEVA
• Drug: capecitabine
  capecitabine at 1250 mg/ m2 days 1-28
  Other Name: XELODA
• Drug: gemcitabine
  gemcitabine at 800 mg/ m2 on days 1 and 15
  Other Name: Gemzar
• Drug: Epirubicin
  epirubicin at 30 mg/mq day 1 and 15
  Other Name: farmorubicina
• Drug: nab-paclitaxel
  nab-paclitaxel at the recommended phase II dose day 1 and 15
  Other Name: abraxane

• Experimental: PAXG regimen
  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
  Interventions:

  • Drug: cisplatin
  • Drug: capecitabine
  • Drug: gemcitabine
  • Drug: nab-paclitaxel
• Active Comparator: PEXG regimen
  cisplatin at 30 mg/m2 on days 1 and 15, epirubicin 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
  Interventions:

  • Drug: cisplatin
  • Drug: capecitabine
  • Drug: gemcitabine
  • Drug: Epirubicin

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).