Trial to Investigate Intensified Neoadjuvant Chemotherapy in Locally Advanced Pancreatic Cancer (NEOLAP)

AIO-Studien

Status and phase

Completed

Phase 2

Conditions

Ductal Adenocarcinoma of the Pancreas

Treatments

Drug: Gem/nab-Pac

Drug: FOLFIFINOX

Study type

Interventional

Funder types

Other

Industry

Identifiers

NCT02125136

2013-004796-12 (EudraCT Number)

AIO-PAK-0113

AX-CL-PANC-PI-003324 (Other Grant/Funding Number)

Details and patient eligibility

About

The aim ot the study is to investigate the efficacy and safety of two new intensified chemotherapy regimens (gemcitabine (Gem)/nab- paclitaxel (PAC), FOLFIRINOX) as neoadjuvant chemotherapy protocol in locally advanced, non-metastatic pancreatic cancer (LAPC) and consecutive conversion of the tumor to resectability.

Full description

This is a prospective open randomized multicenter phase II trial with two arms.

Patients suffering from histologically confirmed LAPC (and assessed as unresectable or borderline resectable according to National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines "pancreatic adenocarcinoma" version 1.2013) without metastases will receive two different neoadjuvant treatment regimens:

First all patients receive two cycles Gem/nab-PAC (duration of each cycle 28 days) as neoadjuvant chemotherapy in equal measure and a first restaging is performed after these two cycles based on imaging criteria. If there is no progression according to Response evaluation criteria in solid tumors (RECIST 1.1) criteria at the first restaging, the patients are randomized in a 1:1 relation to:

Two further cycles Gem/nab-PAC (duration of each cycle 28 days). or Four further cycles FOLFIRINOX (duration of each cycle 14 days). After the neoadjuvant chemotherapy a 2nd restaging is performed based on imaging criteria. All patients without progression at this restaging or at an earlier time point undergo obligatory exploratory laparotomy irrespective of imaging criteria to assess resectability. If they are evaluated as converted to resectable during this exploratory laparotomy, pancreas resection in curative intent will be performed. All patients with successful R0 or R1 pancreatic resection will receive three further cycles adjuvant chemotherapy with Gem/nab-PAC. Adjuvant chemotherapy will start within 4 to 8 weeks after pancreatic resection surgery.

Further treatment of patients with PD after 1st or 2nd restaging as well as patients with unresectable status based on exploratory laparotomy is under the discretion of the local investigators (e.g. second-line chemotherapy in case of distant relapse or local radiochemotherapy in case of local progression or definitive irresectability).

All patients are followed up for local recurrence, progression and survival until death or for at least one year after last application of study drugs whichever is sooner.

The translational research conducts exploratory analyses for potential biomarkers of possible prognostic or predictive value for efficacy of neoadjuvant chemotherapy in LAPC; including analyses of circulating tumor cells, molecular pathways of pancreatic adenocarcinoma including SPARC expression.

Enrollment

168 estimated patients

Sex

All

Ages

18 to 75 years old

Volunteers

No Healthy Volunteers

Inclusion criteria

Adult patients ≥ 18 years and ≤ 75 years of age
Histologic or cytologic proven ductal adenocarcinoma of the pancreas (histologic confirmation of diagnosis is preferred)
No distant metastases
De novo, treatment-naïve unresectable or borderline resectable LAPC; evaluation of unresectable and borderline resectable status according to NCCN- Clinical Practice Guidelines in Oncology "pancreatic adenocarcinoma" version 1.2013. Applicable criterion/criteria have to be indicated.
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
Total bilirubin ≤ 2 mg/dL. Patients with a biliary stent may be included provided that bilirubin level after stent insertion decreased to ≤ 2 mg/dL and there is no cholangitis.
Adequate renal, hepatic and bone marrow function, defined as
Serum creatinine ≤ 1.25 x Upper limit of normal (ULN)
Calculated creatinine clearance ≥ 60 mL/min according to Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula
Aspartate aminotransferase (AST)/(serum glutamic oxaloacetic transaminase)GOT and/or Alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (GPT) ≤ 2.5 x ULN
Partial thromboplastin time (PTT) ≤ 1.5 x ULN and Quick value ≥ 70%
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
Haemoglobin ≥ 8g/dL
Platelets ≥ 100 x 109/L
Females of childbearing potential (FCBP) must have a negative pregnancy test within 7 days of the first application of study treatment and must agree to use effective contraceptive birth control measures (Pearl Index < 1) during the course of the trial and for at least 1 month after last application of study treatment.

A female subject is considered to be of childbearing potential unless she is age ≥ 50 years and naturally amenorrhoeic for ≥ 2 year, or unless she is surgically sterile.

Males must agree not to father a child during the course of the trial and for at least 6 months after last administration of study drugs.
Signed and dated informed consent before the start of any specific protocol procedures
Patient's legal capacity to consent to study participation

Exclusion criteria

Evidence of distant metastases. In case of radiological suspicion of peritoneal carcinomatosis or ascites histological or cytological verification is required e.g. by means of exploratory laparoscopy
Local relapse of the pancreatic adenocarcinoma prior treated with surgical resection
Any previous treatment of the pancreatic carcinoma (radiotherapy, chemoradiotherapy, chemotherapy, targeted tumor therapy, local ablative therapy)
Contraindication for pancreas resection (pancreatic head resection, distal pancreatectomy with splenectomy, or complete pancreatectomy)
Larger surgical interventions within 4 weeks before study enrolment and/or diagnostic laparotomy with or without gastroenterostomy and with or without biliodigestive anastomosis within 2 weeks before first application of study treatment. Wound healing must be also completed before first application of study treatment.
Known chronic diarrhoea
Peripheral polyneuropathy > grade 1
Known dihydropyrimidine dehydrogenase (DPD) deficiency
Medical history of interstitial lung disease (ILD) or pulmonary fibrosis
Hypersensitivity against any of the study drugs (nab-paclitaxel, gemcitabine, oxaliplatin, irinotecan, 5-fluorouracil, folinic acid), or the ingredients of these drugs
Active or uncontrolled bacterial, viral, or fungal infection that requires systemic treatment
Known HIV- infection or active Hepatitis B virus (HBV)- or Hepatitis C virus (HCV) infection
Convulsion disorder that requires anticonvulsive treatment
Clinically significant cardiovascular or vascular disease or disorder ≤ 6 months before study enrolment (e.g. myocardial infarction, unstable angina pectoris, chronic heart failure New York Heart Association (NYHA) ≥ grade 2, uncontrolled arrhythmia, cerebral infarction)
Any other severe concomitant disease or disorder, which could influence patient's ability to participate in the study and his/her safety during the study or interfere with interpretation of study results e.g. severe hepatic, renal, pulmonary, metabolic, or psychiatric disorders
Requirement for concomitant antiviral treatment with sorivudine or brivudine
Requirement of immunosuppressive treatment
Continuing anticoagulant therapy with coumarin derivatives (treatment with low-molecular weight heparin allowed)
Continuing abuse of alcohol, drugs, or medical drugs
Pregnant or breast feeding females
Participation in any other clinical trial or treatment with any experimental drug within 28 days before enrolment to the study or during study participation until the end of treatment visit.
Previous or concurrent malignant tumor disease other than underlying tumor disease with the exception of cervical cancer in situ, adequately treated basal cell carcinoma or squamous cell carcinoma of the skin, superficial bladder tumors (Ta,Tis, and T1) or any curatively treated tumors > 5 years prior to enrolment