Clinical trial NCT04010552: Nalirinox Neo-pancreas RAS Mut ctDNA Study
Official title: A Phase II Trial to Assess the Evolution of KRAS Mutation Load by Liquid Biopsy in Patients With Resectable Pancreatic Ductal Adenocarcinoma Treated With Neoadjuvant NALIRINOX
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Resectable Pancreatic Ductal Adenocarcinoma
Lead sponsor: Fundación de investigación HM
Sponsor class: OTHER
Collaborators: name: Syntax for Science, S.L
First posted: 2019-07-08
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: This study is a multicenter, single-arm, interventional, open-label, non-randomized, phase II clinical trial, to evaluate the association of KRAS mutational load and histological tumour response after chemotherapy treatment in patients with PDAC. Due to its single-arm design patients will be assigned to a single group (non-randomized) and there will be no masking (open-label).
Primary purpose: TREATMENT

Brief summary: Pancreatic cancer has an unfavorable prognosis with a reduced possibility of long-term survival. The only treatment with curative potential is surgery, but it is only possible in 15-20% of cases.

There are patients with clear criteria for surgical entry, others at the limit of the possibility of surgery, and patients with such advanced disease (either locally or with metastasis) that surgery is not indicated.

The objective of neoadjuvant chemotherapy treatment (received before surgery) is to reduce the tumor before surgery and reduce the risk of subsequent metastases and local recurrences, in borderline tumors or those resectable with high-risk criteria.

The FOLFIRINOX scheme, composed of 5-fluorouracil / folinic acid, oxaliplatin and irinotecan, is recommended as neoadjuvant treatment, but the response is still low. This study will use a modified FOLFIRINOX (NALIRINOX) regimen with a form of irinotecan attached to liposomes that allows greater action on tumor cells.

Mutations in the KRAS gene are associated with a greater growth capacity of tumor cells and are present in 90% of pancreatic cancers in advanced stages. They would be less frequent in earlier phases but little is known about the impact that chemotherapy treatment and subsequent surgery could have on the increase or decrease of these mutations, as well as their implication. The follow-up of these mutations with repeated pancreatic biopsies is not viable, but it can be monitored by simple blood samples in which the genetic material of the tumor can be analyzed.


Eligibility criteria: Inclusion Criteria:

1. Male or females, aged 18 years or older
2. Histologically or cytologically confirmed diagnosis of PDAC
3. Candidates for pancreatic cancer surgery (no comorbidities that can exclude for surgery)
4. Life expectance of at least 12 months
5. Carbohydrate antigen 19-9 (CA19-9) levels \< 500 U/ml
6. ECOG performance status ≤ 1
7. Adequate bone marrow function:

   * Hemoglobin \>9 g/dL
   * Platelets \>100.000 µL
   * Absolute neutrophil count (ANC) \>1500 µl
   * Serum albumin \> 3 g/dL
8. Adequate hepatic function:

   * Aspartate aminotransferase (AST) \<3 upper limits of normal (ULN)
   * Alanine Aminotransferase (ALT) \<3 ULN
   * Total Bilirubin \< 1.5 ULN. If values are \> 1.5 external drainage with a stent is allowed.
9. Adequate renal function:

   - Clearance of creatinine (ClCr) \>60 ml/min
10. Sexually active men and women of childbearing potential must use efficient contraceptive methods. Contraceptive methods comprise: oral contraceptives, intrauterine devices, sexual abstinence, tubal ligation, IUD, barrier methods or another contraceptive considered appropriate by the investigator. Women of childbearing potential must have a negative serum pregnancy test before study entry.
11. Agree to participate and signed the ICF.

Exclusion Criteria:

1. Patients with metastatic disease
2. Patients ≥ 75 years.
3. Uncontrolled coagulopathy
4. Patients with a contraindication to surgery (locally advanced disease or patients not amenable to pancreatic surgery due to a previous comorbidity)
5. Patients with prior or concurrent malignant disease that required treatment with chemotherapy in the past.
6. Previous cytotoxic therapy within 36 months for other no-cancer disease (ie arthritis rheumatoid)
7. Known or suspected reactions to any component of the study medication (5-FU/LV, nal- IRI or oxaliplatin) or to components of similar chemical or biologic composition
8. Concurrent participation in any other clinical trial likely to interfere with the therapeutic schedule
9. Human immunodeficiency virus (HIV) positivity, active Hepatitis B or Hepatitis C infection.
10. Uncontrolled illness including ongoing or active infection, symptomatic congestive heart failure, unstable angina, cardiac arrhythmia, myocardial infarction, or left ventricular ejection fraction (LVEF) \< 50, among others, or psychiatric illness/social situations that would limit compliance with study requirements.
11. Pregnant or breast-feeding women.
12. Any medical condition that, based on investigator's criteria, places the subject at risk, makes the subject ineligible or may jeopardize protocol compliance.

Primary outcomes:
measure: Proportion of subjects with a good histological tumour response in the resected specimens after neoadjuvant chemotherapy with NALIRINOX and surgical removal according to the Ryan's classification in KRAS positive and negative patients
timeFrame: 8 weeks after surgical intervention
Secondary outcomes:
measure: R0 resection
timeFrame: Through the study completion (estimated to be 15 months)
measure: 1-year survival and Overal survival (OS) in baseline KRAS+ and KRAS- subjects
timeFrame: Through the study completion (estimated to be 15 months)
measure: Progression Free Survival (PFS)
timeFrame: Through the study completion (estimated to be 15 months)
measure: Assessment of the proportion of KRAS- subjects switching to KRAS+ (and from KRAS+ to negative) after neoadjuvant NALIRINOX
timeFrame: Through the study completion (estimated to be 15 months)
measure: Assessment of the number of KRAS- subjects switching to KRAS+ (and from KRAS+ to negative) after neoadjuvant NALIRINOX
timeFrame: Through the study completion (estimated to be 15 months)
measure: Impact on R0 resection for KRAS- subjects switching to KRAS+ (and from KRAS+ to negative) after neoadjuvant NALIRINOX
timeFrame: Through the study completion (estimated to be 15 months)
measure: Impact on histological tumour response for KRAS- subjects switching to KRAS+ (and from KRAS+ to negative) after neoadjuvant NALIRINOX
timeFrame: Through the study completion (estimated to be 15 months)
measure: Impact on PFS for KRAS- subjects switching to KRAS+ (and from KRAS+ to negative) after neoadjuvant NALIRINOX
timeFrame: Through the study completion (estimated to be 15 months)
measure: Impact on 1-year survival for KRAS- subjects switching to KRAS+ (and from KRAS+ to negative) after neoadjuvant NALIRINOX
timeFrame: Through the study completion (estimated to be 15 months)
measure: Impact on OS for KRAS- subjects switching to KRAS+ (and from KRAS+ to negative) after neoadjuvant NALIRINOX
timeFrame: Through the study completion (estimated to be 15 months)
measure: Number of AEs and SAEs (according to CTCAE) to describe the safety profile of the neoadjuvant NALIRINOX scheme
timeFrame: Through the study completion (estimated to be 15 months)
Other outcomes:
Locations:
city: Hospitalet de Llobregat
country: Spain
facility: Hestia Duran I Reynals
state: Barcelona
city: Sanchinarro
country: Spain
facility: Hospital Universitario Madrid Sanchinarro
state: Madrid
city: Barcelona
country: Spain
facility: Hospital Universitari Vall D'Hebron
Study officials:
affiliation: Director
name: Antonio Cubillo, MD
role: STUDY_DIRECTOR
References: