Cholesterol Disruption in Combination With the Standard of Care in Patients With Advanced Pancreatic Adenocarcinoma

A Phase 1 Feasibility Study of Cholesterol Metabolism Reprogramming (Evolocumab, Atorvastatin and Ezetimibe) in Combination With the Standard of Care in Patients With Advanced or Metastatic Pancreatic Adenocarcinoma

Status

Active, not recruiting

Phases

Early Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04862260

Enrollment

Registered

2021-04-27

Start date

2021-10-04

Completion date

2026-12-31

Last updated

2026-03-19

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Metastatic Cancer, Pancreas Cancer, Pancreatic Cancer, Pancreatic Ductal Adenocarcinoma

Keywords

Statin, Atorvastatin, Lipitor, PCSK9 monoclonal antibody, PCSK9 inhibitor, PCSK9, Evolocumab, Repatha, Alirocumab, Praluent, Lipid droplets and vacuoles, NPC1L1 transporter, HMG Co A reductase, LDL receptor, LRP1 receptor, SRB1 receptor, Lipids, Cancer, Cholesterol, Pancreas cancer, Pancreas/Pancreatic Cancer Metastatics, FOLFIRINOX

Brief summary

Cardiovascular diseases and cancers, the two leading causes of death in Canada, require cholesterol to sustain their progression. All cells require cholesterol, but cancer cells have much higher needs to sustain growth, division and metastasis. The availability of new cholesterol-lowering drugs developed to protect patients from heart diseases has resulted in unprecedented low levels of cholesterol. The combination of atorvastatin, ezetimibe and Repatha, which are 3 cholesterol-lowering drugs used in combination, is safe, well tolerated and efficient over years of treatment. Recent reports indicate that abundant cholesterol supplies are required to sustain the progression of pancreatic ductal adenocarcinomas. This proof-of-concept study aims to verify the feasibility, the acceptability and gain preliminary data on adding a cholesterol shortage on top of FOLFIRINOX (standard chemotherapy) in newly diagnosed patients with locally advanced pancreatic adenocarcinomas or metastatic pancreatic adenocarcinomas. It is expected that a drug-induced cholesterol shortage will slow-down or stop the progression of pancreatic adenocarcinomas while increasing the response to chemotherapy.

Interventions

DRUGCholesterol metabolism disruption

Cholesterol metabolism disruption using a combination of atorvastatin, ezetimibe and evolocumab in metastatic pancreatic adenocarcinomas

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 99 Years

Healthy volunteers

Inclusion criteria

To be eligible to this trial, patients must fulfill the following inclusion criteria: 1. Have a histologically confirmed, treatment-naive locally advanced and inoperable (LaiPDAC) or metastatic pancreatic ductal adenocarcinoma (mPDAC). 2. Be at least 18 years or older at the time of signing the informed consent. 3. Have a life expectancy of at least 12 weeks. 4. Performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale. 5. Have measurable disease as assessed by RECIST v1.1. 6. Agrees and amenable to a tumor (if deemed safe only) and liver biopsy (all participants) at baseline and on day 42 +/- 3 days. Patient that are anticoagulated at baseline are eligible provided it is deemed safe by the investigator to stop anticoagulation momentarily in order to safely proceed to a biopsy. 7. Eligible to standard-dose FOLFIRINOX as assessed by the principal investigator or a sub-investigator. FOLFIRINOX doses can be adapted according to SOC. 8. Demonstrate normal organ function as defined below. These assessments must be done within 7 days of Cycle 1 Day-7. Hemoglobin (Hb) ≥ 90 g/L Absolute neutrophil count ≥ 1.5 x 10 9/L Platelet count ≥ 100 x 10 9/L INR ≤ 1.3 (unless patient is anticoagulated\*) aPTT ≤ 1.5 x ULN (switching to LMWH will be recommended) Total bilirubin ≤ 1.5 x ULN OR Direct bilirubin (for patients with total bilirubin ≥ 1.5 x ULN) AST and ALT ≤ 3 x ULN CPK ≤ 1.5 x ULN Serum creatinine ≤ 1.5 x ULN OR Estimated GFR (as per institutional standards) ≥ 50 ml/min 9. Provide written informed consent and able to follow the trial treatment and visit schedule. 10. For Women Of Child-Bearing Potential (WOCBP), a negative serum pregnancy test must be obtained prior to receiving the study medication. 11. WOCBP should agree to use 2 different methods of birth control OR abstain from heterosexual intercourse for the duration of the trial and up to 90 days after the last study medication administration. 12. Male subjects should agree to use an adequate method of contraception for the duration of the trial and up to 90 days after the last study medication administration. Male subjects should refrain from donating sperm during this period.

Exclusion criteria

To be eligible to this trial, patients must not fulfill any of the following

Design outcomes

Primary

Measure	Time frame	Description
Safety as measured by the rate of adverse events	2 years	To determine causality and grading severity of each adverse event (AEs) using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Characterization of dose-limiting toxicities	2 years	To determine the dose at which no more than 1 out of 6 patients experience a drug related dose-limiting toxicity. To confirm that the combination of daily atorvastatin 40 mg, ezetimibe 10 mg twice daily and monthly evolocumab 420 mg meets the criterion to be the recommended phase II dose (RP2D).

Secondary

Measure	Time frame	Description
LDLR (low-density lipoprotein receptor) tumoral and hepatic changes in response to the multipathway cholesterol embargo.	1 year	Assessment of the level of LDLR in the tumor (hepatic metastasis ) and the liver by immunohistochemistry.
LRP1 (Low-density lipoprotein Receptor-Related Protein 1) tumoral and hepatic changes in response to the multipathway cholesterol embargo.	1 year	Assessment of the level of LRP1 in the tumor (hepatic metastasis ) and the liver by immunohistochemistry.
NPC1L1 (Niemann-Pick C1-Like 1 protein) tumoral and hepatic changes in response to the multipathway cholesterol embargo.	1 year	Assessment of the level of NPC1L1 in the tumor (hepatic metastasis ) and the liver by immunohistochemistry.
SRB1 (Scavenger Receptor class B type 1) tumoral and hepatic changes in response to the multipathway cholesterol embargo.	1 year	Assessment of the level of SRB1 in the tumor (hepatic metastasis ) and the liver by immunohistochemistry.
MHC-1 (Major Histocompatibility Complex class 1) tumoral and hepatic changes in response to the multipathway cholesterol embargo.	1 year	Assessment of the level of MHC-1 in the tumor (hepatic metastasis ) and the liver by immunohistochemistry
PD-L1 (Programmed Death-Ligand-1) changes in response to the multipathway cholesterol embargo.	1 year	Assessment of the level of PD-L1 (Programmed Death-Ligand-1) in the tumor (hepatic metastasis ) and the liver by immunohistochemistry.
Change in tumoral and hepatic levels of TILs (Tumor-Infiltrating Lymphocytes)	1 year	Assessment of tumoral and hepatic levels of TILs by immunohistochemistry
CD36 (Cluster of Differentiation 36) changes in response to the multipathway cholesterol embargo	1 year	Assessment of tumoral and hepatic levels in the tumor (hepatic metastasis ) and the liver by immunohistochemistry.