Clinical trial NCT04862260: Cholesterol Disruption in Combination With the Standard of Care in Patients With Advanced Pancreatic Adenocarcinoma
Official title: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: EARLY_PHASE1
Conditions: Pancreatic Ductal Adenocarcinoma
Pancreatic Cancer
Pancreas Cancer
Metastatic Cancer
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
Lead sponsor: CHU de Quebec-Universite Laval
Sponsor class: OTHER
Collaborators: name: Canadian Institutes of Health Research (CIHR)
name: Biovalorem
First posted: 2021-04-27
Enrollment: 3
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility criteria: 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 exclusion criteria:

1. Locally advanced pancreatic ductal adenocarcinoma deemed operable.
2. Any pancreatic ductal adenocarcinoma deemed operable or borderline operable that can be treated with neoadjuvant chemotherapy.
3. Known additional malignancy that is progressing or that requires treatment. Exceptions include basal cell carcinoma of the skin, in situ bladder or in situ cervical cancer. Other malignancy may be eligible after consultation with the promotor-investigator.
4. Spinal cord compression or brain metastases unless treated, stable and not requiring steroids for at least 4 weeks prior to the initiation of study treatment.
5. Baseline myalgia or myositis of any etiology.
6. Prior treatment with FOLFIRINOX in the adjuvant setting.
7. History of clinically significant intolerance or myositis with any statin.
8. History of clinically significant intolerance or hypersensitivity to PCSK9 inhibitors or ezetimibe.
9. Baseline grade ≥ 2 ULN Creatine Phosphokinase (CPK) elevation.
10. Liver tumor burden that is deemed unsafe by the investigator.
11. Major surgery or procedure from which the patient has not yet recovered.
12. Any medical condition that puts the patient at high medical risk, including but not limited to active uncontrolled infection or active bleeding diathesis.
13. Any history of disease that, in the opinion of the investigator, puts liver function at risk including but not limited to autoimmune hepatitis or history of hepatitis B, hepatitis C or human immunodeficiency virus (HIV). Screening at baseline for those conditions is not required.
14. Use of any drugs that are contraindicated as per protocol and that cannot be changed or modified to an acceptable alternative.
15. Active smoker. Complete usage of tobacco must have been stopped for at least 3 months.
16. Abnormally low hematocrit, as assessed by the oncologist.

Primary outcomes:
measure: Safety as measured by the rate of adverse events
timeFrame: 2 years
measure: Characterization of dose-limiting toxicities
timeFrame: 2 years
Secondary outcomes:
measure: LDLR (low-density lipoprotein receptor) tumoral and hepatic changes in response to the multipathway cholesterol embargo.
timeFrame: 1 year
measure: LRP1 (Low-density lipoprotein Receptor-Related Protein 1) tumoral and hepatic changes in response to the multipathway cholesterol embargo.
timeFrame: 1 year
measure: NPC1L1 (Niemann-Pick C1-Like 1 protein) tumoral and hepatic changes in response to the multipathway cholesterol embargo.
timeFrame: 1 year
measure: SRB1 (Scavenger Receptor class B type 1) tumoral and hepatic changes in response to the multipathway cholesterol embargo.
timeFrame: 1 year
measure: MHC-1 (Major Histocompatibility Complex class 1) tumoral and hepatic changes in response to the multipathway cholesterol embargo.
timeFrame: 1 year
measure: PD-L1 (Programmed Death-Ligand-1) changes in response to the multipathway cholesterol embargo.
timeFrame: 1 year
measure: Change in tumoral and hepatic levels of TILs (Tumor-Infiltrating Lymphocytes)
timeFrame: 1 year
measure: CD36 (Cluster of Differentiation 36) changes in response to the multipathway cholesterol embargo
timeFrame: 1 year
Other outcomes:
measure: Investigation of changes in the lipid profile induced by the addition of cholesterol-lowering drugs to FOLFIRINOX in metastatic pancreatic ductal adenocarcinomas (mPDAC) patients.
timeFrame: 1 year
measure: Investigation of changes in circulating apo B levels induced by the addition of cholesterol-lowering drugs to FOLFIRINOX in locally advanced or metastatic pancreatic ductal adenocarcinomas (mPDAC) patients.
timeFrame: 1 year
measure: Investigation of changes in Apo A1 levels induced by the addition of cholesterol-lowering drugs to FOLFIRINOX in locally advanced or metastatic pancreatic ductal adenocarcinomas (mPDAC) patients.
timeFrame: 1 year
measure: Investigation of changes in PCSK9 induced by the addition of cholesterol-lowering drugs to FOLFIRINOX in locally advanced or metastatic pancreatic ductal adenocarcinomas (mPDAC) patients.
timeFrame: 1 year
measure: Efficacy as measured by objective response rate
timeFrame: 1 year
measure: Efficacy as measured by overall survival
timeFrame: 1 year
measure: Efficacy as measured by progression free survival
timeFrame: 1 year
measure: Investigation of changes in insulin, phytosterols, ANGPTL3, ANGPTL4, ANGPTL8 and Apo C3 levels induced by the addition of cholesterol-lowering drugs to FOLFIRINOX in locally advanced or metastatic pancreatic ductal adenocarcinomas (mPDAC) patients.
timeFrame: 1 year
measure: To explore the feasibility of a larger multicenter trial
timeFrame: 1 year
Locations:
city: Montreal
country: Canada
facility: CHUM
state: Quebec
city: Quebec city
country: Canada
facility: CHU de Québec-Université Laval
state: Quebec
Study officials:
affiliation: CHU de Québec-Université Laval
name: Anne Gangloff, MD PhD FRCPC
role: STUDY_CHAIR
affiliation: CHU de Québec-Université Laval
name: Maxime Chénard-Poirier, MD FRCPC
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU de Québec-Université Laval
name: Félix Couture, MD FRCPC
role: STUDY_DIRECTOR
affiliation: CHU de Québec-Université Laval
name: Vincent Castonguay, MD FRCPC
role: STUDY_DIRECTOR
affiliation: CHU de Québec-Université Laval
name: Olivier Dumas, MD FRCPC
role: STUDY_DIRECTOR
affiliation: CHU de Québec-Université Laval
name: Anne-Marie Carreau, MD FRCPC
role: STUDY_DIRECTOR
affiliation: CHU de Québec-Université Laval
name: Frédéric Calon, PhD
role: STUDY_DIRECTOR
affiliation: Institut de recherches cliniques de Montréal
name: Nabil G. Seidah, PhD
role: STUDY_DIRECTOR
affiliation: CHUM
name: Francine Aubin, MD FRCPC
role: PRINCIPAL_INVESTIGATOR
References: