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Cholesterol Disruption in Combination With FOLFIRINOX in Patients With Metastatic Pancreatic Adenocarcinoma

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ClinicalTrials.gov Identifier: NCT04862260
Recruitment Status : Recruiting
First Posted : April 27, 2021
Last Update Posted : November 19, 2021
Sponsor:
Collaborators:
Canadian Institutes of Health Research (CIHR)
Biovalorem
Information provided by (Responsible Party):
CHU de Quebec-Universite Laval

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 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.

Condition or disease Intervention/treatment Phase
Pancreatic Ductal Adenocarcinoma Pancreatic Cancer Pancreas Cancer Metastatic Cancer Drug: Cholesterol metabolism disruption Early Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 12 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1 Feasibility Study of Cholesterol Metabolism Disruption (Evolocumab, Atorvastatin and Ezetimibe) in Combination With FOLFIRINOX in Patients With Metastatic Pancreatic Adenocarcinoma
Actual Study Start Date : November 4, 2021
Estimated Primary Completion Date : June 2023
Estimated Study Completion Date : June 2023


Arm Intervention/treatment
Experimental: Multipathway cholesterol metabolism disruption
Twelve to fifteen patients will receive a combination of daily atorvastatin 40 mg, twice daily ezetimibe 10 mg and evolocumab 420 mg subcutaneously every month. This multipathway cholesterol metabolism disruption will be combined to standard chemotherapy (FOLFIRINOX).
Drug: Cholesterol metabolism disruption
Cholesterol metabolism disruption using a combination of atorvastatin, ezetimibe and evolocumab in metastatic pancreatic adenocarcinomas
Other Name: A combination of a lipophilic statin (Atorvastatin, Lipitor), a NPC1L1 inhibitor (Ezetimibe, Ezetrol) and a PCSK9 inhibitor (Evolocumab, Repatha) with chemotherapy in pancreatic cancer




Primary Outcome Measures :
  1. Safety as measured by the rate of adverse events [ Time Frame: 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.

  2. Characterization of dose-limiting toxicities [ Time Frame: 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 Outcome Measures :
  1. LDLR (low-density lipoprotein receptor) changes in response to the multipathway cholesterol embargo. [ Time Frame: 1 year ]
    Assessment of the level of LDLR in the tumor (hepatic metastasis ) and the liver by immunohistochemistry.

  2. LRP1 (Low-density lipoprotein Receptor-Related Protein 1) changes in response to the multipathway cholesterol embargo. [ Time Frame: 1 year ]
    Assessment of the level of LRP1 in the tumor (hepatic metastasis ) and the liver by immunohistochemistry.

  3. NPC1L1 (Niemann-Pick C1-Like 1 protein) changes in response to the multipathway cholesterol embargo. [ Time Frame: 1 year ]
    Assessment of the level of NPC1L1 in the tumor (hepatic metastasis ) and the liver by immunohistochemistry.

  4. SRB1 (Scavenger Receptor class B type 1) changes in response to the multipathway cholesterol embargo. [ Time Frame: 1 year ]
    Assessment of the level of SRB1 in the tumor (hepatic metastasis ) and the liver by immunohistochemistry.

  5. Changes in TILs (Tumor Infiltrating Lymphocytes) in response to the multipathway cholesterol embargo. [ Time Frame: 1 year ]
    Assessment of the level of TILs (Tumor Infiltrating Lymphocytes) in the tumor (hepatic metastasis ) by the pathologist.

  6. PD-L1 (Programmed Death-Ligand-1) changes in response to the multipathway cholesterol embargo. [ Time Frame: 1 year ]
    Assessment of the level of PD-L1 (Programmed Death-Ligand-1) in the tumor (hepatic metastasis ) and the liver by immunohistochemistry.

  7. Tumoral lipid droplet content changes in response to the multipathway cholesterol embargo. [ Time Frame: 1 year ]
    Assessment of tumoral lipid droplet content changes using red oil staining in biopsies taken both prior and ~40 days after combining cholesterol-lowering drugs with FOLFIRINOX.


Other Outcome Measures:
  1. Investigation of changes in the lipid profile induced by the addition of cholesterol-lowering drugs to FOLFIRINOX in metastatic pancreatic ductal adenocarcinomas (mPDAC) patients. [ Time Frame: 1 year ]
    Changes in Total cholesterol, HDL cholesterol, LDL cholesterol and triglycerides using serial assessment. All measures are in mmol/L.

  2. Investigation of changes in circulating apo B levels induced by the addition of cholesterol-lowering drugs to FOLFIRINOX in metastatic pancreatic ductal adenocarcinomas (mPDAC) patients. [ Time Frame: 1 year ]
    Changes in Apolipoprotein B (g/L) using serial assessment.

  3. Investigation of changes in Apo A1 levels induced by the addition of cholesterol-lowering drugs to FOLFIRINOX in metastatic pancreatic ductal adenocarcinomas (mPDAC) patients. [ Time Frame: 1 year ]
    Changes in Apolipoprotein A1 (g/L) using serial assessment.

  4. Investigation of changes in PCSK9 induced by the addition of cholesterol-lowering drugs to FOLFIRINOX in metastatic pancreatic ductal adenocarcinomas (mPDAC) patients. [ Time Frame: 1 year ]
    Changes in total, free and phosphorylated PCSK9 (Proprotein Convertase Subtilisin/Kexin type 9, ng/L) levels using serial assessment (measured by mass spectrometry).

  5. Efficacy as measured by objective response rate [ Time Frame: 1 year ]
    To obtain a preliminary assessment of the efficacy of the combination of cholesterol metabolism disruption and FOLFIRINOX: tumoral response assessment will be centrally evaluated using RECIST v1.1.

  6. Efficacy as measured by overall survival [ Time Frame: 1 year ]
    Overall Survival (OS) at 1 year

  7. Efficacy as measured by progression free survival [ Time Frame: 1 year ]
    Progression Free Survival (PFS) at 1 year



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

To be eligible to this trial, patients must fulfill the following inclusion criteria:

  1. Have a histologically confirmed, treatment-naive metastatic pancreatic ductal adenocarcinoma with liver metastases.
  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 and liver biopsy at baseline and on day 41 +/- 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.
  8. Demonstrate normal organ function as defined below. These assessments must be done within 7 days of Cycle 1 Day-7.
  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. 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 chief investigator.
  2. 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.
  3. Baseline myalgia or myositis of any etiology.
  4. Prior treatment with FOLFIRINOX in the adjuvant setting.
  5. History of clinically significant intolerance or myositis with any statin.
  6. History of clinically significant intolerance or hypersensitivity to PCSK9 inhibitors or ezetimibe.
  7. Baseline grade 2 ULN Creatine Phosphokinase (CPK) elevation.
  8. Liver tumor burden that is deemed unsafe by the investigator.
  9. Major surgery or procedure from which the patient has not yet recovered.
  10. Any medical condition that puts the patient at high medical risk, including but not limited to active uncontrolled infection or active bleeding diathesis.
  11. 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.
  12. Use of any drugs that are contraindicated as per protocol and that cannot be changed or modified to an acceptable alternative.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04862260


Contacts
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Contact: Anne Gangloff, MD PhD FRCPC 418-525-4444 ext 47275 anne.gangloff@crchudequebec.ulaval.ca
Contact: France-Hélène Joncas, M.Sc 418-525-4444 ext 42296 france-helene.joncas@crchudequebec.ulaval.ca

Locations
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Canada, Quebec
CHU de Québec-Université Laval Recruiting
Quebec city, Quebec, Canada, G1R 2J6
Contact: Anne Gangloff, MD    418-525-4444 ext 47275    anne.gangloff@crchudequebec.ulaval.ca   
Contact: France-Hélène Joncas, M.Sc    418-525-4444 ext 42296    france-helene.joncas@crchudequebec.ulaval.ca   
Sponsors and Collaborators
CHU de Quebec-Universite Laval
Canadian Institutes of Health Research (CIHR)
Biovalorem
Investigators
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Study Chair: Anne Gangloff, MD PhD FRCPC CHU de Québec-Université Laval
Principal Investigator: Maxime Chénard-Poirier, MD FRCPC CHU de Québec-Université Laval
Study Director: Félix Couture, MD FRCPC CHU de Québec-Université Laval
Study Director: Vincent Castonguay, MD FRCPC CHU de Québec-Université Laval
Study Director: Olivier Dumas, MD FRCPC CHU de Québec-Université Laval
Study Director: Anne-Marie Carreau, MD FRCPC CHU de Québec-Université Laval
Study Director: Frédéric Calon, PhD CHU de Québec-Université Laval
Study Director: Nabil G. Seidah, PhD Institut de recherches cliniques de Montréal
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Responsible Party: CHU de Quebec-Universite Laval
ClinicalTrials.gov Identifier: NCT04862260    
Other Study ID Numbers: CHLOE pancreas
First Posted: April 27, 2021    Key Record Dates
Last Update Posted: November 19, 2021
Last Verified: November 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by CHU de Quebec-Universite Laval:
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
Additional relevant MeSH terms:
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Adenocarcinoma
Pancreatic Neoplasms
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Endocrine Gland Neoplasms
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases
Atorvastatin
Ezetimibe
Evolocumab
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Enzyme Inhibitors