Cholesterol Disruption in Combination With FOLFIRINOX in Patients With Metastatic Pancreatic Adenocarcinoma
Study Details
Study Description
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 |
|---|---|---|
|
Early Phase 1 |
Study Design
Arms and Interventions
| 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 Names:
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Outcome Measures
Primary Outcome Measures
- 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 Outcome Measures
- LDLR (low-density lipoprotein receptor) 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) 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) 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) 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.
- Changes in TILs (Tumor Infiltrating Lymphocytes) in response to the multipathway cholesterol embargo. [1 year]
Assessment of the level of TILs (Tumor Infiltrating Lymphocytes) in the tumor (hepatic metastasis ) by the pathologist.
- 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.
- Tumoral lipid droplet content changes in response to the multipathway cholesterol embargo. [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
- Investigation of changes in the lipid profile induced by the addition of cholesterol-lowering drugs to FOLFIRINOX in metastatic pancreatic ductal adenocarcinomas (mPDAC) patients. [1 year]
Changes in Total cholesterol, HDL cholesterol, LDL cholesterol and triglycerides using serial assessment. All measures are in mmol/L.
- 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. [1 year]
Changes in Apolipoprotein B (g/L) using serial assessment.
- Investigation of changes in Apo A1 levels induced by the addition of cholesterol-lowering drugs to FOLFIRINOX in metastatic pancreatic ductal adenocarcinomas (mPDAC) patients. [1 year]
Changes in Apolipoprotein A1 (g/L) using serial assessment.
- Investigation of changes in PCSK9 induced by the addition of cholesterol-lowering drugs to FOLFIRINOX in metastatic pancreatic ductal adenocarcinomas (mPDAC) patients. [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).
- Efficacy as measured by objective response rate [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.
- Efficacy as measured by overall survival [1 year]
Overall Survival (OS) at 1 year
- Efficacy as measured by progression free survival [1 year]
Progression Free Survival (PFS) at 1 year
Eligibility Criteria
Criteria
Inclusion Criteria:
To be eligible to this trial, patients must fulfill the following inclusion criteria:
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Have a histologically confirmed, treatment-naive metastatic pancreatic ductal adenocarcinoma with liver metastases.
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Be at least 18 years or older at the time of signing the informed consent.
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Have a life expectancy of at least 12 weeks.
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Performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale.
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Have measurable disease as assessed by RECIST v1.1.
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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.
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Eligible to standard-dose FOLFIRINOX as assessed by the principal investigator or a sub-investigator.
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Demonstrate normal organ function as defined below. These assessments must be done within 7 days of Cycle 1 Day-7.
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Provide written informed consent and able to follow the trial treatment and visit schedule.
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For Women Of Child-Bearing Potential (WOCBP), a negative serum pregnancy test must be obtained prior to receiving the study medication.
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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.
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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:
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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.
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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.
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Baseline myalgia or myositis of any etiology.
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Prior treatment with FOLFIRINOX in the adjuvant setting.
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History of clinically significant intolerance or myositis with any statin.
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History of clinically significant intolerance or hypersensitivity to PCSK9 inhibitors or ezetimibe.
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Baseline grade 2 ULN Creatine Phosphokinase (CPK) elevation.
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Liver tumor burden that is deemed unsafe by the investigator.
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Major surgery or procedure from which the patient has not yet recovered.
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Any medical condition that puts the patient at high medical risk, including but not limited to active uncontrolled infection or active bleeding diathesis.
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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.
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Use of any drugs that are contraindicated as per protocol and that cannot be changed or modified to an acceptable alternative.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | CHU de Québec-Université Laval | Quebec city | Quebec | Canada | G1R 2J6 |
Sponsors and Collaborators
- CHU de Quebec-Universite Laval
- Canadian Institutes of Health Research (CIHR)
- Biovalorem
Investigators
- 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
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- CHLOE pancreas