Evaluation of a Cardiovascular Active Prevention in Chronic Myeloid Leukemia on the Cardiovascular Morbi-mortality (PALERMO)

Phase III Study, Randomized, Multicenter, Evaluating the Efficacy of a Cardiovascular Active Prevention Vs Usual Clinical Practice, on the Morbi-mortality Decrease in Chronic Myeloid Leukemia Patients Treated with Tyrosine Kinase Inhibitor

According to the French National Cancer Institute, 35 000 new hematologic cancers are observed in France representing 10% of the new cancers. Chronic Myeloid Leukemia (CML) is a cancer involving the bone marrow and blood cells, the median age at diagnosis is 53 years in the Western world. The prognosis is worse than many other cancers with net survival at 5 years of 26%.

Since the approval of imatinib, additional tyrosine kinase inhibitors (TKIs) have been approved by the European Medicine Agency, including the second-generation TKIs nilotinib, dasatinib, and bosutinib and the third-generation TKI ponatinib. Despite their effect on the evolution of CML, there is increasing of cardiovascular toxicities which can impact patient morbidity and mortality. The majority of the cardiovascular toxicities are associated with the second- and third-generation TKIs. Nilotinib and ponatinib cardiovascular toxicity including arterial and venous thromboembolism has decrease the benefit/risk ratio, 10% of patients treated with nilotinib 300 mg twice daily and 15.9% treated with 400 mg twice daily experienced a vascular complication including myocardial infarction /ischemic heart disease, cerebrovascular accidents, or peripheral arterial disease. Regarding ponatinib, serious arterial occlusive adverse reactions occurred in 19% of patients.

In an attempt to reduce major adverse cardiovascular events MACE due to nilotinib and ponatinib, currently, then approach is driven by usual clinical practice without any robust published evidence. The investigators aim to perform a national clinical trial, multicenter, prospective, randomized, with two parallel comparative arms: experimental group with cardiovascular active prevention vs non active cardiovascular active prevention based on usual clinical practice. Our hypothesis is that active prevention of cardiovascular toxicities with optimal medical treatment improves the benefit-risk ratio in CML patients. The primary objective is Event Free Survival (EFS) at month 24.

Study Overview

• Status: Terminated
• Conditions: Chronic Myeloid Leukemia (CML)
• Intervention / Treatment: Combination product: Optimal medical treatment; Combination product: usual clinical practice

Detailed Description

At admission eligible patients are proposed to participate. Written consent is signed after complete oral and written explanation of the protocol is signed.

The efficacity of the cardiovascular active prevention will be studied by comparing the rate of Event free Survival between patients in the Experimental Arm Versus usual Clinical practices

The duration of participation for a subject is equal to 2 years

• Study Type: Interventional
• Enrollment (Actual): 80
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Angers, France
    • CHU

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Adults over 18 years
• CML "Philadelphia chromosome" in chronic phase treated with nilotinib or ponatinib for, in first or second line
• Written informed consent must be obtained prior to protocol-specific procedures
• Affiliation to a social security category

Exclusion Criteria:

• Revascularization already decided and scheduled
• Life threatening disease
• Recent history of myocardial infarction or stroke
• Unstable angina
• Hypotension (Blood pressure < 90/50mmHg)
• Pregnancy and lactation
• Women of childbearing potential not using appropriate contraceptive measures
• Contraindication for statin
• Contraindication for aspirin
• Contraindication for ACEi or AT2 antagonists treatment
• Known hypersensitivity to rosuvastatin or fluvastatin, other ingredients in the product
• Known hypersensitivity to aspirin, other ingredients in the product, other salicylates or non-steroidal anti-inflammatory drugs
• Known hypersensitivity to ACEi or AT2 antagonists treatment, other ingredients in the product
• Hereditary or idiopathic angioedema ; or history of angioedema
• Hyperaldosteronism
• Active liver disease, or unexplained, persistent elevations in serum transaminases
• Severe renal impairment (creatinine clearance <30 ml/min)
• Myopathy
• Concomitant cyclosporine treatment
• History of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy
• Severe heart failure
• Concurrent severe diseases which exclude the administration of therapy
• Patients under reinforced protection, deprived of liberty by judicial or administrative decision, hospitalized without consent or admitted to a health or social establishment for purposes other than research
• Absence of affiliation to a social security agency
• Inability to understand the instructions or objectives of the study
• Absence of signed informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: active prevention; optimal medical treatment	Combination product: Optimal medical treatment; Life style modifications, Monitoring of the risk factors and Optimal medical treatment Lipid-lowering treatment, anti-platelet treatment and ACEi or AT2 antagonists treatment for a total duration of 24 months
Sham Comparator: usual clinical practice; usual clinical practice in each center	Combination product: usual clinical practice; usual clinical practice in each center

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Improvementof the Event Free Survival (EFS) rate in CML patients with an active and systematic prevention for cardiovascular risk.	The Event Free Survival (EFS) is based on the analysis of the time to an event occurrence.	24 months

Collaborators and Investigators

• Sponsor: University Hospital, Angers
• Investigators: Principal Investigator: HENNI SAMIR, MD, PhD, Angers Teaching Hospital

Study record dates

Study Major Dates

• Study Start (Actual): December 20, 2019
• Primary Completion (Actual): April 16, 2024
• Study Completion (Actual): April 16, 2024

Study Registration Dates

• First Submitted: November 15, 2018
• First Submitted That Met QC Criteria: November 15, 2018
• First Posted (Actual): November 19, 2018

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: March 14, 2025
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Chronic Myeloid Leukemia; Blood; Vascular medicine
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Chronic Disease; Disease Attributes; Neoplasms by Histologic Type; Hematologic Diseases; Bone Marrow Diseases; Myeloproliferative Disorders; Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Other Study ID Numbers: PHRC-K-2017

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No