Cardiovascular Assessment of Ponatinib as Third Line Treatment in Chronic Phase Chronic Myeloid Leukemia

Chronic Myeloid Leukemia (CML) Clinical Trial

— CarPAs  

Official title:

Cardiovascular Assessment of Ponatinib as Third Line Treatment Option in Chronic Phase Chronic Myeloid Leukemia After Failure of Imatinib and Bosutinib (CarPAs)

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT04709731
• Other study ID #: AssociazioneIPLMC
• Secondary ID: 2018-001334-18
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: February 1, 2021
• Est. completion date: April 1, 2025

Study information

• Verified date: January 2021
• Source: Associazione Italiana Pazienti Leucemia Mieloide Cronica
• Contact: Michaela De Palo
• Phone: 0283427930
• Email: michaela.depalo[@]galseq.com, studiclinici[@]galseq.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study will address the therapeutic activity and the safety/biological profile of Ponatinib when used as third line therapy of Chronic Myeloid Leukemia in Chronic Phase after the only two TKIs known for their cardiovascular safety, i.e. Imatinib and Bosutinib.

Description:

Phase 2, single-arm, multicentre, open label study which aims to investigate the therapeutic activity and the cardiovascular safety profile of Ponatinib when used as third line therapy of Chronic Myeloid Leukemia in Chronic Phase, after using the only two Tyrosine Kinase Inhibitors (TKIs) known for the safest cardiovascular profile, i.e. Imatinib and Bosutinib. Patients will be stratified according to the cause of discontinuation of the second TKI: intolerance or resistance. The safety of Ponatinib will be assessed by a combination of clinical tests such as ECG, Doppler ultrasound studies to assess arterial and venous vessels, blood pressure monitoring and lipid profiles, combined with inflammatory cytokine analysis which is a known predictor of subsequent cardiovascular adverse events.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 50
• Est. completion date: April 1, 2025
• Est. primary completion date: October 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 99 Years

Eligibility

Inclusion Criteria:

1. Signed and dated Informed Consent approved by Local Ethical Committee before any protocol-specific screening procedures.

2. CML diagnosis, Chronic Phase (CP), treated with imatinib and bosutinib. Previous treatment with dasatinib or nilotinib will not be allowed.

3. Resistant or intolerant to imatinib and/or bosutinib.

4. Able to take oral therapy.

5. Female or male, 18 years of age or older.

6. ECOG performance status 0-2.

7. Minimum life expectancy of 3 months or more.

8. Adequate organ function as defined by the following criteria:

• Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) = 2.5 x upper limit of normal (ULN) or AST and ALT = 5 x ULN if liver function abnormalities are due to underlying malignancy
• Total serum bilirubin = 1.5 x ULN (except patients with documented Gilbert's syndrome)
• Creatinine = 1.5 x ULN
• Prothrombin time (PT) < 1.5 × ULN
• Lipase = 1.5 × ULN for institution
• Amylase = 1.5 × ULN for institution

9. Normal QTcF interval on screening electrocardiogram (ECG) evaluation, defined as QTcF of = 450 ms in males or = 470 ms in females.

10. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.

11. Female and male patients who are of childbearing potential must agree to use an effective form of contraception (2 forms of contraception) with their partners throughout participation in this study and for at least 90 days after the last dose of treatment.

12. For females of childbearing potential, a negative pregnancy test must be documented prior to enrolment.

Exclusion Criteria:

1. Current treatment on another therapeutic clinical trial.

2. Received TKI therapy within 7 days prior to receiving the first dose of ponatinib, or have not recovered (> grade 1 by NCI CTCAE, v. 4.0) from AEs (except alopecia) due to agents previously administered.

3. Underwent autologous or allogeneic stem cell transplant < 60 days prior to receiving the first dose of ponatinib; any evidence of on-going graft versus-host disease (GVHD), or GVHD requiring immunosuppressive therapy.

4. Take medications that are known to be associated with Torsades de Pointes.

5. Require concurrent treatment with immunosuppressive agents, other than corticosteroids prescribed for a short course of therapy.

6. Have previously been treated with ponatinib.

7. Have active central nervous system (CNS) disease as evidenced by cytology or pathology. In the absence of clinical CNS disease, lumbar puncture is not required. History itself of CNS involvement is not exclusionary if CNS has been cleared with a documented negative lumbar puncture.

8. Have significant or active cardiovascular disease, specifically including, but not

restricted to:

1. Myocardial infarction within 3 months prior to first dose of ponatinib,

2. History of clinically significant atrial arrhythmia or any ventricular arrhythmia,

3. Unstable angina within 3 months prior to first dose of ponatinib,

4. Congestive heart failure within 3 months prior to first dose of ponatinib.

9. Have a significant bleeding disorder unrelated to CML or Ph+ ALL.

10. Have a history of pancreatitis or alcohol abuse.

11. Have uncontrolled hypertriglyceridemia (triglycerides > 450 mg/dL).

12. Have malabsorption syndrome or other gastrointestinal illness that could affect absorption of orally administered ponatinib.

13. Have been diagnosed with another primary malignancy within the past 3 years (except for non-melanoma skin cancer or cervical cancer in situ, or controlled prostate cancer, which are allowed within 3 years).

14. Pregnancy or breastfeeding.

15. Underwent major surgery (with the exception of minor surgical procedures, such as catheter placement or BM biopsy) within 14 days prior to first dose of ponatinib.

16. Have ongoing or active infection (including known history of human immunodeficiency virus [HIV], hepatitis B virus [HBV], or hepatitis C virus [HCV]). Testing for these viruses is not required in the absence of history.

17. Other severe acute or chronic medical or psychiatric conditions, or laboratory abnormalities that would impart, in the judgment of the investigator and/or sponsor, excess risk associated with study participation or study drug administration.

Related Conditions & MeSH terms

• Chronic Myeloid Leukemia (CML)
• Leukemia
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Leukemia, Myeloid
• Leukemia, Myeloid, Chronic-Phase

Intervention

Drug:
• Ponatinib 15mg QD
Ponatinib 15 mg tablet, taken orally once daily
• Ponatinib 30mg QD
Ponatinib 30 mg tablet, taken orally once daily

Locations

Country	Name	City	State
Italy	Presidio Ospedaliero "Oncologico Businco" - Cagliari (CA)	Cagliari
Italy	AOU "Policlinico Vittorio Emanuele" - Catania (CT)	Catania
Italy	Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico - Milano (MI)	Milano
Italy	Ospedale San Gerardo - Monza (MB)	Milano
Italy	Azienda Ospedaliera Universitaria "Federico II" - Napoli (NA)	Napoli
Italy	Fondazione IRCCS Policlinico San Matteo - Pavia (PV)	Pavia
Italy	Grande Ospedale Metropolitano "Bianchi-Melacrino-Morelli" - Reggio Calabria (RC)	Reggio Calabria
Italy	AUSL Reggio Emilia (RE)	Reggio Emilia
Italy	AOU Policlinico Umberto I "Università La Sapienza" - Roma (RM)	Roma
Italy	ASL Roma 2 "Ospedale S. Eugenio" - Roma (RM)	Roma
Italy	Azienda Ospedaliero-Universitaria Senese - Siena (SI)	Siena
Italy	AOU Città della Salute e della Scienza - Torino (TO)	Torino
Italy	AOU Integrata Verona "Ospedale Borgo Roma" - Verona (VN)	Verona

Sponsors (1)

Lead Sponsor	Collaborator
Associazione Italiana Pazienti Leucemia Mieloide Cronica

Country where clinical trial is conducted

Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Exposure adjusted Rate of Arterial Occlusive Events and Serious Arterial Occlusive Events at 1 year after study treatment initiation of each patient	Exposure adjusted Rate of Arterial Occlusive Events (AOE) and Serious AOE (SOE) at 1 year after study treatment initiation of each patient	1 year