Investigating cardiovascular adverse events related to cancer treatment: a study of extreme toxicity using induced pluripotent stem cells

Recruiting

• Conditions: 10027655; 10082206; cardiovascular adverse events after cancer treatment

• Registration Number: NL-OMON44465
• Lead Sponsor: niversitair Medisch Centrum Groningen

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Last Update Posted: 12 August 2024

Recruitment & Eligibility

• Status: Recruiting
• Sex: Not specified
• Target Recruitment: 48

Inclusion Criteria

1. any proven cancer treated with curative intent;
2. age >= 18 and <= 50 years;
3. able to comply with the protocol;
4. signed written informed consent.
Furthermore, there are specific inclusion criteria for every subject group:
[A-TOX]: severe cardiovascular toxicity* during 1 to 3 cycles of anthracyclines (i.e. 60 to 180 mg/m2 doxorubicin or 90 to 270 mg/m2 epirubicin);
[A-NO]: >= 3 months after end of cancer treatment which included the maximum tolerable dose of anthracyclines (i.e. 450 to 500 mg/m2 doxorubicin or 850 to 900 mg/m2 epirucibin);
[T-TOX]: severe cardiovascular toxicity* within 1 to 6 cycles of trastuzumab (6 mg/kg/3wks or equivalent);
[T-NO]: >= 3 months after end of cancer treatment which included a year of trastuzumab (18 cycles of 6 mg/kg/3wks or equivalent).
[C-TOX]: severe cardiovascular toxicity* during 1 to 3 cycles of cisplatin (i.e. 100 to 300 mg/m2);
[C-NO]: >= 1 year after end of cancer treatment which included high-dose cisplatin (i.e. a cumulative dose of 400 to 1000 mg/m2);
[B-TOX]: severe cardiovascular toxicity* during 1 to 3 cycles of bleomycin (i.e. 90 to 270 USP);
[B-NO]: >= 1 year after end of cancer treatment which included high-dose bleomycin (i.e. a cumulative dose >= 360 USP);;* Severe cardiovascular toxicity is defined as any of grade 3 - 4 toxicity according to CTCAE 4.03, including but not limited to:
* - in the category *Cardiac disorders*:
o acute coronary syndrome (symptomatic, unstable angina and/or acute myocardial infarction, cardiac enzymes abnormal, hemodynamically stable - or more severe);
o cardiac arrest;
o heart failure (severe with symptoms at rest or with minimal activity or exertion; intervention indicated - or more severe)
o left ventricular systolic dysfunction (symptomatic due to drop in ejection fraction responsive to intervention - or more severe);
o myocardial infarction (severe symptoms; cardiac enzymes abnormal; hemodynamically stable; ECG changes consistent with infarction - or more severe);
o restrictive cardiomyopathy (symptomatic heart failure or other cardiac symptoms, responsive to intervention - or more severe);
o right ventricular dysfunction (severe symptoms, associated with hypoxemia, right heart failure; oxygen indicated - or more severe);
* - in the category *Nervous system disorders*:
o stroke (severe neurologic deficit - or more severe);
* - in the category *Vascular disorders*:
o peripheral ischemia (recurring or prolonged (>= 24 hours) and/or invasive intervention indicated - or more severe);
o thromboembolic event (thrombosis (e.g., uncomplicated pulmonary
embolism [venous], non-embolic cardiac mural [arterial] thrombus), medical
intervention indicated - or more severe);
* - in the category *Respiratory, thoracic and mediastinal disorders*:
o pneumonitis (severe symptoms; limiting self-care ADL; oxygen indicated - or more severe);
o pulmonary fibrosis (severe hypoxemia; evidence of right-sided heart failure; radiographic pulmonary fibrosis > 50 - 75% - or more severe);
* - in the category *Renal and urinary disorders*:
o acute kidney injury (creatinine > 3 x baseline or > 4.0 mg/dL; hospitalization indicated - or more severe);
o chronic kidney disease (estimated Glomerular Filtration Rate or creatinine clearance 29 - 15 ml/min/1.73 m2 - or more severe).

Exclusion Criteria

1. history of cardiovascular disease prior to start of cancer treatment, as evidenced by any of the following:
a. symptomatic or treated cardiovascular disease prior to start of cancer treatment;
b. LVEF < 55% at any performed MUGA scan or echocardiography prior to start of cancer treatment;
2. any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol, or insufficient understanding of the Dutch language;
3. any contraindication for skin biopsy, including:
a. extensive skin disorder precluding biopsy of unaffected skin;
b. known allergy to local anesthetics;
4. use of anticoagulants and INR > 3;
5. pregnant or lactating female.
Furthermore, there are specific exclusion criteria for the *resilient* subject groups [A-NO], [T-NO], [C-NO], and [B-NO]:
6. history of cardiovascular disease during or after cancer treatment, as evidenced by any of the following:
a. any symptomatic or treated cardiovascular disease;
b. LVEF < 55% at any performed MUGA scan or echocardiography.

Study & Design

• Study Type: Observational invasive
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>The primary endpoint will be a comparison in iPSC-CM/iPSC-EC morphology,<br /><br>function and molecular profile (RNA sequencing, proteomic profiling) before and<br /><br>after exposure to anthracyclines, trastuzumab, cisplatin, bleomycin and<br /><br>radiation in iPSC derived from the highly susceptible groups and the highly<br /><br>resilient control groups. </p><br>

Secondary Outcome Measures

Name	Time	Method
<p>n.a.</p><br>