Investigating Cardiovascular Adverse Events Related to Cancer Treatment (InvestiCAT)

Investigating Cardiovascular Adverse Events Related to Cancer Treatment: a Study of Extreme Toxicity Using Induced Pluripotent Stem Cells

Cisplatin, anthracyclines, bleomycin and trastuzumab can cause severe cardiovascular or pulmonary toxicity. Why some patients are susceptible to extreme toxicity of cancer treatment is largely unknown. Unraveling extreme cardiovascular toxic responses in cancer patients may help understand the pathophysiology of cardiovascular toxicity of these agents and help in understanding the more subtle, long-term cardiovascular side effects that affect a larger part of cancer survivors. With induced pluripotent stem cells we will obtain patient-derived cells to recapitulate and mimic and study pathological (cardiovascular) responses and (cardiovascular) toxicity in vitro.

Study Overview

• Status: Recruiting
• Conditions: Toxicity Due to Chemotherapy; Cancer, Treatment-Related; Cardiovascular Morbidity
• Intervention / Treatment: Drug: Anthracyclines; Drug: Trastuzumab; Drug: Cisplatin; Drug: Bleomycin

• Study Type: Observational
• Enrollment (Estimated): 48

Contacts and Locations

• Study Contact: Name: J.A. Gietema, MD, PhD; Phone Number: +31 50 3612821; Email: j.a.gietema@umcg.nl
• Study Contact Backup: Name: L.C. Steggink, MD; Phone Number: +31 50 361 2821; Email: l.c.steggink@umcg.nl

Study Locations

• Netherlands
  • Groningen, Netherlands, 9713 GZ
    • Recruiting
    • University Medical Center Groningen
    • Contact: J.A. Gietema, MD, PhD; Phone Number: +31 50 3612821; Email: j.a.gietema@umcg.nl
    • Contact: L.C. Steggink, MD; Phone Number: +31 50 3612821; Email: l.c.steggink@umcg.nl
    • Principal Investigator: J.A. Gietema, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients treated for a malignancy with any of the described cytotoxic agents.

Description

Inclusion Criteria:

In order to be eligible to participate in this study, a subject must meet all of these 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.

There are specific inclusion criteria for every subject group:

• severe toxicity during 1 to 3 cycles of anthracyclines;
• ≥ 3 months after end of cancer treatment which included the maximum tolerable dose of anthracyclines without (severe) toxicity;
• severe toxicity within 1 to 6 cycles of trastuzumab;
• ≥ 3 months after end of cancer treatment which included a year of trastuzumab without (severe) toxicity.
• severe toxicity during 1 to 3 cycles of cisplatin;
• ≥ 1 year after end of cancer treatment which included high-dose cisplatin without toxicity;
• severe toxicity during 1 to 3 cycles of bleomycin;
• ≥ 1 year after end of cancer treatment which included high-dose bleomycin without toxicity.

Severe toxicity is defined as any of grade 3 - 4 toxicity according to CTCAE 4.03.

A potential subject who meets any of the following exclusion criteria will be excluded from participation in this study:

1. history of cardiovascular disease prior to start of cancer treatment, as evidenced by any of the following: symptomatic or treated cardiovascular disease prior to start of cancer treatment; 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: extensive skin disorder precluding biopsy of unaffected skin; known allergy to local anaesthetics; use of anticoagulants and INR > 3;

4. pregnant or lactating female.

   Furthermore, there are specific exclusion criteria for the control groups:

5. history of cardiovascular disease during or after cancer treatment, as evidenced by any of the following: any symptomatic or treated cardiovascular disease; LVEF < 55% at any performed MUGA scan or echocardiography.

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Cross-Sectional

Number of groups / cohorts

8

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Anthracylines-treated with toxicity; Patients with toxicity during/after treatment with anthracylines.	Drug: Anthracyclines; Chemotherapy regimen containing anthracyclines.
Anthracyclines-treated without toxicity; Patients without toxicity during/after treatment with anthracylines.	Drug: Anthracyclines; Chemotherapy regimen containing anthracyclines.
Trastuzumab-treated with toxicity; Patients with toxicity during/after treatment with trastuzumab.	Drug: Trastuzumab; Systemic treatment including trastuzumab.
Trastuzumab-treated without toxicity; Patients without toxicity during/after treatment with trastuzumab.	Drug: Trastuzumab; Systemic treatment including trastuzumab.
Cisplatin-treated with toxicity; Patients with toxicity during/after treatment with cisplatin.	Drug: Cisplatin; Chemotherapy including cisplatin.
Cisplatin-treated without toxicity; Patients without toxicity during/after treatment with cisplatin.	Drug: Cisplatin; Chemotherapy including cisplatin.
Bleomycin-treated with toxicity; Patients with toxicity during/after treatment with bleomycin.	Drug: Bleomycin; Chemotherapy including bleomycin.
Bleomycin-treated without toxicity; Patients without toxicity during/after treatment with bleomycin.	Drug: Bleomycin; Chemotherapy including bleomycin.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparison between iPSC-derived cells	Comparison between iPSC-derived cells from toxicity cases and controls, for each of the four different agents.	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlate the findings from the iPSC-derived cells with the clinical phenotype of cardiovascular toxicity	Correlate the findings from the iPSC-derived cells with the clinical phenotype of (cardiovascular) toxicity, assessed by circulating biomarkers and cardiac or vascular imaging.	3 years

Collaborators and Investigators

• Sponsor: University Medical Center Groningen
• Investigators: Principal Investigator: J.A. Gietema, MD, PhD, University Medical Center Groningen

Study record dates

Study Major Dates

• Study Start (Actual): December 12, 2017
• Primary Completion (Estimated): January 1, 2024
• Study Completion (Estimated): January 1, 2024

Study Registration Dates

• First Submitted: June 22, 2017
• First Submitted That Met QC Criteria: June 22, 2017
• First Posted (Actual): June 26, 2017

Study Record Updates

• Last Update Posted (Estimated): November 14, 2023
• Last Update Submitted That Met QC Criteria: November 13, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: cisplatin; trastuzumab; toxicity; anthracyclines; bleomycin
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms, Second Primary; Antineoplastic Agents; Antineoplastic Agents, Immunological; Antibiotics, Antineoplastic; Trastuzumab; Bleomycin
• Other Study ID Numbers: 201700454

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