PROACT: Can we Prevent Chemotherapy-related Heart Damage in Patients With Breast Cancer and Lymphoma? (PROACT)

Preventing Cardiac Damage in Patients Treated for Breast Cancer and Lymphoma: a Phase 3 Randomised, Open Label, Blinded Endpoint, Superiority Trial of Enalapril to Prevent Anthracycline-induced CardioToxicity

PROACT will establish the effectiveness of the angiotensin-converting enzyme inhibitor (ACEI) enalapril maleate (enalapril) in preventing cardiotoxicity in patients with breast cancer and non-Hodgkin lymphoma undergoing adjuvant epirubicin-based chemotherapy.

Study Overview

• Status: Completed
• Conditions: Breast Cancer; Non Hodgkin Lymphoma
• Intervention / Treatment: Drug: Enalapril

Detailed Description

PROACT is a phase 3 randomised, open label, blinded endpoint, superiority trial of enalapril to prevent anthracycline-induced in patients treated for breast cancer and lymphoma.

Anthracyclines used in the treatment of breast cancer cause damage to heart muscle cells; this results in cell death (cardiotoxicity). In UK contemporary practice, epirubicin is the most frequently used anthracycline.

Patients due to receive adjuvant anthracycline chemotherapy (planned epirubicin dose >300mg/m2) for breast cancer at four specialist centres in the North of England will be invited to participate. 170 eligible patients will be randomised in a 1:1 ratio, to either enalapril plus usual care or to usual care. Enalapril will be commenced prior to the first anthracycline dose, titrated to a maximum tolerated dose, and continued during chemotherapy. Chemotherapy will continue per usual care; typically six treatment cycles. Patients will have a blood test performed at the end of each chemotherapy cycle to measure cardiac troponin, and at one month following the last epirubicin dose. Investigators and patients will be blinded to the troponin results. Patients will have an echocardiogram at baseline and following their chemotherapy; they will be assessed in a blinded manner by a central Core Laboratory.

• Study Type: Interventional
• Enrollment (Actual): 111
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: David Austin; Phone Number: 55909 01642 850850; Email: david.austin@nhs.net
• Study Contact Backup: Name: Victoria Hildreth; Phone Number: 0191 208 5825; Email: PROACT@ncl.ac.uk

Study Locations

• United Kingdom
  • Teesside
    • Middlesbrough, Teesside, United Kingdom, TS4 3BW
      • South Tees Hospitals NHS FT

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Written informed consent.
• Adult patients with histopathologically* confirmed breast carcinoma who have received surgery for their breast cancer; planned to receive 6 cycles of EC 90 (total planned dose 540mg/m2 epirubicin) or FEC 75 (total planned dose 450mg/m2 epirubicin) adjuvant chemotherapy regimen. Patients with HER2+ breast cancer are eligible for inclusion.

OR

• Adult patients with histopathologically confirmed non-Hodgkin lymphoma (NHL), planned to receive 6 cycles of R-CHOP or CHOP (total planned dose 300mg/m2 doxorubicin) chemotherapy**

  • Patients with HER2+ breast cancer are eligible for inclusion. ** Patients who will receive an alternative anti-CD20 monoclonal antibody are eligible (for example O-CHOP), as long as the total planned doxorubicin dose is ≥300mg/m2 over 6 cycles

Exclusion Criteria:

• Positive baseline cardiac troponin T (≥14ng/L);
• known contraindication to ACE inhibitor e.g. renal artery stenosis, severe aortic stenosis;
• are taking, or have a previous intolerance to ACEI (e.g. angioedema);
• patient already taking other agents acting on the renin-angiotensin-aldosterone system e.g. Aliskiren, angiotensin receptor blockers (ARBs), Entresto (sacubitril/valsartan), spironolactone, eplerenone;
• LVEF <50%*;
• estimated GFR < 30 mL/min/1.73m2 at baseline;
• hyperkalaemia defined as serum potassium ≥5.5mmol/L;
• symptomatic hypotension, or Systolic Blood Pressure <100mmHg;
• poorly-controlled hypertension (Blood Pressure >160/100mmHg**, or ambulatory BP of 150/95mmHg);
• previous myocardial infarction;
• known metastatic breast cancer;
• previous exposure to anthracycline chemotherapy;
• are pregnant or breastfeeding;
• previous Herceptin treatment or planned Herceptin treatment within four weeks following anthracycline chemotherapy;
• for patients of childbearing potential: refusal to use adequate contraception throughout the trial;***
• any other invasive cancer diagnosed and treated in the past 5 years;
• symptomatic or severe asymptomatic radiation-induced cardiac disease;
• judgement by the investigator that the patient has a prognosis of < 1 year or are unlikely to complete 6 cycles of chemotherapy;
• judgement by the investigator that the patient is high risk for tumour lysis syndrome (applicable only to NHL patients);

• judgement by the Investigator that the patient should not participate in the study, for example, if the patient is unlikely to comply with study procedures, restrictions, and requirements.

  *<50% as defined by Simpson's biplane method; if absolute measurements are not possible, then a visually normal assessment of LVEF is acceptable for inclusion.

  **White coat hypertension is more common, and should be ruled out by an ambulatory blood pressure monitor

  ***Female patients between the ages of 18 and 50 will receive a pregnancy test at baseline. Adequate methods of contraception are those that can achieve a failure rate of less than

  1% per year when used consistently and correctly, such methods include:

• combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation

  • oral
  • intravaginal
  • transdermal

• progestogen-only hormonal contraception associated with inhibition of ovulation

  • oral
  • injectable
  • implantable
• intrauterine device (IUD)
• intrauterine hormone-releasing system (IUS)
• bilateral tubal occlusion
• vasectomy/vasectomised partner
• true sexual abstinence

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention	Drug: Enalapril; Enalapril is an Angiotensin Converting Enzyme (ACE) inhibitor which supresses the reninangiotensin-aldosterone system resulting in increased plasma renin activity and decreased aldosterone secretion
No Intervention: Standard care

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cardiac troponin T release	Cardiac troponin T release during anthracycline treatment	One month after last dose of anthracycline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cardiac function	Cardiac function assessed by echocardiogram	One month after last dose of anthracycline
Adherence to enalapril	Ability of participant to adhere to enalapril	One month after last dose of anthracycline
Adverse Events / Reactions	Number and severity of Adverse Events and Reactions	One month after last dose of anthracycline
Anxiety or distress related to trial participation	Anxiety or distress related to trial participation	One month after last dose of anthracycline
Cancer and chemotherapy outcomes	Cancer and chemotherapy outcomes in the population under study	One month after last dose of anthracycline
Cardiac troponin I release	cardiac troponin I release during anthracyline treatment	One month after last dose of anthracycline

Collaborators and Investigators

• Sponsor: South Tees Hospitals NHS Foundation Trust
• Collaborators: Newcastle University; Newcastle-upon-Tyne Hospitals NHS Trust; University of Durham
• Investigators: Study Chair: Victoria Hildreth, Study Chair

Study record dates

Study Major Dates

• Study Start (Actual): October 4, 2017
• Primary Completion (Actual): August 4, 2023
• Study Completion (Actual): August 4, 2023

Study Registration Dates

• First Submitted: August 24, 2017
• First Submitted That Met QC Criteria: August 25, 2017
• First Posted (Actual): August 29, 2017

Study Record Updates

• Last Update Posted (Actual): February 20, 2024
• Last Update Submitted That Met QC Criteria: February 16, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Neoplasms by Site; Breast Diseases; Lymphoma; Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Enzyme Inhibitors; Protease Inhibitors; Angiotensin-Converting Enzyme Inhibitors; Enalapril
• Other Study ID Numbers: 2016152

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No