Safety of Continuing HER-2 Directed Therapy in Overt Left Ventricular Dysfunction

Official title

Safety of Continuing HER-2 Directed Therapy in Overt Left Ventricular Dysfunction: A Randomized, Controlled Trial

Overview

Trastuzumab is an important treatment for HER 2 positive breast cancer. But trastuzumab can cause injury to the heart, and this is one of the main reasons it cannot be administered as planned. Heart injury can often be successfully treated using cardiac medications. The objectives of SCHOLAR-2 are to evaluate whether is it safe and effective to continue trastuzumab, pertuzumab or trastuzumab-emtansine (T-DM1) in patients with early stage HER-2 positive breast cancer despite mild, minimally symptomatic or asymptomatic systolic left ventricular dysfunction as compared with a guideline-driven approach of withholding or discontinuing trastuzumab, pertuzumab or trastuzumab-emtansine (T-DM1). In SCHOLAR-2, we will compare two thresholds of withholding or discontinuing trastuzumab/pertuzumab/trastuzumab-emtansine: a threshold that is currently advocated for by existing treatment practice guidelines versus a more aggressive threshold that allows trastuzumab/pertuzumab/trastuzumab-emtansine to continue at lower levels of LVEF than currently supported by guideline documents.

Detailed description

SCHOLAR-2 is a Phase II open-label randomized controlled trial with blinded outcome event ascertainment with a target sample size of 130.

Control Group Recommendations for continuing or holding trastuzumab, pertuzumab, or trastuzumab-emtansine (T-DM1) for the control group are guided by an adaptation of the 2008 Canadian recommendations.

Intervention Group The intervention group will continue to receive trastuzumab, pertuzumab, or trastuzumab-emtansine (T-DM1) in the setting of asymptomatic decline in LVEF up to an LVEF of 40% as outlined in the criteria listed in Table 3. For reasons of practicality, in the intervention group, the first dose of trastuzumab, pertuzumab, or trastuzumab-emtansine (T-DM1) after randomization can be administered up to 3 weeks late. This will allow time for the participant to be reviewed by a cardiologist and to receive ACE-I/angiotensin receptor blocker and/or beta-blocker, and for dose titration.

Study assessments will occur:

1. 3 weeks after randomization 2. 6 weeks after randomization 3. Follow-up at every 3 months thereafter until 12 months after the last dose of trastuzumab, pertuzumab, or trastuzumab-emtansine (T-DM1)

Interventions

• Drug Trastuzumab
  Trastuzumab is a HER-2 targeting monoclonal antibody that improves overall survival and reduces the risk of recurrent disease in early stage HER-2 positive breast cancer.
• Drug Pertuzumab
  Pertuzumab (also called 2C4, trade name Perjeta) is a monoclonal antibody used in combination with trastuzumab and docetaxel for the treatment of metastatic HER2-positive breast cancer; it also used in the same combination as a neoadjuvant in early HER2-positive breast cancer
• Drug Trastuzumab emtansine
  Ado-trastuzumab emtansine is approved to treat: Breast cancer that is HER2 positive and has already been treated with a taxane and trastuzumab.

Primary outcome measures

• primary efficacy outcome [Time frame: one year]
• co-primary safety outcomes [Time frame: one year]

Secondary outcome measures (1)

• secondary outcome measures the composite of NYHA class III or IV heart failure, breast cancer relapse, or all-cause mortality. [Time frame: one year]

Eligibility criteria

Inclusion criteria

• Stage I-III HER-2 positive breast cancer
• Receiving adjuvant or neoadjuvant therapy with trastuzumab, pertuzumab, or trastuzumab-emtansine (T-DM1)
• Evidence of left ventricular dysfunction, as defined by at least one of:

a) LVEF < 54% or b) LVEF ≥54% and either i) fall in LVEF of ≥15% from prior to trastuzumab, pertuzumab, or trastuzumab-emtansine (T-DM1) exposure, or ii) New York Heart Association (NYHA) class II heart failure symptoms within the past 6 months

Exclusion criteria

• Current use of both angiotensin converting enzyme inhibitor (ACEI) /angiotensin receptor blocker (ARB) and beta-blocker
• Contra-indication to both ACE-I/ARB and beta-blockers
• NYHA class III or IV heart failure
• LVEF <40%
• Systolic blood pressure <100mmHg
• Current or planned pregnancy or breastfeeding

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Brazil · 4 centers

• Hospital de Clínicas de Porto Alegre — Porto Alegre
• Irmandade Da Santa Casa De Misericórdia De Porto Alegre — Porto Alegre
• Hospital Alemão Oswaldo Cruz — São Paulo
• Clínica de Pesquisa e Centro de Estudos em Oncologia Ginecológica e Mamária Ltda — São Paulo

Canada · 3 centers

• Juravnski Cancer Centre — Hamitlon
• Ottawa Hospital Research Institute — Ottawa
• Toronto General Hospital, University Health Network — Toronto

Russia · 1 center

• E.Meshalkin National medical research center of the Ministry of Health of the Russian Fede — Novosibirsk

Identifiers

NCT: NCT04680442 · PHRI.SCHOLAR-2

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗