Clinical trial NCT04680442: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Breast Cancer
Heart Failure
Lead sponsor: Population Health Research Institute
Sponsor class: OTHER
First posted: 2020-12-23
Enrollment: 130
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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)

Eligibility criteria: Inclusion Criteria:

1. Stage I-III HER-2 positive breast cancer
2. Receiving adjuvant or neoadjuvant therapy with trastuzumab, pertuzumab, or trastuzumab-emtansine (T-DM1)
3. 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:

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

Primary outcomes:
measure: primary efficacy outcome
timeFrame: one year
measure: co-primary safety outcomes
timeFrame: one year
Secondary outcomes:
measure: secondary outcome measures the composite of NYHA class III or IV heart failure, breast cancer relapse, or all-cause mortality.
timeFrame: one year
Other outcomes:
Locations:
city: Porto Alegre
country: Brazil
facility: Hospital de Clínicas de Porto Alegre
state: Rio Grande do Sul
city: Porto Alegre
country: Brazil
facility: Irmandade Da Santa Casa De Misericórdia De Porto Alegre
state: Rio Grande do Sul
city: São Paulo
country: Brazil
facility: Hospital Alemão Oswaldo Cruz
city: São Paulo
country: Brazil
facility: Clínica de Pesquisa e Centro de Estudos em Oncologia Ginecológica e Mamária Ltda
city: Hamitlon
country: Canada
facility: Juravnski Cancer Centre
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa Hospital Research Institute
state: Ontario
city: Toronto
country: Canada
facility: Toronto General Hospital, University Health Network
state: Ontario
city: Novosibirsk
country: Russian Federation
facility: E.Meshalkin National medical research center of the Ministry of Health of the Russian Federation
Study officials:
affiliation: McMaster University
name: Darryl Leong, PhD. MBBSm
role: PRINCIPAL_INVESTIGATOR
affiliation: Hamilton Health Sciences Corporation
name: Som Mukherjee, MD MSc FRCPC
role: PRINCIPAL_INVESTIGATOR
References: