HER-2 Directed Therapy for Heart Failure

(SCHOLAR-2 Trial)

Recruiting in Palo Alto (17 mi)

+6 other locations

Overseen by Darryl Leong, MD

Age: Any Age

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Population Health Research Institute

Must not be taking: Ace inhibitors, Beta-blockers

Disqualifiers: Severe heart failure, Low blood pressure, others

No Placebo Group

Prior Safety Data

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are currently using both ACE inhibitors (a type of heart medication) and beta-blockers.

What data supports the effectiveness of the drug Pertuzumab, Perjeta, Trastuzumab, Herceptin, Trazimera, Herzuma, Ontruzant, Trastuzumab emtansine, Kadcyla, ado-trastuzumab emtansine, trastuzumab-DM1, T-DM1 for heart failure?

The combination of pertuzumab and trastuzumab has shown effectiveness in treating HER2-positive metastatic breast cancer, particularly in cases resistant to other treatments, by improving progression-free and overall survival. While this data is specific to cancer, it suggests potential benefits of these drugs in targeting HER2-related conditions. ^{1 2 3 4 5}

Is HER-2 directed therapy generally safe for humans?

HER-2 directed therapies like pertuzumab and trastuzumab emtansine (T-DM1) have been studied for safety in patients with HER2-positive breast cancer. While they are generally well tolerated, there is a potential risk of heart-related side effects, such as changes in heart rhythm and heart function, which should be monitored during treatment. ^{4 6 7 8 9}

How is the drug Pertuzumab, Trastuzumab, and Trastuzumab emtansine unique for treating heart failure?

This drug combination is unique because it targets the HER-2 protein, which is not a standard approach in heart failure treatment. Traditional heart failure therapies focus on managing symptoms and neurohormonal pathways, while this treatment may offer a novel mechanism by directly targeting specific proteins involved in heart function. ^{10 11 12 13 14}

Research Team

Som Mukherjee, MD MSc FRCPC

Principal Investigator

Hamilton Health Sciences Corporation

Darryl Leong, MD

Principal Investigator

McMaster University

Eligibility Criteria

This trial is for patients with early stage HER-2 positive breast cancer who are undergoing treatment with trastuzumab, pertuzumab, or T-DM1 and have mild heart issues. They must not be pregnant, breastfeeding, or have severe heart failure or very low blood pressure.

Inclusion Criteria

My breast cancer is at stage I-III and is HER2 positive.

My heart function is below normal or has worsened after cancer treatment.

I am currently on treatment with trastuzumab, pertuzumab, or T-DM1.

Exclusion Criteria

Your heart's pumping function is less than 40%.

Current or planned pregnancy or breastfeeding

I am currently taking both ACE inhibitors and beta-blockers.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive trastuzumab, pertuzumab, or trastuzumab-emtansine (T-DM1) with monitoring of LVEF and potential cardiologist review

12 months

Visits at 3 weeks, 6 weeks, and every 3 months thereafter

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Treatment Details

Interventions

• Pertuzumab (Monoclonal Antibodies)
• Trastuzumab (Monoclonal Antibodies)
• Trastuzumab emtansine (Monoclonal Antibodies)

Trial Overview The study tests if it's safe to continue using HER-2 targeted therapies like trastuzumab, pertuzumab, and T-DM1 in patients with some heart dysfunction versus stopping them as current guidelines suggest.

Participant Groups

Group I: Intervention Group Experimental Treatment 3 Interventions

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.

Group II: Control Group Active Control 3 Interventions

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.

Pertuzumab is already approved in Canada, Japan for the following indications:

Approved in Canada as Perjeta for:

• Early breast cancer
• Metastatic breast cancer

Approved in Japan as Perjeta for:

• Early breast cancer
• Metastatic breast cancer

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

Juravnski Cancer Centre Hamitlon, Canada

Ottawa Hospital Research Institute Ottawa, Canada

Toronto General Hospital, University Health Network Toronto, Canada

Who Is Running the Clinical Trial?

Population Health Research Institute

Lead Sponsor

Trials

165

Patients Recruited

717,000+

Findings from Research

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination efficacy of pertuzumab and trastuzumab for trastuzumab emtansine-resistant cells exhibiting attenuated lysosomal trafficking or efflux pumps upregulation. Yamashita-Kashima, Y., Shu, S., Osada, M., et al.[2021]

Combining trastuzumab emtansine (T-DM1) with pertuzumab showed enhanced antitumor activity in both cultured tumor cells and mouse models of HER2-positive cancer, indicating a synergistic effect in inhibiting cancer cell growth.

In a phase Ib/II study involving patients with metastatic breast cancer, the combination was well-tolerated with mostly mild adverse events, and T-DM1 could be administered at the maximum tolerated dose, suggesting promising safety and preliminary efficacy for this treatment strategy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dual targeting of HER2-positive cancer with trastuzumab emtansine and pertuzumab: critical role for neuregulin blockade in antitumor response to combination therapy. Phillips, GD., Fields, CT., Li, G., et al.[2022]

In a study of 74 women with stage IV breast cancer, those with consistent HER2 positive status had better progression-free survival (PFS) when treated with taxane-trastuzumab (± pertuzumab) compared to those who lost HER2 expression, highlighting the importance of HER2 status in treatment efficacy.

Patients who converted from HER2 negative to positive status experienced significant benefits from first-line treatments, suggesting that re-evaluating HER2 status in metastatic lesions can guide more effective treatment decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of anti-HER2 therapy in metastatic breast cancer by discordance of HER2 expression between primary and metastatic breast cancer. Van Raemdonck, E., Floris, G., Berteloot, P., et al.[2021]

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of T-DM1 Plus Neratinib in Patients With Metastatic HER2-Positive Breast Cancer: NSABP Foundation Trial FB-10. Abraham, J., Montero, AJ., Jankowitz, RC., et al.[2020]

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metastatic Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: Current Treatment Standards and Future Perspectives. Dormann, C.[2022]

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiotoxic effects of the novel approved anti-ErbB2 agents and reverse cardioprotective effects of ranolazine. De Lorenzo, C., Paciello, R., Riccio, G., et al.[2022]

In a phase 2 study involving patients with HER2-positive metastatic breast cancer, T-DM1 did not significantly affect the QTc interval, indicating a favorable safety profile regarding heart rhythm risks.

The combination of pertuzumab and T-DM1 was well tolerated, showing no new safety concerns, which supports further research into both treatments for this type of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of Trastuzumab Emtansine (T-DM1) on QT Interval and Safety of Pertuzumab Plus T-DM1 in Patients With Previously Treated Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer. Gupta, M., Wang, B., Carrothers, TJ., et al.[2022]

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase IIa trial of trastuzumab emtansine with pertuzumab for patients with human epidermal growth factor receptor 2-positive, locally advanced, or metastatic breast cancer. Miller, KD., Diéras, V., Harbeck, N., et al.[2022]

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of the addition of pertuzumab to T-DM1 ± taxane in patients with HER2-positive, locally advanced or metastatic breast cancer: a pooled analysis. Zhang, J., Li, J., Zhu, C., et al.[2022]

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Relative Efficacy of Sacubitril-Valsartan, Vericiguat, and SGLT2 Inhibitors in Heart Failure with Reduced Ejection Fraction: a Systematic Review and Network Meta-Analysis. Aimo, A., Pateras, K., Stamatelopoulos, K., et al.[2022]

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Chronic heart failure--the epidemic of the 21st century]. Czuriga, I.[2014]

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New medications for heart failure. Gordin, JS., Fonarow, GC.[2023]

The REFORM trial is a phase IV study investigating the safety and efficacy of the SGLT2 inhibitor dapagliflozin in diabetic patients with heart failure, utilizing various advanced assessments over a one-year period.

Preliminary evidence suggests that SGLT2 inhibitors like dapagliflozin may offer significant cardiovascular benefits, including reductions in heart failure hospitalizations and cardiovascular death, potentially making them a preferred treatment option for patients with both diabetes and heart failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Research into the effect Of SGLT2 inhibition on left ventricular remodelling in patients with heart failure and diabetes mellitus (REFORM) trial rationale and design. Singh, JS., Fathi, A., Vickneson, K., et al.[2022]

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Where are we in 2021 with heart failure with reduced ejection fraction?-current outlook and expectations from new promising clinical trials. Dębska-Kozłowska, A., Książczyk, M., Lelonek, M.[2022]

References

1. Germany pubmed.ncbi.nlm.nih.gov

Combination efficacy of pertuzumab and trastuzumab for trastuzumab emtansine-resistant cells exhibiting attenuated lysosomal trafficking or efflux pumps upregulation. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Dual targeting of HER2-positive cancer with trastuzumab emtansine and pertuzumab: critical role for neuregulin blockade in antitumor response to combination therapy. [2022]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Efficacy of anti-HER2 therapy in metastatic breast cancer by discordance of HER2 expression between primary and metastatic breast cancer. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of T-DM1 Plus Neratinib in Patients With Metastatic HER2-Positive Breast Cancer: NSABP Foundation Trial FB-10. [2020]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Metastatic Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: Current Treatment Standards and Future Perspectives. [2022]

6. New Zealand pubmed.ncbi.nlm.nih.gov

Cardiotoxic effects of the novel approved anti-ErbB2 agents and reverse cardioprotective effects of ranolazine. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Effects of Trastuzumab Emtansine (T-DM1) on QT Interval and Safety of Pertuzumab Plus T-DM1 in Patients With Previously Treated Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Phase IIa trial of trastuzumab emtansine with pertuzumab for patients with human epidermal growth factor receptor 2-positive, locally advanced, or metastatic breast cancer. [2022]

9. New Zealand pubmed.ncbi.nlm.nih.gov

Safety and efficacy of the addition of pertuzumab to T-DM1 ± taxane in patients with HER2-positive, locally advanced or metastatic breast cancer: a pooled analysis. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Relative Efficacy of Sacubitril-Valsartan, Vericiguat, and SGLT2 Inhibitors in Heart Failure with Reduced Ejection Fraction: a Systematic Review and Network Meta-Analysis. [2022]

11. Hungary pubmed.ncbi.nlm.nih.gov

[Chronic heart failure--the epidemic of the 21st century]. [2014]

12. United States pubmed.ncbi.nlm.nih.gov

New medications for heart failure. [2023]

13. England pubmed.ncbi.nlm.nih.gov

Research into the effect Of SGLT2 inhibition on left ventricular remodelling in patients with heart failure and diabetes mellitus (REFORM) trial rationale and design. [2022]

14. United States pubmed.ncbi.nlm.nih.gov

Where are we in 2021 with heart failure with reduced ejection fraction?-current outlook and expectations from new promising clinical trials. [2022]