HER-2 Directed Therapy for Heart Failure

(SCHOLAR-2 Trial)

Recruiting at 6 trial locations

Overseen By Sumathy Rangarajan, MSc

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: Population Health Research Institute

Must not be taking: Ace inhibitors, Beta-blockers

Disqualifiers: Severe heart failure, Low blood pressure, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 3

Duration: 12 months

130 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the safety and effectiveness of continuing specific breast cancer treatments (trastuzumab, pertuzumab, or T-DM1) despite mild heart dysfunction. Typically, these treatments stop if they affect the heart, but the researchers aim to determine if continuing them with close monitoring is a better option. Participants should have early-stage HER-2 positive breast cancer and mild heart issues, such as changes in heart function without serious symptoms. The trial includes two groups: one follows current guidelines on stopping treatment, and the other continues treatment under certain conditions. The study seeks to find the best balance between treating cancer and protecting the heart. As a Phase 2 trial, it focuses on measuring the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to important findings.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the medications trastuzumab, pertuzumab, and trastuzumab emtansine (T-DM1) can be linked to heart issues, but they remain generally safe with careful monitoring. Studies have found that trastuzumab may cause heart problems, though these are often manageable. Regular heart check-ups can help detect any issues early. Pertuzumab carries a slightly higher risk of heart problems compared to a placebo, but most issues are mild and asymptomatic. T-DM1 also presents a low rate of heart-related side effects, with most being minor changes in heart function. Overall, these treatments can be safe with close monitoring of heart health. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments—pertuzumab, trastuzumab, and trastuzumab emtansine—because they specifically target the HER-2 protein, which plays a role in some types of heart failure. Unlike standard heart failure treatments such as ACE inhibitors or beta-blockers, these drugs are designed to address heart issues related to cancer therapies by focusing directly on HER-2. This targeted approach could offer a more precise treatment option for patients whose heart failure is linked to HER-2, potentially leading to better outcomes.

What evidence suggests that this trial's treatments could be effective for heart failure?

This trial will compare the effects of continuing HER2-directed therapies in patients with heart failure. Research has shown that trastuzumab, pertuzumab, and trastuzumab emtansine (T-DM1) effectively treat HER2-positive breast cancer. When combined with trastuzumab, pertuzumab can extend the time before cancer worsens by over six months. However, it may cause heart problems in a small number of patients, with only 1.1% developing heart failure. Trastuzumab presents a varied risk of heart issues, with some studies showing up to 35.6% of patients experiencing heart function problems. T-DM1 has a lower rate of heart issues, mostly involving slight drops in heart function. Overall, these treatments are strong against cancer but require careful heart monitoring. Participants in this trial will join either a control group or an intervention group to evaluate the impact on heart function. ^{2 5 6 7 8}

Who Is on the Research Team?

Som Mukherjee, MD MSc FRCPC

Principal Investigator

Hamilton Health Sciences Corporation

Darryl Leong, MD

Principal Investigator

McMaster University

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Pertuzumab
• Trastuzumab
• Trastuzumab emtansine

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.

How Is the Trial Designed?

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 European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Perjeta for:

• Early breast cancer
• Metastatic breast cancer

Approved in United States as Perjeta for:

• Early breast cancer
• Metastatic breast cancer

Approved in Canada as Perjeta for:

• Early breast cancer
• Metastatic breast cancer

Approved in Japan as Perjeta for:

• Early breast cancer
• Metastatic breast cancer

Who Is Running the Clinical Trial?

Population Health Research Institute

Lead Sponsor

Trials

165

Recruited

717,000+

Published Research Related to This Trial

Pertuzumab and TDM1, both approved for breast cancer treatment, were found to have significant cardiotoxic effects, with TDM1 showing the strongest impact on cardiac cell viability and function in both in vitro and in vivo models.

Ranolazine was effective in reducing the cardiotoxic side effects of pertuzumab and TDM1, suggesting it could be a potential cardioprotective agent when used alongside these cancer therapies.

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 study involving 27 patients with HER2-positive metastatic breast cancer who had progressed on previous therapies, the combination of ado-trastuzumab emtansine (T-DM1) and neratinib showed promising efficacy, with 63% of evaluable patients achieving an objective response.

The recommended phase II dose for this combination was established as T-DM1 at 3.6 mg/kg and neratinib at 160 mg/d, with manageable safety profiles, although some patients experienced grade 3 toxicities like diarrhea and nausea.

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]

The combination of tucatinib, trastuzumab, and capecitabine has shown significant improvements in progression-free survival (PFS) and overall survival (OS) for patients with HER2-positive breast cancer who have previously received standard treatments, including those with brain metastases.

New therapies like neratinib and margetuximab also demonstrate longer PFS compared to traditional treatments, although improvements in overall survival have not yet been established, highlighting the ongoing need for effective options in later lines of therapy.

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]

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]

In a phase IIa study involving 64 patients with HER2-positive metastatic breast cancer, the combination of trastuzumab emtansine (T-DM1) and pertuzumab showed an overall objective response rate (ORR) of 41%, with a higher ORR of 57% in first-line patients, indicating promising efficacy for this treatment.

The combination therapy was generally safe, with common side effects including fatigue (61%) and nausea (50%), and no unexpected toxicities were reported, suggesting that this treatment can be administered at full doses without significant safety concerns.

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]

In T-DM1-resistant HER2-positive breast cancer cells, the combination of trastuzumab and pertuzumab (TRAS + PER) showed enhanced antitumor effects, significantly inhibiting cell proliferation and inducing apoptosis compared to either drug alone.

The study demonstrated that TRAS + PER effectively suppressed tumor growth in a xenograft model of T-DM1-resistant cancer, suggesting it could be a promising treatment option for patients who develop resistance to T-DM1 while maintaining HER2 expression.

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]

New medications, ivabradine and sacubitril/valsartan, have been approved for heart failure with reduced ejection fraction, marking the first new class of treatments since 2005, and they have shown improved clinical outcomes.

Ivabradine works by decreasing heart rate through targeting If channels, while sacubitril/valsartan enhances beneficial vasodilatory peptides and reduces all-cause mortality, demonstrating effectiveness alongside existing therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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

Guideline-directed optimal medical therapy is crucial for treating heart failure with reduced ejection fraction (HFrEF), but despite this, patients still face high mortality rates, highlighting the need for improved treatment strategies.

Recent trials following the PARADIGM-HF study are exploring new medications and individualized treatment approaches, aiming to simplify dosing and enhance therapeutic effects for HFrEF patients.

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]

Heart failure remains a significant public health issue with high mortality rates, even with optimal medical treatment, highlighting the need for ongoing advancements in management strategies.

Current treatments focus on blocking harmful neurohormonal systems, using medications like diuretics, ACE inhibitors, and beta-blockers, while advanced cases may require additional therapies or surgical interventions such as heart transplants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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

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]

SGLT2 inhibitors (SGLT2i) showed a trend towards reducing the risk of cardiovascular death or heart failure hospitalization compared to sacubitril/valsartan and vericiguat, indicating their potential effectiveness in heart failure treatment.

SGLT2i demonstrated the greatest reduction in heart failure hospitalization rates compared to standard care and vericiguat, suggesting they may be the most effective therapy among the treatments analyzed.

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]

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]

In a review of six studies involving 996 patients with HER2-positive breast cancer, the addition of pertuzumab to trastuzumab emtansine (T-DM1) ± taxane did not significantly improve objective response or clinical benefit rates compared to T-DM1 alone.

While the combination treatment was associated with increased risks of certain adverse events like diarrhea and rash, it also showed a decreased risk of thrombocytopenia, indicating a complex safety profile that requires careful monitoring.

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8640623/

Pertuzumab Cardiotoxicity in Patients With HER2-Positive ... In this analysis, a decrease in LVEF of ≥ 10% to < 50% occurred in 6.5% of pertuzumab recipients, and HF occurred in 1.1%. In Lenihan's paper, no data on ...

2. perjeta-hcp.com perjeta-hcp.com/adjuvant/efficacy.html

PERJETA® (pertuzumab) Adjuvant Outcomes | HCP PERJETA can cause subclinical and clinical cardiac failure manifesting as decreased left ventricular ejection fraction (LVEF) and congestive heart failure (CHF) ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3607520/

Cardiac Tolerability of Pertuzumab Plus Trastuzumab Plus ... Pertuzumab, trastuzumab, and docetaxel significantly improved median progression-free survival by 6.1 months and resulted in a significant improvement in ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S0923753419344497

Pooled analysis of cardiac safety in patients with cancer ... Patients treated with pertuzumab experienced relatively low levels of asymptomatic LVSD or symptomatic HF. There was no notable increase in cardiac side-effects ...

5. nejm.org nejm.org/doi/full/10.1056/NEJMoa1703643

Adjuvant Pertuzumab and Trastuzumab in Early HER2 ... The NeoSphere trial showed a numerically higher 5-year rate of progression-free survival among patients receiving only 12 weeks of pertuzumab than among ...

6. perjeta-hcp.com perjeta-hcp.com/neoadjuvant/safety.html

PERJETA® (pertuzumab) Neoadjuvant Safety | HCP PERJETA can cause left ventricular dysfunction, including symptomatic heart failure · Assess LVEF prior to initiation of PERJETA and at regular intervals during ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/21665955/

Pooled analysis of cardiac safety in patients with ... - PubMed Conclusions: Patients treated with pertuzumab experienced relatively low levels of asymptomatic LVSD or symptomatic HF. There was no notable increase in cardiac ...

8. esmoopen.com esmoopen.com/article/S2059-7029(22)00406-9/fulltext

Cardiac safety of dual anti-HER2 blockade with ... This exploratory analysis of the cardiac safety of pertuzumab and trastuzumab in the APHINITY trial found that, after 74 months of median ...