T-DM1 + Pertuzumab for Breast Cancer

Recruiting at 3 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Dana-Farber Cancer Institute

Must not be taking: Potent CYP3A4 inhibitors

Disqualifiers: Pregnancy, Active infection, Liver disease, Uncontrolled hypertension, 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: 6

Duration: 18 weeks

164 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This research study is studying a combination of drugs as a possible treatment for breast cancer that has tested positive for a protein called HER2. The names of the study interventions involved in this study are: * Trastuzumab emtansine (also called T-DM1) * Pertuzumab

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications, but it does mention that potent CYP3A4 inhibitors (a type of drug that affects how your body processes certain medications) should be avoided during the study. It's best to discuss your current medications with the study team.

Is the combination of T-DM1 and Pertuzumab safe for humans?

The combination of T-DM1 (Trastuzumab emtansine) and Pertuzumab has been studied for safety in patients with HER2-positive breast cancer. The studies show that the safety profile of this combination is consistent with what has been observed in previous studies of these drugs individually, indicating it is generally safe for human use. ^{1 2 3 4 5}

What makes the drug T-DM1 combined with Pertuzumab unique for treating HER2-positive breast cancer?

The combination of T-DM1 and Pertuzumab is unique because it targets two different parts of the HER2 protein on cancer cells, potentially overcoming resistance to T-DM1 alone and offering a new option for patients with advanced HER2-positive breast cancer. ^{1 3 5 6 7}

What data supports the effectiveness of the drug combination T-DM1 and Pertuzumab for breast cancer?

Research shows that combining T-DM1 with pertuzumab can be effective for treating HER2-positive breast cancer, even in cases where cancer cells have become resistant to T-DM1 alone. This combination has shown better tolerability and similar effectiveness compared to other treatments in advanced breast cancer. ^{3 5 8 9 10}

Who Is on the Research Team?

Otto Metzger, MD

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

This trial is for men and women over 18 with early-stage HER2+ breast cancer, who are in good health (ECOG 0 or 1), can provide tissue samples, and agree to use contraception. Excluded are those with active infections, liver disease, pregnancy/nursing status, significant neuropathy symptoms, other serious diseases that could interfere with treatment, prior treatment for current breast cancer or recent IV antibiotics.

Inclusion Criteria

The breast imaging should include the armpit on the same side.

I am fully active or can carry out light work.

My breast cancer is HER2-positive, Stage II or III, and my tumor is at least 2 cm big.

Exclusion Criteria

I currently have an infection that is not getting better.

I have not taken IV antibiotics for an infection in the last week.

I have high blood pressure or heart disease that is not well-managed.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive T-DM1 and Pertuzumab every 3 weeks for 6 cycles

18 weeks

6 visits (in-person)

Surgery

Excision of tumor/mastectomy of biopsy residual tumor within 42 days of the last cycle of therapy

6 weeks

Follow-up

Participants are monitored for disease and survival every 6 months for 5 years and annually until year 10

10 years

What Are the Treatments Tested in This Trial?

Interventions

• Excision of tumor/mastectomy
• Pertuzumab
• T-DM1

Trial Overview The study tests a combination of two drugs: Trastuzumab emtansine (T-DM1) and Pertuzumab as pre-operative treatments for HER2+ breast cancer. It aims to evaluate the effectiveness of this drug duo before surgical interventions like tumor excision or mastectomy.

How Is the Trial Designed?

Group I: T-DM1 and Pertuzumab Experimental Treatment 3 Interventions

T-DM1 3.6 mg per kg of body weight via IV every 3 weeks for 6 doses and Pertuzumab loading dose of 840 mg via IV on Cycle 1 Day 1 followed by maintenance dose of 420 mg via IV every 3 weeks for 6 doses. Excision of tumor/mastectomy of biopsy residual tumor within 42 days of the last cycle of therapy.

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?

Dana-Farber Cancer Institute

Lead Sponsor

Trials

1,128

Recruited

382,000+

Genentech, Inc.

Industry Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

Published Research Related to This Trial

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]

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 the phase 3 MARIANNE trial involving 1095 patients with HER2-positive advanced breast cancer, trastuzumab emtansine (T-DM1) demonstrated similar overall survival rates compared to trastuzumab plus a taxane, while showing better tolerability and fewer severe side effects.

Patients receiving T-DM1 had a longer median overall survival when they achieved an objective tumor response, indicating that T-DM1 is a viable first-line treatment option for those unsuitable for taxane-based therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab emtansine with or without pertuzumab versus trastuzumab with taxane for human epidermal growth factor receptor 2-positive advanced breast cancer: Final results from MARIANNE. Perez, EA., Barrios, C., Eiermann, W., et al.[2020]

In the KRISTINE study involving 444 patients with HER2-positive breast cancer, neoadjuvant treatment with trastuzumab emtansine plus pertuzumab (T-DM1+P) resulted in a lower pathologic complete response rate (44.4%) compared to docetaxel, carboplatin, trastuzumab plus pertuzumab (TCH+P) (55.7%), indicating that while T-DM1+P may be less effective in achieving complete tumor response, it has a better safety profile.

T-DM1+P was associated with significantly fewer grade 3 or greater adverse events (31.8% vs. 67.7% for TCH+P) during neoadjuvant treatment, although it led to more serious adverse events during adjuvant treatment, highlighting the need to balance efficacy and safety when choosing treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant Trastuzumab Emtansine and Pertuzumab in Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: Three-Year Outcomes From the Phase III KRISTINE Study. Hurvitz, SA., Martin, M., Jung, KH., et al.[2020]

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]

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 the phase III EMILIA trial, trastuzumab emtansine (T-DM1) demonstrated a significantly better safety profile compared to capecitabine plus lapatinib (CAP + LAP) in treating HER2-positive metastatic breast cancer, leading to fewer severe treatment-related adverse events.

The management of adverse events resulted in lower costs for T-DM1 (CAD 3380) compared to CAP + LAP (CAD 6901), indicating that T-DM1 not only provides effective treatment but also offers substantial savings to the Canadian public health-care system.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety Profile and Costs of Related Adverse Events of Trastuzumab Emtansine for the Treatment of HER2-Positive Locally Advanced or Metastatic Breast Cancer Compared to Capecitabine Plus Lapatinib from the Perspective of the Canadian Health-Care System. Piwko, C., Prady, C., Yunger, S., et al.[2019]

In a phase Ib/IIa study involving patients with HER2-positive metastatic breast cancer (MBC) and locally advanced breast cancer (LABC), the combination of trastuzumab emtansine (T-DM1) with docetaxel showed high efficacy, achieving an 80% objective response rate in MBC and a 60.3% pathologic complete response rate in LABC.

Despite the promising efficacy, nearly half of the patients experienced adverse events (AEs) that required dose modifications, with neutropenia being the most common severe AE, affecting 72% of MBC patients and 29% of LABC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab emtansine (T-DM1) plus docetaxel with or without pertuzumab in patients with HER2-positive locally advanced or metastatic breast cancer: results from a phase Ib/IIa study. Martin, M., Fumoleau, P., Dewar, JA., et al.[2022]

Citations

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. 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]

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

Trastuzumab emtansine with or without pertuzumab versus trastuzumab with taxane for human epidermal growth factor receptor 2-positive advanced breast cancer: Final results from MARIANNE. [2020]

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

Neoadjuvant Trastuzumab Emtansine and Pertuzumab in Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: Three-Year Outcomes From the Phase III KRISTINE Study. [2020]

5. 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]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Drug interaction potential of trastuzumab emtansine (T-DM1) combined with pertuzumab in patients with HER2-positive metastatic breast cancer. [2019]

7. 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]

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

Safety Profile and Costs of Related Adverse Events of Trastuzumab Emtansine for the Treatment of HER2-Positive Locally Advanced or Metastatic Breast Cancer Compared to Capecitabine Plus Lapatinib from the Perspective of the Canadian Health-Care System. [2019]

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

Trastuzumab Emtansine With or Without Pertuzumab Versus Trastuzumab Plus Taxane for Human Epidermal Growth Factor Receptor 2-Positive, Advanced Breast Cancer: Primary Results From the Phase III MARIANNE Study. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Trastuzumab emtansine (T-DM1) plus docetaxel with or without pertuzumab in patients with HER2-positive locally advanced or metastatic breast cancer: results from a phase Ib/IIa study. [2022]