T-DM1 + Tucatinib for Breast Cancer

Not currently recruiting at 1269 trial locations

Overseen By Leon C. Hwang

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Alliance for Clinical Trials in Oncology

Must be taking: Taxane, Trastuzumab

Must not be taking: CYP3A4 inhibitors, CYP2C8 inducers

Disqualifiers: Stage IV cancer, Hepatitis B/C, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 42 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to evaluate how well a combination of two drugs, trastuzumab emtansine (T-DM1) and tucatinib, can prevent breast cancer recurrence in individuals with high-risk, HER2-positive breast cancer. T-DM1 targets and kills cancer cells, while tucatinib inhibits cancer cell growth. Participants will receive either both T-DM1 and tucatinib or T-DM1 with a placebo. Suitable candidates for this trial include those with HER2-positive breast cancer who have residual disease after surgery and have previously received specific chemotherapy treatments. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants an opportunity to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot use strong CYP3A4 or CYP2C8 inhibitors within 2 weeks before starting the trial, or strong CYP3A4 or CYP2C8 inducers within 5 days before starting. It's best to discuss your current medications with the trial team.

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

Research has shown that combining trastuzumab emtansine (T-DM1) and tucatinib is generally safe for patients with HER2-positive breast cancer. Studies have found that this combination can improve patient outcomes without causing unexpected side effects. Most patients experienced common side effects like tiredness or nausea, which can usually be managed with standard care. No new safety concerns have emerged with this treatment compared to using T-DM1 alone, indicating that adding tucatinib does not significantly increase the risk of serious side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Trastuzumab Emtansine (T-DM1) and Tucatinib for breast cancer because this approach targets cancer cells in a new way. Unlike other treatments that mainly focus on disrupting cancer cell growth, Tucatinib specifically inhibits the HER2 protein, which is often overexpressed in aggressive breast cancers. By combining T-DM1, an antibody-drug conjugate, with Tucatinib, this treatment aims to deliver a one-two punch: directly attacking cancer cells while blocking their growth signals. This dual-action approach has the potential to be more effective and less toxic than existing treatments, offering new hope for patients with HER2-positive breast cancer.

What evidence suggests that T-DM1 and tucatinib might be effective for preventing breast cancer relapse?

Research has shown that using trastuzumab emtansine (T-DM1) with tucatinib can effectively treat HER2-positive breast cancer. In this trial, some participants will receive this combination, which studies have found helps patients live longer without cancer progression. Adding tucatinib to T-DM1 has shown promising results, especially for those with advanced or metastatic breast cancer. This suggests that the combination might be more effective than T-DM1 alone, another treatment arm in this trial, at preventing cancer recurrence. ^{1 2 3 6 7}

Who Is on the Research Team?

Ciara C. O'Sullivan, MB, BCh, BAO

Principal Investigator

Mayo Clinic

Are You a Good Fit for This Trial?

This trial is for patients with high risk, HER2 positive breast cancer who have had some treatment but still have invasive disease. They should not be pregnant or nursing and must not have metastatic (stage IV) breast cancer or a history of severe allergies to the drugs used in this study. Participants need good heart function and cannot have had another invasive breast cancer within the last 3 years.

Inclusion Criteria

My breast and lymph node cancer has been fully removed.

Both of my breast cancer lesions are HER2 positive, and the largest one meets the trial criteria.

My last major treatment was within the last 3 months.

Exclusion Criteria

My nerve damage does not severely affect my daily activities.

History of intolerance or hypersensitivity to specified medications

Pregnant or nursing women of childbearing potential without a negative serum pregnancy test

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive T-DM1 IV and either tucatinib or placebo orally for up to 14 cycles, each cycle lasting 21 days

42 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

10 years

What Are the Treatments Tested in This Trial?

Interventions

• Trastuzumab Emtansine
• Tucatinib

Trial Overview The trial is testing if combining T-DM1 (a targeted therapy that delivers chemo directly to cancer cells) with tucatinib (which blocks enzymes needed for tumor growth) prevents relapse better than T-DM1 alone in those at high risk of their HER2 positive breast cancer returning.

How Is the Trial Designed?

Group I: Arm II (trastuzumab emtansine, tucatinib) Experimental Treatment 4 Interventions

Patients receive T-DM1 IV over 30-90 minutes on day 1 and tucatinib PO BID on days 1-21. Treatment repeats every 21 days for up to 14 cycles in the absence of disease progression or unacceptable toxicity.

Group II: Arm I (trastuzumab emtansine, placebo) Active Control 4 Interventions

Patients receive T-DM1 IV over 30-90 minutes on day 1 and placebo PO BID on days 1-21. Treatment repeats every 21 days for up to 14 cycles in the absence of disease progression or unacceptable toxicity.

Trastuzumab Emtansine is already approved in United States, European Union, United Kingdom for the following indications:

Approved in United States as Kadcyla for:

• Metastatic breast cancer in patients whose tumors overexpress the HER2 protein and who have received prior therapy with trastuzumab and a taxane, either separately or in combination.
• Adjuvant treatment of patients with HER2-positive early breast cancer (EBC) who have residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment

Approved in European Union as Kadcyla for:

• Metastatic breast cancer in patients whose tumors overexpress the HER2 protein and who have received prior therapy with trastuzumab and a taxane, either separately or in combination.

Approved in United Kingdom as Kadcyla for:

• Metastatic breast cancer in patients whose tumors overexpress the HER2 protein and who have received prior therapy with trastuzumab and a taxane, either separately or in combination.

Who Is Running the Clinical Trial?

Alliance for Clinical Trials in Oncology

Lead Sponsor

Trials

521

Recruited

224,000+

Seagen Inc.

Industry Sponsor

Trials

212

Recruited

73,800+

Founded

1997

Headquarters

Bothell, USA

Known For

Antibody-Drug Conjugates

Top Products

Adcetris (brentuximab vedotin), Tukysa (tucatinib), Padcev (enfortumab vedotin-ejfv), Tivdak (tisotumab vedotin-tftv)

Dr. Roger Dansey

Seagen Inc.

Chief Medical Officer since 2018

MD from University of Witwatersrand

David R. Epstein

Seagen Inc.

Chief Executive Officer since 2022

BSc in Pharmacy from Rutgers University, MBA from Columbia University

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Ado-trastuzumab emtansine (T-DM1) is effective for treating HER2-positive breast cancers, but this case report highlights a serious risk of fatal pulmonary toxicity, specifically acute eosinophilic pneumonia, associated with its use.

The patient had previously received two HER2-targeted therapies, suggesting that prior treatments may contribute to the risk of additive toxicity when using T-DM1, indicating the need for careful monitoring in patients undergoing multiple lines of HER2-targeted therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute eosinophilic pneumonia: a fatal reaction to ado-trastuzumab. LaMorte, D., Desmond, D., Ellis, J., et al.[2023]

Tucatinib, when combined with T-DM1, was found to have a maximum tolerated dosage of 300 mg twice daily, showing acceptable toxicity levels in a phase 1b trial involving 57 patients with ERBB2/HER2-positive metastatic breast cancer.

The treatment demonstrated preliminary antitumor activity, with most adverse events being mild (grade 1 or 2), although some patients experienced more serious reactions like thrombocytopenia and hepatic transaminitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tucatinib Combined With Ado-Trastuzumab Emtansine in Advanced ERBB2/HER2-Positive Metastatic Breast Cancer: A Phase 1b Clinical Trial. Borges, VF., Ferrario, C., Aucoin, N., et al.[2019]

Trastuzumab emtansine (T-DM1) has demonstrated significant efficacy in treating HER2-positive metastatic breast cancer, showing improved progression-free and overall survival compared to standard treatments in the phase III EMILIA trial.

T-DM1 has a favorable safety profile and is being studied in ongoing trials to determine its effectiveness in earlier stages of HER2-positive breast cancer, indicating its potential for broader application in treatment protocols.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab emtansine (T-DM1) for HER2-positive breast cancer. Boyraz, B., Sendur, MA., Aksoy, S., et al.[2022]

The novel AJICAP® technology allows for site-specific conjugation of antibodies, resulting in a trastuzumab-maytansinoid ADC that has a higher maximum tolerated dose compared to the commercially available T-DM1, indicating an improved therapeutic index.

Initial safety studies in rats showed that the AJICAP-ADC demonstrated greater stability and tolerability than T-DM1, suggesting it could be a more effective treatment option for HER2-positive metastatic breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biological Evaluation of Maytansinoid-Based Site-Specific Antibody-Drug Conjugate Produced by Fully Chemical Conjugation Approach: AJICAP®. Seki, T., Yamada, K., Ooba, Y., et al.[2022]

Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that effectively targets HER2-positive breast cancer while minimizing off-target side effects, combining the benefits of targeted therapy with potent cytotoxic action.

T-DM1 has shown significant improvements in patient prognosis when used in neoadjuvant therapy and as a rescue treatment for advanced breast cancer, with ongoing clinical trials exploring its efficacy in other solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical research progress of T-DM1 in breast cancer]. Li, LX., Ma, F.[2021]

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 study of 128 female patients with HER2-positive metastatic breast cancer who previously received trastuzumab emtansine (T-DM1), the median progression-free survival (rwPFS) was 5.7 months, indicating some effectiveness of post-T-DM1 therapies.

Patients who continued anti-HER2 therapy after T-DM1 had a better median rwPFS of 6.3 months compared to 4.8 months for those who did not, suggesting that ongoing anti-HER2 treatment may provide additional benefits, although overall effectiveness remains limited.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world effectiveness of post-trastuzumab emtansine treatment in patients with HER2-positive, unresectable and/or metastatic breast cancer: a retrospective observational study (KBCSG-TR 1917). Nakayama, T., Yoshinami, T., Yasojima, H., et al.[2023]

Ado-trastuzumab emtansine (T-DM1) was approved in the U.S. for treating HER2 positive metastatic breast cancer based on the EMILIA phase III trial, which showed it was more effective than the standard treatment of lapatinib plus capecitabine.

Ongoing and planned trials are exploring T-DM1's use in various stages of breast cancer, and the review discusses its toxicity management and potential resistance mechanisms, highlighting its importance in current cancer treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ado-trastuzumab emtansine (T-DM1) in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer: latest evidence and clinical potential. Peddi, PF., Hurvitz, SA.[2022]

In a study of 232 Japanese patients with HER2-positive advanced breast cancer, trastuzumab emtansine (T-DM1) was found to be well tolerated, with 98.3% of patients experiencing adverse events but only 2.2% discontinuing treatment due to these events.

The most common serious adverse effects included thrombocytopenia in 29.7% of patients and hepatotoxicity in 11.2%, but no new safety concerns were identified, indicating that T-DM1 is a viable treatment option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety Evaluation of Trastuzumab Emtansine in Japanese Patients with HER2-Positive Advanced Breast Cancer. Watanabe, J., Ito, Y., Saeki, T., et al.[2022]

In a study of 893 HER2+ advanced breast cancer patients treated with ado-trastuzumab emtansine (T-DM1), early adverse events that required dose interruptions or reductions did not significantly affect overall survival (OS) or progression-free survival (PFS).

The analysis, using data from the EMILIA and TH3RESA clinical trials, indicated that early dose adjustments due to adverse events are not linked to worse long-term outcomes, suggesting that T-DM1 remains an effective treatment option even when dose modifications are necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of early adverse events resulting in ado-trastuzumab emtansine dose adjustments on survival outcomes of HER2+ advanced breast cancer patients. Tang, E., Rowland, A., McKinnon, RA., et al.[2020]

Trastuzumab emtansine (T-DM1) demonstrated superior inhibitory effects on HER-2-positive colon cancer cells with KRAS/BRAF mutations compared to other treatments like cetuximab and trastuzumab, suggesting its potential as an effective therapy for this challenging cancer type.

The combination of T-DM1 with metformin enhanced the drug's efficacy by increasing caveolin-1 expression, which improved T-DM1 uptake and led to significant tumor growth inhibition in a xenograft mouse model.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Application of trastuzumab emtansine in HER-2-positive and KRAS/BRAF-mutated colon cancer cells. Chung, YC., Chiu, HH., Wei, WC., et al.[2020]

In a study of 128 patients with advanced HER2+ breast cancer treated with ado-trastuzumab emtansine (T-DM1), the median progression-free survival was 8.7 months and overall survival was 20.4 months, indicating its efficacy in a real-world setting.

The safety profile of T-DM1 was consistent with existing literature, but the study noted higher rates of peripheral neuropathy (21.9%) and liver toxicity (19.5%), which are important considerations for its use in treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of T-DM1 in patients with advanced HER2-positive breast cancer The Royal Marsden experience. Battisti, NML., Rogerson, F., Lee, K., et al.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT01983501

NCT01983501 | A Study of Tucatinib (ONT-380) Combined ... This is a Phase 1b, open-label study of tucatinib (ONT-380) given in combination with ado-trastuzumab emtansine (T-DM1) to patients with HER2+ breast cancer.

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40989560/

Real-world efficacy and safety of trastuzumab deruxtecan ... Interpretation: In this real-world study, T-DXd was more effective than T-DM1 as a second-line treatment and tucatinib as a third-line treatment, in line with ...

3. aacr.org aacr.org/about-the-aacr/newsroom/news-releases/tucatinib-plus-trastuzumab-emtansine-may-benefit-patients-with-advanced-or-metastatic-her2-positive-breast-cancer/

Tucatinib Plus Trastuzumab Emtansine May Benefit ... Tucatinib Plus Trastuzumab Emtansine May Benefit Patients With Advanced or Metastatic HER2-positive Breast Cancer.

4. breastcancer.org breastcancer.org/research-news/tukysa-plus-kadcyla-better-for-metastatic-breast-cancer

Adding Tukysa to Kadcyla Better for Metastatic Disease Combining Tukysa (chemical name: tucatinib) with Kadcyla (chemical name: T-DM1 or ado-trastuzumab emtansine) resulted in better progression-free survival.

5. cancernetwork.com cancernetwork.com/view/tucatinib-t-dm1-yield-exciting-results-in-her2-metastatic-breast-cancer

Tucatinib/T-DM1 Yield 'Exciting' Results in HER2+ ... Adding trastuzumab emtansine to tucatinib appears to significantly improve progression-free survival in patients with metastatic HER2-positive breast cancer.

6. aacrjournals.org aacrjournals.org/cancerres/article/84/9_Supplement/GS01-10/743442/Abstract-GS01-10-HER2CLIMB-02-Randomized-Double

Abstract GS01-10: HER2CLIMB-02: Randomized, Double ... HER2CLIMB-02 demonstrated that the addition of tucatinib to T-DM1 significantly improved median PFS in patients with previously treated HER2+ LA/MBC.

7. onclive.com onclive.com/view/tucatinib-plus-t-dm1-improves-pfs-in-previously-treated-her2-metastatic-breast-cancer

Tucatinib Plus T-DM1 Improves PFS in Previously Treated ... The combination of tucatinib and ado-trastuzumab emtansine elicited an improvement in progression-free survival compared with placebo plus T-DM1 in patients ...