What is the mechanism of action of this treatment?

HER2-targeted therapies are crucial for treating HER2-positive breast cancer, a subtype characterized by overexpression of the HER2 protein, which promotes cancer cell growth. Tyrosine Kinase Inhibitors (TKIs) like Neratinib and Lapatinib inhibit the HER2 receptor's kinase activity, blocking downstream signaling pathways that lead to cell proliferation. Monoclonal antibodies like Trastuzumab bind to the HER2 receptor, preventing its activation and marking cancer cells for immune system destruction. These treatments are significant because they specifically target cancer cells, potentially leading to better outcomes and fewer side effects compared to traditional chemotherapy.

What side effects are associated with this type of intervention?

Common treatments for HER2-positive breast cancer, such as Neratinib, T-DM1, Lapatinib, and Trastuzumab, often have a range of side effects. Neratinib, a tyrosine kinase inhibitor, can cause diarrhea, nausea, vomiting, and fatigue. T-DM1 (trastuzumab emtansine) may lead to liver toxicity, low platelet counts, and fatigue. Lapatinib, often used in combination with capecitabine, can result in diarrhea, rash, and hand-foot syndrome. Trastuzumab is associated with cardiac toxicity, infusion reactions, and fatigue. Patients should discuss these potential side effects with their healthcare provider to manage and mitigate them effectively.

What prior FDA approvals exist?

The FDA has approved several drugs targeting the HER2 receptor for the treatment of breast cancer. Trastuzumab (Herceptin) was one of the first, followed by pertuzumab (Perjeta), which is often used in combination with trastuzumab. Ado-trastuzumab emtansine (T-DM1, Kadcyla) is an antibody-drug conjugate approved for patients who have previously received trastuzumab and chemotherapy. More recently, fam-trastuzumab deruxtecan (T-DXd, Enhertu) has been approved for HER2-positive breast cancer patients who have received prior anti-HER2-based regimens. Neratinib, an oral tyrosine kinase inhibitor, is approved for extended adjuvant treatment of early-stage HER2-positive breast cancer following adjuvant trastuzumab-based therapy.

What other types of research exist?

Promising alternatives to Neratinib for HER2-positive breast cancer include Trastuzumab Deruxtecan, which has shown efficacy in previously treated HER2-positive breast cancer and in patients with active brain metastases (TUXEDO-1 trial). Another option is the combination of Tucatinib, Trastuzumab, and Capecitabine, which has demonstrated safety and efficacy in treating leptomeningeal metastasis in HER2-positive breast cancer (TBCRC049 study). Additionally, Trastuzumab Emtansine (T-DM1) has been effective in patients with brain metastases and as part of adjuvant therapy in combination with Neratinib.

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Kadcyla + Neratinib for Breast Cancer

Phase 2

Recruiting

Research Sponsored by University Health Network, Toronto

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Male or female patients ≥ 18 years of age with histologically confirmed, resected HER2 positive stage I-III breast cancer, with residual invasive disease following prior neoadjuvant trastuzumab (+/- pertuzumab)-based chemotherapy

No contraindications to T-DM1 or neratinib

Must not have

Clinical or radiographic evidence of suspected or confirmed metastatic disease

Known positive serology for HIV that is not currently controlled with anti-retroviral therapy

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to 5 years

Awards & highlights

All Individual Drugs Already Approved

Approved for 5 Other Conditions

No Placebo-Only Group

Summary

This trial is for patients with early-stage HER2+ breast cancer who still have small amounts of cancer after initial treatments. They will take a drug called neratinib along with their usual treatment. Neratinib works by blocking signals that help cancer cells grow. The study aims to see if this combination improves patient outcomes.

Who is the study for?

This trial is for adults over 18 with HER2+ stage I-III breast cancer, who've had surgery and are on T-DM1 therapy but still show signs of cancer at a molecular level. They should be in good health otherwise, able to follow the study plan, and willing to use effective birth control.

What is being tested?

The trial tests if adding neratinib (a pill taken daily) to standard T-DM1 therapy can clear remaining cancer traces after initial treatment. It's given for up to a year unless there's recurrence or side effects leading to stopping the drug.

What are the potential side effects?

Neratinib may cause diarrhea, liver issues, rash, stomach pain, nausea, vomiting. Side effects vary by individual and some may require medical attention or discontinuation of the medication.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I am over 18, had breast cancer surgery, and still have cancer after treatment with trastuzumab.

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I have no known allergies or adverse reactions to T-DM1 or neratinib.

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I have been on hormone therapy for my cancer for at least 12 weeks.

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I am taking T-DM1 for cancer and still have minimal residual disease after 2-6 cycles.

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I am a man and I agree to use effective birth control.

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I am fully active or can carry out light work.

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I have received 2-6 cycles of a specific cancer drug after surgery.

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My cancer has not returned or spread to other parts of my body.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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My cancer has spread to other parts of my body.

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I have HIV that is not being treated with medication.

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I have been treated with a HER2 tyrosine kinase inhibitor before.

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I have heart problems or diseases.

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I have a stomach or bowel problem that affects how my body absorbs medication.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to 5 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to 5 years

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to 5 years for reporting.

Treatment Details

Side effects data

From 2022 Phase 2 trial • 11 Patients • NCT03094052

100%

Diarrhea

100%

Constipation

82%

Nausea

45%

Abdominal distension

45%

Fatigue

36%

Dizziness

36%

Headache

27%

Dyspnea

27%

Hot flashes

27%

Anorexia

27%

Vomiting

27%

Pruritus

27%

Weight loss

18%

Skin and subcutaneous tissue disorders - Other, specify

18%

Dysgeusia

18%

Bloating

18%

Fever

18%

Abdominal pain

18%

Gastrointestinal disorders - Other, specify

18%

Aspartate aminotransferase increased

18%

Alanine aminotransferase increased

18%

Sinus bradycardia

Muscle weakness upper limb

Neck pain

Rash acneiform

Lymphedema

Rash maculo-papular

Vaginal dryness

Back pain

Anal hemorrhage

Paresthesia

Gastroesophageal reflux disease

Pain

Infections and infestations - Other, specify

Urinary tract pain

Flu like symptoms

Fracture

Flatulence

Mucositis oral

Chills

General disorders and administration site conditions - Other, specify

Ejection fraction decreased

Oral dysesthesia

Peripheral sensory neuropathy

Creatinine increased

Upper respiratory infection

Vaginal infection

Stomach pain

Bruising

Fall

Joint range of motion decreased

Musculoskeletal and connective tissue disorder - Other, specify

Arthralgia

Vaginal discharge

Vaginal hemorrhage

Wheezing

Anxiety

Insomnia

Cholecystitis

100%

80%

60%

40%

20%

Study treatment Arm

Treatment (Neratinib)

Awards & Highlights

All Individual Drugs Already Approved

Therapies where all constituent drugs have already been approved are likely to have better-understood side effect profiles.

Approved for 5 Other Conditions

This treatment demonstrated efficacy for 5 other conditions.

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

1Treatment groups

Experimental Treatment

Group I: Neratinib ArmExperimental Treatment1 Intervention

Standard T-DM1 (3.6mg/kg) IV infusion every 3 weeks administered with Neratinib (160 mg) orally once daily up to 1 year.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Neratinib

FDA approved

0 / 13Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

HER2-targeted therapies are crucial for treating HER2-positive breast cancer, a subtype characterized by overexpression of the HER2 protein, which promotes cancer cell growth. Tyrosine Kinase Inhibitors (TKIs) like Neratinib and Lapatinib inhibit the HER2 receptor's kinase activity, blocking downstream signaling pathways that lead to cell proliferation. Monoclonal antibodies like Trastuzumab bind to the HER2 receptor, preventing its activation and marking cancer cells for immune system destruction. These treatments are significant because they specifically target cancer cells, potentially leading to better outcomes and fewer side effects compared to traditional chemotherapy.

Preclinical Characteristics of the Irreversible Pan-HER Kinase Inhibitor Neratinib Compared with Lapatinib: Implications for the Treatment of HER2-Positive and HER2-Mutated Breast Cancer.New drugs for breast cancer.[Trastuzumab (Herceptin) and breast cancer: mechanisms of resistance].