What side effects are associated with this type of intervention?

Kinase inhibitors, such as Neratinib, commonly cause side effects including diarrhea, rash, and liver toxicity. Antibody-drug conjugates like Trastuzumab Deruxtecan often lead to side effects such as decreased neutrophil count, anemia, nausea, and interstitial lung disease. Both classes of drugs can have significant impacts on the patient's quality of life and require careful monitoring and management of side effects.

What prior FDA approvals exist?

The FDA has approved several treatments for cancer that are similar to Neratinib and Trastuzumab Deruxtecan. Neratinib, a kinase inhibitor, is approved for the extended adjuvant treatment of HER2-positive breast cancer following adjuvant trastuzumab-based therapy. Trastuzumab Deruxtecan, an antibody-drug conjugate, is approved for the treatment of HER2-positive breast cancer that has metastasized or cannot be surgically removed, particularly in patients who have received prior anti-HER2-based regimens. Other similar FDA-approved treatments include Ado-Trastuzumab Emtansine (another antibody-drug conjugate) for HER2-positive metastatic breast cancer and Lapatinib (a kinase inhibitor) for advanced or metastatic breast cancer in combination with other therapies.

What other types of research exist?

Promising alternatives include: 1) Larotrectinib and Entrectinib for TRK fusion-positive cancers, which have shown potential advantages in clinical response and survival. 2) Dabrafenib and Trametinib for BRAF V600-mutant cancers, which have demonstrated efficacy in various tumor types. 3) Pembrolizumab plus Cetuximab for treatment-refractory metastatic head and neck cancer, showing encouraging response rates. 4) Tipifarnib for HRAS mutant squamous cell carcinoma of the head and neck, with notable objective response rates in phase II trials.

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Kinase Inhibitor

Trastuzumab Deruxtecan + Neratinib for Cancer

Phase 1

Waitlist Available

Led By Andrew A Davis

Research Sponsored by National Cancer Institute (NCI)

Eligibility Criteria Checklist

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

Must have

Patients must have at least one lesion suitable for biopsy without significant risk to the patient

Patients who had clinically significant side effects from prior cancer therapy must have recovered to grade 1 or below

Must not have

Patients with active additional malignancy or a personal history of additional malignancy that may affect outcome of disease under treatment

Concomitant use of certain medications or substances

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to 1 year

Awards & highlights

No Placebo-Only Group

Summary

This trial tests the safety and best dose of combining neratinib and trastuzumab deruxtecan for patients with advanced HER2-positive tumors. Neratinib stops cancer cell growth, and trastuzumab deruxtecan delivers chemotherapy directly to the cancer cells. The goal is to find the best dose and see how well this combination works. Neratinib has been shown to overcome trastuzumab resistance in HER2-positive breast cancer.

Who is the study for?

Adults with advanced solid tumors that can't be removed by surgery or have spread, and have changes in the HER2 gene. They must not have had previous treatments with neratinib or DS-8201a, should not be pregnant or breastfeeding, and need to agree to use contraception. People with certain heart conditions, severe lung issues, recent major surgeries or radiation therapy are excluded.

What is being tested?

The trial is testing the combination of two anti-cancer drugs: Trastuzumab Deruxtecan and Neratinib Maleate for safety and optimal dosing against cancers with HER2 gene alterations. It includes various assessments like scans and biopsies to monitor effects.

What are the potential side effects?

Potential side effects include reactions related to the immune system such as inflammation of organs (like lungs), digestive problems including diarrhea, blood disorders which could affect cell counts, fatigue from treatment-related anemia, possible heart complications due to drug interactions.

Eligibility Criteria

Inclusion Criteria

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

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I have a tumor that can be safely biopsied.

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I have recovered from serious side effects of my previous cancer treatment.

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I am 18 years old or older.

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I have chronic hepatitis B but my viral load is undetectable.

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My heart condition allows me to perform daily activities with slight limitations.

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I am HIV-positive but stable on my medication and healthy.

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My tumor is HER2 positive based on specific tests.

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My kidney function is within the required range.

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I am mostly active and can carry out light work.

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My brain metastases have been treated.

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I have had at least one treatment for my cancer after it spread.

Exclusion Criteria

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

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I have another type of cancer that could affect my current treatment.

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I am not taking any medications that could interfere with the trial.

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I have previously been treated with neratinib or DS-8201a.

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I have a long-term stomach problem that mainly causes diarrhea.

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I cannot swallow pills.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to 1 year

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to 1 year

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to 1 year for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Incidence of dose limiting toxicities

Incidence of treatment-emergent adverse events

Secondary study objectives

DXd (MAAA-1181a) tissue concentration

Duration of response

Incidence of adverse events

+5 more

Other study objectives

Deoxyribonucleic acid (DNA) damage

Quantitative HER2 protein

Tumor mutation profile

Side effects data

From 2024 Phase 2 trial • 95 Patients • NCT04989816

77%

Anaemia

73%

White blood cell count decreased

61%

Neutrophil count decreased

53%

Platelet count decreased

43%

Nausea

40%

Decreased appetite

39%

Hypoalbuminaemia

32%

Aspartate aminotransferase increased

32%

Vomiting

28%

Weight decreased

26%

Hypokalaemia

25%

Asthenia

25%

Alanine aminotransferase increased

24%

Hypocalcaemia

22%

Hyponatraemia

19%

Fatigue

19%

Constipation

17%

Lymphocyte count decreased

15%

Diarrhoea

13%

Covid-19

12%

Blood alkaline phosphatase increased

12%

Blood bilirubin increased

12%

Gamma-glutamyltransferase increased

Hyperuricaemia

Dizziness

Pyrexia

Hyperglycaemia

Abdominal distension

Oedema peripheral

Insomnia

Bilirubin conjugated increased

Blood creatinine increased

White blood cell count increased

Thrombocytopenia

Hypochloraemia

Abdominal pain

Dyspepsia

Hypoaesthesia

Pneumonia

Hepatic function abnormal

Amylase increased

Blood lactate dehydrogenase increased

Ejection fraction decreased

Hypoproteinaemia

Back pain

Cough

Mouth ulceration

Coronavirus infection

Interstitial lung disease

Productive cough

Covid-19 pneumonia

Gastrointestinal haemorrhage

Febrile neutropenia

Death

Dysphagia

Upper gastrointestinal haemorrhage

Jaundice cholestatic

Gastrointestinal infection

Myelosuppression

Malnutrition

Cerebral infarction

Arrhythmia

Mental disorder

Sepsis

Haemorrhage intracranial

Haematuria

Renal failure

Pulmonary embolism

Deep vein thrombosis

100%

80%

60%

40%

20%

Study treatment Arm

T-DXd

Awards & Highlights

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: Treatment (neratinib, trastuzumab deruxtecan)Experimental Treatment7 Interventions

Patients receive neratinib PO QD on days 1-21 (days 8-21 of cycle 1, then days 1-21 in cycles thereafter for PD study) of each cycle and trastuzumab deruxtecan IV over 30-90 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection, CT scan and echocardiograpahy or MUGA scan throughout study. Additionally, patients may undergo a tissue biopsy at baseline.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Biospecimen Collection

2004

Completed Phase 3

~2020

Echocardiography

2013

Completed Phase 4

~11580

Computed Tomography

2017

Completed Phase 2

~2740

Multigated Acquisition Scan

2015

Completed Phase 3

~270

Trastuzumab Deruxtecan

2021

Completed Phase 2

~100

Biopsy

2014

Completed Phase 4

~1090

0 / 16Eligibility 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

Kinase inhibitors, like Neratinib, block specific enzymes that signal cancer cells to grow, thereby slowing or stopping tumor growth. Antibody-drug conjugates, such as Trastuzumab Deruxtecan, combine a monoclonal antibody targeting cancer cells with a chemotherapy drug, delivering the drug directly to the cancer cells and minimizing damage to healthy cells. These targeted treatments are crucial for cancer patients as they can be more effective and have fewer side effects compared to traditional chemotherapy.

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