What side effects are associated with this type of intervention?

Common treatments for thyroid cancer, such as Lapatinib (an EGFR, ErbB2, Erk-1, Erk-2, and AKT inhibitor) and Dabrafenib (a BRAF inhibitor), are associated with several side effects. Lapatinib can cause diarrhea, rash, fatigue, and hand-foot syndrome. Dabrafenib is known to cause skin-related issues such as squamous cell carcinoma, fever, fatigue, and joint pain. Both treatments may also lead to hair changes, including partial alopecia and hair curling. 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 targeted therapies for thyroid cancer, particularly for cases with specific genetic mutations. Dabrafenib, a BRAF inhibitor, is approved for treating BRAF V600E-mutant anaplastic thyroid cancer. Another similar drug, Vemurafenib, also targets BRAF mutations and is used in similar contexts. For targeting the EGFR and ErbB2 pathways, drugs like Lenvatinib and Sorafenib, which are multi-kinase inhibitors, have been approved for differentiated thyroid cancer that is refractory to radioactive iodine treatment. These drugs inhibit multiple kinases involved in tumor growth and angiogenesis, including VEGFR, FGFR, and RET, among others.

What other types of research exist?

Promising novel alternatives to Lapatinib and Dabrafenib for Thyroid Cancer patients include: 1) Selpercatinib and Pralsetinib, which target RET mutations and fusions, showing significant efficacy in thyroid cancers with these alterations. 2) Larotrectinib and Entrectinib, which target NTRK gene fusions, offering a new treatment avenue for patients with these specific genetic changes. 3) Cabozantinib and Vandetanib, which are multi-kinase inhibitors targeting VEGFR, RET, and other kinases, providing broader anti-tumor activity.

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Protein Kinase Inhibitor

Dabrafenib + Lapatinib for Thyroid Cancer

Phase 1

Waitlist Available

Led By Eric J Sherman

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

Fludeoxyglucose F 18 (FDG)-avid lesion (standard uptake variable maximum [SUVmax] >= 3) on a FDG-positron emission tomography (PET) scan

Absent or insufficient radioactive iodine uptake in either all lesions or an index lesion which has never been resected or received external beam radiation therapy as documented on a radioactive iodine scan (insufficient uptake must be confirmed by either an endocrinologist or nuclear medicine physician)

Must not have

History or evidence of cardiovascular risks including any of the following: history of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within the past 24 weeks prior to randomization, history or evidence of current class II, III, or IV heart failure as defined by the NYHA functional classification system, intra-cardiac defibrillators, abnormal cardiac valve morphology (>= grade 2) documented by ECHO; (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study); subjects with moderate valvular thickening should not be entered on study, history or evidence of current clinically significant uncontrolled cardiac arrhythmias; clarification: subjects with atrial fibrillation controlled for > 30 days prior to dosing are eligible, treatment refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive therapy

Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

Timeline

Screening 3 weeks

Treatment Varies

Follow Up baseline to day 7 of cycle 1

Awards & highlights

No Placebo-Only Group

Summary

This trial is testing the combination of lapatinib and dabrafenib in patients with hard-to-treat thyroid cancer. The drugs work by blocking proteins that help cancer cells grow. The goal is to find the best dose and observe any anti-tumor activity. Dabrafenib has shown antitumor activity in various cancers, including thyroid cancer, and lapatinib is a tyrosine kinase inhibitor used in breast cancer treatment.

Who is the study for?

This trial is for patients with thyroid cancer that's spread or can't be removed by surgery, and hasn't improved after standard treatments. Participants must have a specific BRAF V600E or V600K mutation in their tumor, good organ function, no recent cancer treatments, and an ability to swallow pills. Women who can have children need to use non-hormonal birth control during the study.

What is being tested?

The trial is testing the combination of two drugs: Dabrafenib and Lapatinib. These drugs are believed to block enzymes important for cancer cell growth. The study aims to find the best dose with acceptable side effects for patients whose thyroid cancer has not been controlled by other treatments.

What are the potential side effects?

Potential side effects include but are not limited to diarrhea, rash, fatigue, nausea and vomiting. There may also be liver issues like increased enzymes in blood tests or heart problems such as decreased heart function.

Eligibility Criteria

Inclusion Criteria

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

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My PET scan shows a highly active lesion with an SUVmax of 3 or more.

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My cancer does not absorb radioactive iodine well, as confirmed by a specialist.

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My cancer has spread, cannot be surgically removed, and standard treatments are not effective.

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I am mostly active and can care for myself.

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I can take pills and don't have major gut issues affecting drug absorption.

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My cancer is advanced, cannot be surgically removed, and standard treatments are not effective.

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My platelet count is at least 100,000 per microliter of blood.

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My liver tests are within the normal range required by the study.

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I am mostly able to care for myself and carry out daily activities.

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I have received more than 600 mCi of radioactive iodine in my lifetime.

Exclusion Criteria

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

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I do not have serious heart problems or uncontrolled high blood pressure.

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I do not have any severe illnesses or social situations that would stop me from following the study's requirements.

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My cancer has never tested positive for RAS mutations.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ baseline to day 7 of cycle 1

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~baseline to day 7 of cycle 1

This trial's timeline: 3 weeks for screening, Varies for treatment, and baseline to day 7 of cycle 1 for reporting.

Treatment Details

Study Objectives

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

Primary study objectives

Maximum tolerated dose (MTD) of lapatinib, in combination with the established dose of dabrafenib

Secondary study objectives

Body tissue

Mean percentage change in transcript levels in the post-treatment tissues relative to pre-treatment tissues for several genes analyzed by reverse-transcriptase-polymerase chain reaction

Side effects data

From 2018 Phase 3 trial • 1286 Patients • NCT00073528

60%

Diarrhoea

34%

Rash

29%

Nausea

19%

Fatigue

17%

Arthralgia

15%

Vomiting

15%

Back pain

13%

Headache

13%

Dry skin

12%

Asthenia

12%

Decreased appetite

12%

Pruritus

11%

Cough

11%

Alopecia

10%

Pain in extremity

10%

Nail disorder

10%

Hot flush

Dyspnoea

Alanine aminotransferase increased

Epistaxis

Dyspepsia

Anaemia

Nasopharyngitis

Aspartate aminotransferase increased

Musculoskeletal pain

Abdominal pain

Constipation

Dizziness

Insomnia

Abdominal pain upper

Mucosal inflammation

Pyrexia

Acne

Paronychia

Stomatitis

Upper respiratory tract infection

Urinary tract infection

Blood alkaline phosphatase increased

Weight decreased

Muscle spasms

Musculoskeletal chest pain

Erythema

Bone pain

Myalgia

Oedema peripheral

Ejection fraction decreased

Left ventricular dysfunction

Chest pain

Erysipelas

Dehydration

Cellulitis

100%

80%

60%

40%

20%

Study treatment Arm

Placebo + Letrozole 2.5 mg

Lapatinib 1500 mg + Letrozole 2.5 mg

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 (lapatinib, dabrafenib)Experimental Treatment11 Interventions

Patients receive dabrafenib PO BID on days 1-28 of each cycle. After two weeks of single agent dabrafenib, patients also start receiving lapatinib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo tumor biopsy, blood sample collection, ECHO or MUGA, as well as PET, CT, and/or MRI during screening and on study.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Multigated Acquisition Scan

2015

Completed Phase 3

~270

Echocardiography

2013

Completed Phase 4

~11580

Lapatinib

2006

Completed Phase 3

~3530

Positron Emission Tomography

2011

Completed Phase 2

~2200

Biospecimen Collection

2004

Completed Phase 3

~2030

Computed Tomography

2017

Completed Phase 2

~2790

Lapatinib Ditosylate

2006

Completed Phase 3

~610

Magnetic Resonance Imaging

2017

Completed Phase 3

~1180

Biopsy

2014

Completed Phase 4

~1150

Dabrafenib Mesylate

2014

Completed Phase 2

~10

Dabrafenib

2011

Completed Phase 3

~4120

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

Lapatinib and Dabrafenib are targeted therapies used in treating thyroid cancer by inhibiting specific pathways involved in tumor growth. Lapatinib blocks the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (ErbB2), as well as downstream signaling molecules like Erk-1, Erk-2, and AKT, which are crucial for cell proliferation. Dabrafenib specifically inhibits the BRAF V600E mutation, disrupting the MAPK/ERK pathway that promotes cancer cell growth. These treatments are important for thyroid cancer patients as they offer a targeted approach, potentially leading to more effective and personalized therapy options.

Breast Cancer Anti-Estrogen Resistance 4 (BCAR4) Drives Proliferation of IPH-926 lobular Carcinoma Cells.Thyroid cancer cell resistance to gefitinib depends on the constitutive oncogenic activation of the ERK pathway.