Lapatinib in Stage IV Melanoma With ERBB4 Mutations

NCT01264081 | Terminated Phase 2 Results FDA Drug

• 2 other identifiers: 11004811-C-0048
• Study Type: interventional
• Target: 34
• Locations: 1 country
• Sites: 1

Brief Summary

Background: \- Studies of melanoma tumor samples have shown that tumor cells from approximately 20 percent of melanoma patients contain a specific mutation of a gene involved in making a protein called ERBB4, and that changes in this gene have been associated with cancer. Lapatinib, a drug that is currently approved for the treatment of breast cancer, has been shown in the laboratory to significantly slow the growth of melanoma cells that contain this specific ERBB4 gene mutation. Researchers are interested in determining whether lapatinib can be effective against melanoma in individuals who have the ERBB4 mutation. Objectives: \- To evaluate the safety and effectiveness of lapatinib as a treatment for melanoma with ERBB4 mutation that has not responded to standard therapy. Eligibility: \- Individuals at least 18 years of age who have stage 4 melanoma that has not responded to standard therapy. Design:

• Participants will be screened with a full physical examination and medical history, as well as tests of tumor tissue taken from previous surgeries or biopsies or from a new biopsy that will be conducted before the start of the study. Test results to determine eligibility will be available within about 2 weeks.
• Participants will take four lapatinib tablets daily (two in the morning, 1 hour before or after breakfast and two in the evening, 1 hour before or after dinner) during every 28-day cycle of treatment. Participants will keep a medication diary to record tablets taken and any side effects from the medication.
• After the first 2 weeks, and every 2 to 4 weeks afterward for the first 12 weeks, participants will have clinic visits with blood samples and other tests to determine if lapatinib is causing their disease to shrink or be controlled. If the disease has not progressed, participants will continue to receive a new lapatinib supply every 28 days for up to 2 years (27 cycles), and will continue to have regular clinic visits to monitor the progress of treatment.
• When tumor tissue is easily accessible and can be easily biopsied, researchers will collect two additional biopsies, one after 2 weeks of treatment and one after 12 weeks of treatment....

Conditions

Malignant Melanoma

Keywords

Lapatinib; Melanoma; ERBB4 Mutation; Malignant Melanoma; Skin Cancer

Outcome Measures

Primary Outcomes (1)

• Count of Participants With a Partial Response (PR) and Complete Response (CR) to Lapatinib Who Have Metastatic Melanoma Harboring ERBB4 Mutations.

  The count of participants with a partial response and complete response is defined by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria. Partial response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Complete response is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Progressive disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The appearance of one or more new lesions is also considered progressions.

  3 years

Secondary Outcomes (1)

• Number of Participants With Serious and Non-Serious Adverse Events

  Date treatment consent signed to date off study, approximately, 3 years

Study Arms (1)

Lapatinib

EXPERIMENTAL

Lapatinib will be administered as an oral dose of 500 mg twice daily in the morning and evening one hour before or after meals.

Drug: Lapatinib

Interventions

Lapatinib DRUG

500 mg PO (orally) twice a day for 28 days (1 cycle). Up to 27 cycles allowed if response seen.

Lapatinib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have histologically confirmed stage IV cutaneous melanoma.
• Patients must have measurable disease defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded). Each lesion must be greater than 10 mm when measured by computed tomography (CT), magnetic resonance imaging (MRI) or caliper measurement by clinical exam; or greater than 20 mm when measured by chest x-ray. Lymph nodes must be greater than 15 mm in short axis when measured by CT or MRI.
• Patients must have no more than two oncogenic somatic ERBB4 mutations detected in one of the 28 exons of the ERBB4 gene analyzed from the tumor and which is not present in the matched normal deoxyribonucleic acid (DNA) as confirmed by sequence analysis of tumor genomic DNA derived from any biopsy specimen obtained at the participating clinical sites. Sequence analysis will be performed at the National Institutes of Health (NIH) Clinical Molecular Profiling Core, a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory.
• Note: Patients with 3 or more mutations in their ERBB4 gene may have an increased resistance to lapatinib and are not eligible for lapatinib treatment
• Patients must not have had chemotherapy, molecular therapy with B-RAF, mouse embryonic fibroblast (MEK), or c-kit inhibitors, hormonal therapy, radiation therapy, or biological therapy for at least 4 weeks prior to starting study medication. Patients who received mitomycin C, nitrosoureas, anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4), or carboplatin must be 6 weeks from the last administration of therapy. Patients must have recovered from any acute toxicity related to prior therapy or surgery, to a grade 1 or less unless specified.
• Patients with no more than 3 intracranial metastases, which have been definitively treated by surgery or radiation therapy may be eligible for study provided there is no evidence of active disease for at least 2 months and no requirement for anticonvulsant therapy or steroids following treatment.
• Age greater than or equal to 18 years.
• Note: Because no dosing or adverse event data are currently available on the use of lapatinib in patients less than 18 years of age, children are excluded from this study but will be eligible for future pediatric single-agent trials, if applicable.
• Life expectancy of greater than 3 months.
• Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 1 (Karnofsky greater than or equal to 70%).
• Patients must have normal organ and marrow function as defined below:
• absolute neutrophil count greater than or equal to 1,500/mcL
• platelets greater than or equal to 100,000/mcL
• total bilirubin within normal institutional limits
• Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase (SGOT))/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase (SGPT)) less than or equal to 3 times institutional upper limit of normal

You may not qualify if:

• Patients may not be currently receiving any other investigational agents.
• Patients may not have received prior treatment with tyrosine kinase inhibitors (e.g., lapatinib erlotinib, or gefitinib).
• Patients currently receiving any medication known to induce/inhibit cytochrome P450 3A4 (CYP3A4) as listed in Appendix D, which in the opinion of the principal investigator, would make the administration of study drug hazardous. Note: patients receiving any strong or moderate CYP3A4 inhibitors will be excluded.
• Patients with active hepatic or biliary disease (with exception of patients with Gilberts syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment)
• Patients with 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.
• Human immunodeficiency virus (HIV)-positive patients on antiretroviral therapy are excluded because most antiretrovirals are strong or moderate CYP3A4 inhibitors.
• Any underlying medical condition which, in the opinion of the principal investigator, will make the administration of study drug hazardous or obscure the interpretation of adverse events
• Patients with any other concurrent malignancy, except for the following:
• adequately treated basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix, or any other cancer from which the patient has been disease-free for five (5) years or more.
• Both men and women and members of all races and ethnic groups are eligible for this trial.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• Davies MA, Samuels Y. Analysis of the genome to personalize therapy for melanoma. Oncogene. 2010 Oct 14;29(41):5545-55. doi: 10.1038/onc.2010.323. Epub 2010 Aug 9.

  PMID: 20697348 BACKGROUND

• Prickett TD, Agrawal NS, Wei X, Yates KE, Lin JC, Wunderlich JR, Cronin JC, Cruz P, Rosenberg SA, Samuels Y. Analysis of the tyrosine kinome in melanoma reveals recurrent mutations in ERBB4. Nat Genet. 2009 Oct;41(10):1127-32. doi: 10.1038/ng.438. Epub 2009 Aug 30.

  PMID: 19718025 BACKGROUND

• Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, Jagiello-Gruszfeld A, Crown J, Chan A, Kaufman B, Skarlos D, Campone M, Davidson N, Berger M, Oliva C, Rubin SD, Stein S, Cameron D. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006 Dec 28;355(26):2733-43. doi: 10.1056/NEJMoa064320.

  PMID: 17192538 BACKGROUND

• Kerkar SP, Kemp CD, Duffy A, Kammula US, Schrump DS, Kwong KF, Quezado M, Goldspiel BR, Venkatesan A, Berger A, Walker M, Toomey MA, Steinberg SM, Giaccone G, Rosenberg SA, Avital I. The GYMSSA trial: a prospective randomized trial comparing gastrectomy, metastasectomy plus systemic therapy versus systemic therapy alone. Trials. 2009 Dec 23;10:121. doi: 10.1186/1745-6215-10-121.

  PMID: 20030854 RESULT

MeSH Terms

Conditions

Melanoma; Skin Neoplasms

Interventions

Lapatinib

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Quinazolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Dr. Udo Rudloff'
• Organization: National Cancer Institute

rudloff@nih.gov

301-496-3098

Study Officials

• Udo Rudloff, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: December 18, 2010
• First Posted: December 21, 2010
• Study Start: May 20, 2011
• Primary Completion: November 22, 2013
• Study Completion: November 22, 2013
• Last Updated: November 13, 2019
• Results First Posted: March 19, 2015

Record last verified: 2019-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)