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A Phase II Study of Lapatinib for the Treatment of Stage IV Melanoma Harboring ERBB4 Mutations


Phase 2
18 Years
N/A
Open (Enrolling)
Both
Malignant Melanoma

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Trial Information

A Phase II Study of Lapatinib for the Treatment of Stage IV Melanoma Harboring ERBB4 Mutations


Background:

- Patients with stage IV melanoma have few available treatment options and an overall
poor prognosis.

- Pre-clinical evidence suggests that lapatinib has activity against metastatic melanoma
harboring ERBB4 mutations.

Objectives:

Primary Objectives:

-Determine the response rate to lapatinib administered as 500 mg orally twice daily on a
continuous schedule in patients with metastatic melanoma harboring ERBB4 mutations.

Secondary Objectives:

- To determine the progression free survival of patients with stage IV melanoma treated
with lapatinib monotherapy.

- To evaluate the safety of lapatinib in patients with metastatic melanoma

- To determine the impact of additional genetic alterations on the response to lapatinib
in melanoma harboring ERBB4 mutations

- To develop a clinically applicable biomarker predictive of response to lapatinib in
patients with melanoma harboring ERBB4 mutations

- To determine the pharmacokinetics of lapatinib administered as 500 mg orally twice
daily on a continuous schedule in patients with metastatic melanoma harboring ERBB4
mutations

Eligibility:

- Patients greater than or equal to 18 years of age with stage IV melanoma, who have
measurable disease and whose tumors express up to two ERBB4 gene mutations.

- Patient must be ECOG performance status of less than or equal to 1 and a life
expectancy of more than 3 months.

- Patients must have adequate organ function.

- Patients must not have had surgery, chemotherapy, hormonal therapy, radiation therapy,
or biological therapy for at least 4 weeks prior to starting study medication.

- Patients must not have an acute, critical illness.

- All patients who are sexually active and able to conceive will be required to use
contraception during treatment with lapatinib.

Design:

- Patients will be screened for the presence of ERBB4 gene mutations in their tumor and
only patients who harbor less than or equal to 2 ERBB4 mutations will be enrolled in
the treatment phase of the study.

- Lapatinib will be administered as an oral dose of 500 mg twice daily (in the morning
and evening) taken one hour before or after meals. Lapatinib will be given
continuously; one cycle equals 28 days. Course 1 equals cycle 1; all subsequent courses
are 8 weeks long (2 cycles). A patient may receive up to 27 cycles (14 courses).

- Up to 25 patients (allowing for a staged accrual of initially 16 patients who will
receive lapatinib and are evaluable after the 1st cycle) will be enrolled over 2-3
years and the trial will be completed over 3-5 years, allowing for completion of
follow-up.

- The primary objective of the trial will be to determine whether lapatinib monotherapy
in this setting is able to be associated with a response rate (PR +CR) that can rule
out 10% (p0=0.10) in favor of an improved response rate of 30% (p1=0.30).

Inclusion Criteria


- INCLUSION CRITERIA:

- Patients must have histologically confirmed stage IV cutaneous melanoma.

- Patients must have measurable disease defined by 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 CT, 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 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 NIH Clinical Molecular Profiling Core, a
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, 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-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.

- 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

- AST(SGOT)/ALT(SGPT) less than or equal to 3 times institutional upper limit of
normal

- creatinine less than or equal to institutional upper limit of normal

OR

--creatinine clearance greater than or equal to 60 mL/min/1.73 m(2) for patients with
creatinine levels above institutional normal.

- Patients must be willing to return to the Clinic for follow-up visits.

- Women of childbearing potential must have a negative beta-HCG (serum or urine) within
14 days prior to study treatment and must be willing to practice effective birth
control to prevent pregnancy while receiving treatment and for four months after
treatment is discontinued. All males of child fathering potential must also be
willing to practice effective birth control.

Note: Lapatinib is a tyrosine kinase inhibitor with the potential for teratogenic or
abortifacient effects. Because there is an unknown but potential risk for adverse events
in nursing infants secondary to treatment of the mother with lapatinib, breastfeeding
should be discontinued if the mother is treated with lapatinib. Should a woman become
pregnant or suspect she is pregnant while she or her partner is participating in this
study, the patient should inform the treating physician immediately.

- Ability to understand and the willingness to sign the Informed Consent Document.

- Patients who agree to participate in the PK portion of the study must be able to
swallow lapatinib tablets for the duration of the PK studies.

EXCLUSION CRITERIA:

- 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 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
Gilbert's 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.

- 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.

INCLUSION OF WOMEN AND MINORITIES:

Both men and women and members of all races and ethnic groups are eligible for this trial.

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Response rate to lapatinib in patients with metastatic melanoma harboring ERBB4 mutations.

Outcome Time Frame:

3 years

Safety Issue:

Yes

Principal Investigator

Udo Rudloff, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)

Authority:

United States: Federal Government

Study ID:

110048

NCT ID:

NCT01264081

Start Date:

December 2010

Completion Date:

November 2015

Related Keywords:

  • Malignant Melanoma
  • Lapatinib
  • Melanoma
  • ERBB4 Mutation
  • Malignant Melanoma
  • Skin Cancer
  • Melanoma

Name

Location

National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892
Memorial Sloan Kettering Cancer CenterNew York, New York  10021
Vanderbilt UniversityNashville, Tennessee  37232-6305