Conditions: Malignant Melanoma
Keywords: Lapatinib Melanoma ERBB4 Mutation Malignant Melanoma Skin Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 34
Healthy volunteers: no

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....

Detailed description:
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 Eastern Cooperative Oncology Group (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 (Partial Response (PR) + Complete Response (CR)) that can rule out 10% (p0=0.10) in favor of an improved response rate of 30% (p1=0.30).

Arms:
arm 1: Lapatinib will be administered as an oral dose of 500 mg twice daily in the morning and evening one hour before or after meals.

Interventions: intervention 1: Lapatinib
Intervention descriptions: intervention 1: 500 mg PO (orally) twice a day for 28 days (1 cycle). Up to 27 cycles allowed if response seen.

Protocol document:
Prot_SAP_000.pdf: 
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11-C-0048 
NCI Protocol #: 
P8786 
 
Local Protocol #: 
11-C-0048D 
 
TITLE:  A Phase II Study of Lapatinib for the Treatment of Stage IV Melanoma 
harboring ERBB4 Mutations 
 
Short Title: Lapatinib for melanoma 
 
Coordinating Center: 
National Cancer Institute, Surgery Branch  
 
*Principal Investigator: 
 
Udo Rudloff, M.D., Ph.D 
10 Center Drive, CRC Room 4-5950 
Bethesda, MD 20892  
Phone: 301-496-3098 
Fax: 301-402-1788 
Udo.Rudloff@nih.gov 
 
Associate Investigators: 
 
Yardena Samuels, Ph.D., NHGRI/NIH* 
Steven A. Rosenberg, M.D., Ph.D., SB/CCR/NCI 
James C. Yang, M.D. SB/CCR/NCI  
Richard Sherry, M.D., SB/CCR/NCI 
Marybeth Hughes, M.D., SB/CCR/NCI  
Udai S. Kammula, M.D., SB/CCR/NCI  
Dan Zlott, PharmD., NIH Clinical Center 
William D. Figg, Pharm.D., MOB/CCR/NCI* 
Adriana Byrnes, Ph.D., SAIC-Frederick, Inc.* 
Mary Ann Toomey, R.N., SB/CCR/NCI* 
 
*non-clinical investigators 
 
Responsible Research Nurse: 
Carole Webb, R.N., M.S.N., SB/CCR/NCI 
 
 
 
 
 
10 Center Drive, CRC Room 4-3752 
 
 
 
 
 
Bethesda, MD 20892 
 
 
 
 
 
Phone: 301.402.8475 
 
 
 
 
 
Fax: 301-451-6933 
 
 
 
 
 
E-mail: Webbcc@mail.nih.gov 
 
 
Study Statistician: 
 
 
Seth M. Steinberg, PhD, BDMS/CCR/NCI 
6116 Executive Blvd, Room 702 
Rockville, MD 20892 
Phone: 301-496-9502 
E-mail: steinbes@mail.nih.gov 
 
 


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11-C-0048 
 
 
Participating Site:   
 
Memorial Sloan Kettering Institute 
New York, NY 
 
Responsible Investigator: 
 
Mark Dickson, M.D. 
  
 
 
 
 
Phone: 212-639-5218 
  
 
 
 
 
E-mail: dicksonm@mskcc.org 
 
 
 
 
 
NCI Supplied Agent: 
Lapatinib (GW572016), NSC# 727989, IND# 70252 
 
Sponsor:  Cancer Therapy Evaluation Program (CTEP, NCI) 
 
Protocol Type/ Version #/ Version Date 
Original/Version 1.1/Version Date: 6-8-10 
 
 
 
 
 
 
 
First Review Version Date: 8-12-10 
 
 
 
 
 
 
 
Second Review Version Date: 8-23-10 
 
 
 
 
 
 
 
Third Review Version Date 10-13-10 
 
 
 
 
 
 
 
Fourth Review Version Date 11-15-10 
 
 
 
 
 
 
 
Fifth Review Version Date 11-18-10 
 
 
 
 
 
 
 
Sixth Review Version Date 3-1-11 
 
 
 
 
 
 
 
Seventh Review Version Date 3-17-11 
 
 
 
 
 
 
 
Eighth Review Version Date 5-5-11 
 
 
 
 
 
 
 
Ninth Review Version Date 9-8-11 
 
 
 
 
 
 
 
Tenth Review Version Date 9-14-11 
 
 
 
 
 
 
 
Eleventh Review Version Date 1-25-12 
 
 
 
 
 
 
 
Twelfth Review Version Date 2-2-12 
 
 


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PRECIS 
 
Background:  
g
 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:  
g
 Patients ≥ 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 ≤ 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: 
g
 Patients will be screened for the presence of ERBB4 gene mutations in their tumor and 
only patients who harbor ≤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 


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(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). 
 
 
TREATMENT SCHEMA 
 
 
 
 
¹ Lapatinib (GW2016) will be self-administered orally (po) 500mg bid; for 28 days in continuous cycles until disease progression 
occurs or the patient meets off-study criteria for a maximum of two years. 
² Optional tumor biopsies will be collected pretreatment and on day 14 of cycle 1 (+/- 5 days) and on day 28 of cycle 3 (+/- 5 
days). 
³ Physical examination (PE) and laboratory blood investigations will be performed bi-weekly for the first 3 cycles and then 
monthly thereafter 
΀ CT, MRI, or ultrasound imaging will be performed pretreatment, on day 28 of cycle 1 (+/- 5 days), on day 28 of cycle 3 (+/- 5 
days), and then after every other two completed cycles thereafter 


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TABLE OF CONTENTS 
 
 
 
 
 
 
Page 
PRECIS/SCHEMA ........................................................................................................................3 
1. 
OBJECTIVES .......................................................................................................................... 8 
1.1. 
Primary Objectives ........................................................................................................... 8 
1.2. 
Secondary Objectives ....................................................................................................... 8 
2. 
BACKGROUND ..................................................................................................................... 8 
2.1 
Melanoma ......................................................................................................................... 8 
2.2 
Lapatinib......................................................................................................................... 11 
2.3 
Rationale......................................................................................................................... 21 
2.4 
Correlative Studies Background..................................................................................... 27 
3. 
PATIENT SELECTION ........................................................................................................ 28 
3.1 
Eligibility Criteria .......................................................................................................... 28 
3.2 
Exclusion Criteria ........................................................................................................... 29 
3.3 
Inclusion of Women and Minorities............................................................................... 30 
3.4 
Research Eligibility Evaluation ...................................................................................... 31 
4. 
REGISTRATION PROCEDURES ....................................................................................... 32 
4.1  
Participating Sites ........................................................................................................... 32 
4.2  
NCI ................................................................................................................................. 32 
5. 
TREATMENT PLAN............................................................................................................ 32 
5.1 
Lapatinib Administration ............................................................................................... 32 
5.2 
Dosing Delays/Modifications ......................................................................................... 33 
5.3 
 On Study Evaluations .................................................................................................... 36 
5.4 
Research Evaluations ..................................................................................................... 37 
5.5 
General Concomitant Medication and Supportive Care Guidelines .............................. 40 
5.6 
Duration of Therapy ....................................................................................................... 41 
5.7 
Follow-Up Evaluations .................................................................................................. 41 
5.8 
Off Treatment Criteria .................................................................................................... 41 
5.9 
Off Study Criteria ........................................................................................................... 41 
6. 
DATA COLLECTION, MONITORING, AND REPORTING ............................................ 42 
6.1. 
Data Collection ............................................................................................................... 42 
6.2 
 Data Reporting .............................................................................................................. 42 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ................................ 43 
7.1 
 Comprehensive Adverse Events and Potential Risks List (CAEPR) ............................ 44 
7.2  
Adverse Event Characteristics ....................................................................................... 46 
7.3 
Expedited Adverse Event Reporting .............................................................................. 46 
7.4 
Routine Data Reporting .................................................................................................. 49 
7.5 
Secondary AML/MDS ................................................................................................... 50 


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7.6 
NCI-IRB Adverse Event Reporting ............................................................................... 50 
8. 
PHARMACEUTICAL INFORMATION ............................................................................. 51 
8.1 
Lapatinib (NSC 727989) ................................................................................................ 51 
8.2 
Availability ..................................................................................................................... 52 
8.3 
Agent Ordering ............................................................................................................... 53 
8.4 
Agent Accountability ..................................................................................................... 53 
9. 
STUDY CALENDAR .......................................................................................................... 54 
10. 
MEASUREMENT OF EFFECT........................................................................................ 55 
10.1 
Antitumor Effect – Solid Tumors ............................................................................... 55 
10.2 
Antitumor Effect – Hematologic Tumors ................................................................... 60 
11. 
REGULATORY CONSIDERATIONS ............................................................................. 60 
11.1 
CTEP Multicenter Guidelines .................................................................................... 60 
11.2 
Collaborative Agreements Language ......................................................................... 61 
12. 
STATISTICAL CONSIDERATIONS............................................................................... 63 
12.1 
Study Design/Endpoints ............................................................................................. 63 
12.2 
Sample Size/Accrual Rate .......................................................................................... 64 
12.3 
Stratification Factors................................................................................................... 64 
12.4 
Analysis of Secondary Endpoints ............................................................................... 64 
12.5 
Reporting and Exclusions ........................................................................................... 64 
13. HUMAN SUBJECTS PROTECTION ................................................................................... 65 
13.1 
Rationale for Subjects Protection ............................................................................... 65 
13.2 
Evaluation of Benefits and Risks/Discomforts ........................................................... 65 
13.3 
Consent and Assent Processes and Documents .......................................................... 66 
REFERENCES ............................................................................................................................. 66 
APPENDIX A:  CLINICAL TRIALS OF LAPATINIB IN BREAST CANCER ....................... 73 
APPENDIX B:  ERBB4 PRIMERS ............................................................................................. 74 
APPENDIX C:  PERFORMANCE STATUS CRITERIA ........................................................... 75 
APPENDIX C:  PERFORMANCE STATUS CRITERIA ........................................................... 75 
APPENDIX D:  LIST OF DRUGS THAT MAY HAVE POTENTIAL CYP3A4 
INTERACTIONS ......................................................................................................................... 76 
APPENDIX E:  LAPATINIB SCREENING SCHEMA .............................................................. 78 
APPENDIX F:  PATIENT MEDICATION DIARY .................................................................... 79 


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APPENDIX G:  LABORATORY METHODOLOGY FOR PHARMACOKINETICS STUDIES
....................................................................................................................................................... 80 
APPENDIX H: PRIMERS USED FOR PCR AMPLIFICATION AND SEQUENCING OF RAS 
AND RAF ISOFORMS ................................................................................................................ 83 
APPENDIX I:  SOP - DNA PCR AND SEQUENCING ASSAYS USING THE ABI 3730 ...... 84 
APPENDIX J:  PRIMERS FOR CDKN2A AND TP53 GENES ................................................. 92 
APPENDIX K:  GUIDELINES FOR MANAGEMENT OF GASTROINTESTINAL ADVERSE 
EVENTS ....................................................................................................................................... 93 
APPENDIX L:  CTEP MULTICENTER GUIDELINES ............................................................ 95 
 


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1. 
OBJECTIVES 
 
1.1. 
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. 
 
1.2. 
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 
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 
 
 
2. 
BACKGROUND 
 
2.1 Melanoma 
Melanoma skin cancer is currently the most rapidly rising solid organ cancer in both 
men and women in the Caucasian U.S population.1, 2  Predicted lifetime risk in the 
U.S. has risen to 1:58 in Caucasian males and 1:25 for Caucasian men in Australia.1, 3  
Overall, it is the sixth leading cancer in men and seventh most common in women 
with an annual incidence of 62,480 new cases and 8,420 deaths.  Metastatic 
melanoma ranks second in terms of loss of years of potential life.2 Metastatic 
melanoma has a poor prognosis with five-year survival of less than 5% with a median 
survival time of 6 months.1, 2  The last time a novel treatment received regulatory 
approval for metastatic melanoma dates back to 1998:4 FDA-approved treatments for 
metastatic melanoma include aldesleukin (IL-2) and dacarbazine (DTIC) 
chemotherapy.5 Aldesleukin has an objective clinical response rate of about 16%, a 
complete response rate of 6%, and cures about 4% patients with metastatic 
melanoma.6  Dacabarzine based chemotherapy has a clinical response rate of up to 
20% but almost no complete responders and all patients eventually recur.7, 8  Aside 
from dacarbazine, the only other single-agent chemotherapy shown to have impact on 
metastatic melanoma is temozolomide (TMZ), which is currently often given by 
many oncologists in the U.S. for off-protocol therapy for metastatic melanoma.8 
 
Given the encouraging results of an immunologic approach to the treatment of 
metastatic melanoma with aldesleukin, several other immunotherapy-based 


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approaches are currently under investigation: anti-CTLA-4 blockade using either 
ipilimumab or tremelimumab yields response rates even lower than the ones achieved 
by conventional cytotoxic chemotherapy listed above, and their toxicity, in particular 
with respect to severe, potentially life-threatening autoimmune events does 
substantially limit their use.9, 10  Adoptive cell therapy (ACT), as pioneered by the 
Surgery Branch/NCI, refers to an immunotherapy approach in which anti-tumor 
lymphocytes are identified and grown ex vivo and then infused back into the patient 
with or without preselection or genetic manipulation, often along with vaccines or 
growth factors that can augment the in vivo impact of the transferred cells.11, 12 While 
with the use of preconditioning lymphodepletion this approach achieves impressive 
response rates of > 70% in select group of patients, only a limited number of patients 
are eligible and the tremendous financial and laboratory resources required prevents 
this approach currently from a more widespread application.13  
 
Targeted therapy in melanoma 
In view of the limited clinical efficacy of the treatment options listed above novel 
strategies on the development of targeted therapies that capitalize on the recent 
advances in the genetic understanding of melanoma pathogenesis have been 
pursued.14  Many of the molecular therapy trials listed below, however, administered 
single agents in a non-selected manner negating the advantage of a genotype-directed 
treatment strategy which is likely why to date none of the novel targeted single agents 
evaluated in melanoma without additional patients’ selection have shown any 
clinically meaningful activity.15  This rather bleak outlook has only very recently 
started to change with novel molecular agents specifically targeting tumors harboring 
the BRAFV600 mutation or with the latest success of imatinib (Gleevec®) in 
melanoma harboring c-KIT mutations.16, 17 
 
RTK/RAS/BRAF/MEK pathway 
BRAF 
The serine/threonine kinase BRAF of the MAPK pathway is mutated in 
approximately two-thirds of melanoma cases and constitutes the most commonly 
mutated oncogene in melanoma.18, 19 BRAFV600 mutations have a 480-fold increase 
in the activity of BRAF over wild type, thus making it an attractive therapeutic 
target.19  
 
The agent that has been most widely investigated in the context of targeted therapy 
against BRAF is the multikinase inhibitor sorafenib.20, 21  In addition to BRAF, 
sorafenib targets Flt-3, CRAF, VEGF and PDGFβ.  As a single agent, sorafenib has 
limited activity in melanoma, as demonstrated in a phase 2 trial showing no responses 
in 37 mostly heavily pretreated patients with metastatic melanoma.22  Similar results 
have been obtained when sorafenib was combined with chemotherapy.23  
 
MEK 
The rationale for MEK inhibition as a prime target for melanoma stems from BRAF’s 
downstream dependence on MEK for signal propagation.  In a phase 1 study of 66 


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patients with various advanced malignancies including melanoma, C-1040 was found 
to be moderately effective.24  A phase 1/2 trial of PD0325901, a second-generation 
MEK inhibitor enrolled 27 patients and demonstrated partial responses in 2/27 and 
stable disease in 5/27.25 The compound AZD6244 is currently in phase II clinical 
trials where patients are selected upon presence of BRAFV600 mutation status.26 
 
PTEN/PI3K/Akt3 pathway 
The PI3K/Akt3 signaling pathway is aberrantly activated in up to 70 % of 
melanomas.27  In preclinical models, strategies using single agent PI3K, Akt, mTOR, 
or combined PI3K/mTOR inhibition have shown to be successful.28, 29  The approach 
to target direct substrates of Akt3, such as mTOR with temsirolimus and everolimus, 
is the clinically most advanced.  However, in a phase 2 trial of 33 patients with 
metastatic melanoma, monotherapy with temsirolimus showed minimal efficacy. 
Similar results were seen in an interim analysis of a two-stage phase 2 trial using 
everolimus as monotherapy in patients with stage IV melanoma.30  
 
c-KIT 
Oncogenic mutations in c-KIT in melanoma follow a very heterogeneous pattern.31 39 
% of melanomas at mucosal sites, 36 % at acral sites, and 28 % of chronically sun-
damaged skin show oncogenic mutations or/and copy increases of KIT. The 
preferential involvement of c-KIT in these rarer types of melanoma, i.e. acral and 
mucosal, may explain the negative results of imatinib in an initial phase 2 trial of 
unselected patients.32  
 
Despite published results of targeted therapy in melanoma being largely unsuccessful, 
two recent prime examples of successful genotype-directed therapy have recently 
started to change the outlook of molecular therapy in this disease: PLX4032 is a novel 
compound designed to target the BRAFV600 mutation in melanoma, where the TKI 
has substantially increased affinity to the mutated molecule compared to the wild type 
receptor.33  PLX 4032 has more than a 1000-fold increased sensitivity to mutant 
BRAFV600 than wild type BRAF kinase, and initial results from several trials 
underway have shown objective response rates of greater than 70% in patients who 
harbor this mutation.16, 33  Similarly, recent findings of a genotype-directed approach 
targeting mutated c-KIT with imatinib in melanoma yielded equally impressive 
results.17 
 
In summary, while unselected molecular therapy in melanoma has yielded largely 
disappointing results, the most recent examples of genotype-directed targeted therapy 
in melanoma including PLX-4032 targeting activating BRAFV600 mutations and 
imatinib targeting c-KIT mutations, have yielded very promising results and ask 
together in light of the paucity of other treatment options for the rapid identification 
of additional targets and treatment strategies. Targeting melanoma harboring 
activating somatic mutations of the Erbb4 receptor with the dual tyrosine kinase 
inhibitor lapatinib might yield similar success as targeting activating EGFR receptor 
mutations in lung cancer with erlotinib or gefitinib, and might increase the 


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armentarium of meaningful therapeutic strategies in this disease. 
2.2 
Lapatinib 
Mechanism of Action 
Lapatinib is an allosteric, orally administered small-molecule tyrosine kinase inhibitor 
that targets both EGFR and Erbb2/HER2 of the Erb growth factor receptor family.34, 
35 It binds in a reversible, competitive way to the ATP-binding cleft of the C-terminal 
kinase domain of the receptor preventing transphosphorylation and activation of the 
bound co-receptor.36, 37  Non-phosphorylated Erb receptors are not able to initiate 
downstream signaling either via binding to the p85 subunit of PI3K leading to 
activation of the PI3K-Akt pathway, nor through binding of the adaptor proteins SOS 
and GAP proteins and signal transduction via the MAPK pathway.38, 39  Members of 
the Erbb family are structurally very similar membrane-spanning tyrosine kinase 
receptors composed of an extracellular domain subdivided into 4 subdomains, an α-
helical transmembrane segment, and an intracellular protein kinase domain (Fig. 1).39  
Erbb receptor activation requires dimerization of two Erbb molecules which normally 
exist as inactive monomers.  Ligand binding induces the release of intramolecular 
bonds (‘autoinhibition’) between the extracellular domains II and IV leading to a 
conformational twist which exposes the dimerization domain in subunit II of the 
receptor.39  Pairing with another receptor leads to activation of the kinase domain, 
phosphorylation of the other receptor, and consequently binding and activation of 
downstream proteins (Fig. 1).39  In general, the nature of the activating ligand and the 
different homo- and heterodimer pairings are the major determinants of which of the 
various downstream targets are activated. Fig. 2 depicts Erb-mediated downstream 
signaling via the MAPK kinase and PI3K-Akt pathways. 
 
 


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Fig 1. Ligand activation of Erb family receptors. Ligand-binding to subregions I and 
III of the ectodomain of the closed, ‘thethered’ from of the receptor prompts a 
conformational ‘switch’ of the molecule characterized by the formation of a ligand-
binding pocket formed by subregions I,II, and III and a 180° twist and exposure of the 
dimerization region of subdomain II as a prerequisite for dimerization and signal 
transduction activation (from Rudloff U, Samuels Y. Cell Cycle 2010) 
 
 
 
Fig. 2 Post-receptor signal transduction pathways of Erb-receptor mediated signal 
transductions occurs mainly via the PI3K-Akt and MAPK kinase pathways (Erbb-
mediated STAT signaling not shown) (Rudloff U, Samuels Y. Cell Cycle 2010) 
 
Activating somatic mutations of Erb receptors (e.g. L858R or del747 mutations of the 
kinase domain of the EGFR receptor in lung cancer) or amplification of the 
Erb2/HER2 receptor in breast cancer lead to abnormal, constitutive Erb receptor 
signaling, activation of mitogenic pathways, and abnormal cellular proliferation.40-42 
When Erb receptors are affected by somatic mutations, Erbb family members 
including EGFR, HER2, ErBB3, or ErBB4 are able to drive the growth of the 
malignancy through increased autophosphorylation and downstream signaling 
following dysregulated homo- and heterodimerization or constitutive activation of the 
kinase domain.40-42  These tumors gain their growth advantage from abnormal Erb 
signaling having become ‘addicted’ to aberrant Erb signaling.  Such ‘oncogene 
addiction’ has been shown to be the the prime model for targeted therapy, like the use 


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11-C-0048 
of the tyrosine kinase inhibitors erlotinib and gefitinib in lung cancer harboring EGFR 
mutations L858R and del747. This success now provides a strong rationale for the use 
of lapatinib in melanoma targeting activating somatic mutations of the ERBB4 
receptor.39, 42  
 
In addition to its excellent activity against EGFR and ERBB2/HER2, lapatinib also 
has activity against ERBB4.34  Lapatinib binds to an inactive form of the ERBB4 
kinase in a mode equivalent to its interaction with the EGFR receptor, a finding 
which is also supported by the fact that all ERBB4 residues contacted by lapatinib at 
its binding site are conserved across multiple species in the EGFR and ERBB2/HER2 
receptor.37 Table 1 lists the inhibitory concentrations (IC50s) for the EGFR, 
ERBB2/HER2, ERBB4 receptor, as well as a large panel of kinases unrelated to the 
Erb receptor family.  Lapatinib is highly selective for EGFR and HER2 enzymes, 
with 50% inhibitory concentrations (IC50) of 10.8 nmol/L and 9.2 nmol/L, 
respectively.34 The additional kinases tested were not inhibited until IC50 values 
reached >3,500 nmol/L, with the exception of ERBB4, for which the IC50 was 347 
nmol/L.  When IC50s for ERBB4 inhibition by lapatinib were determined in various 
cell culture models, the IC50 in vivo (367 nM) were nearly identical to the IC50s 
predicted from the in vitro data and confirmed the high selectivity of lapatinib for the 
Erb receptor family, including ERBB4, compared to other protein kinases (Table 1).34  
 
Table 1. Structure and enzyme inhibitory activity (IC50) of lapatinib (GW2016) 
(from Rusnak DW. Mol Cancer Ther 2001) 


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Pharmacokinetics  
A number of phase I trials evaluating the pharmacokinetics of lapatinib have been 
conducted.  In general, lapatinib is well tolerated without the need for dose 
adjustment up to 1,800 mg once daily and 500 mg twice daily.43-48 
 
Lapatinib serum concentrations increase  
 Proportionally with increase in daily dose 
 Repeat dosing 
 When taken with food, in particular high-fat meals 
 
The pharmacokinetic properties of lapatinib for once daily and twice daily dosing are 
summarized in Table 2 and discussed in the following paragraphs. 


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Table 2. Summary of pharmacokinetic data on different dosing regimens for lapatinib 
(from Burris HA. Clin Cancer Res 2009) 
 
At the dose of 1,250mg daily, steady state geometric mean (95% confidence interval) 
values of Cmax were 2.43 mcg/mL (1.57 to 3.77 mcg/mL) and AUC were 36.2 mcg 
hr/mL (23.4 to 56 mcg.hr/mL).45, 49 
 
Absorption 
On administration of doses of 25, 100, or 175 mg, oral absorption is delayed by ~30 
minutes and Tmax is 3 to 4 hours.43  Time-dependent increases in Cmax and AUC are 
detected at the higher doses (100 and 175 mg) but not at the lower dose. 
At the FDA-approved dose of 1,250 mg/d, the steady-state Cmax and AUC are 2.54 
μg/mL and 36.2 μg h/mL, respectively.50, 51 Administering lapatinib in divided daily 
doses increased the steady-state AUC ~2-fold compared with the same total dose 
administered once daily (Fig. 3).45  


16 
11-C-0048 
 
Fig 3. Steady state 24-h AUC for once daily dosing (fat curve; ο) and twice daily 
dosing (thin curve; ∆) of lapatinib (from Burris HA. Clin Cancer Res 2009) 
 
With multiple daily dosing of lapatinib, steady state was achieved within 6 to 7 
days.45 Systemic exposure to lapatinib is increased when the drug was administered 
with food, the greatest effect occurring with a high-fat meal.52 The AUC was 
increased by 325% and 167% when taken with high- and low-fat meals, 
respectively.52  However, while administration with food increased bioavailability of 
lapatinib, there was also increased variability in drug concentration potentially 
leading to increased toxicity. 52  
 
Distribution 
At concentrations of 1 μmol/L, lapatinib is highly bound (>99%) to albumin and to α-
1 acid glycoprotein.52 The volume of distribution (Vd/L) of the terminal phase of 
lapatinib is >2,200 L, indicating good drug distribution.51, 52 
 
Metabolism 
Lapatinib is primarily metabolized to oxidated metabolites by the cytochrome P450 
(CYP) 3A4, 3A5, 2C19, and 2C8 isozymes.44  Approximately 70% of its metabolism 
is through CYP3A4.  No metabolite constitutes >15% of recovered drug.  One 
metabolite (GW690006) remains active against EGFR but not HER2, whereas other 
metabolites appear to be inactive.51 
 
Elimination 
Lapatinib is primarily eliminated hepatically, with 27% of an oral dose recovered in 
feces and <2% recovered in the urine.50  The elimination t 1/2 is 14.2 hours in single-
dose studies and ~24 hours with repeated dosing (as a result of drug accumulation).50, 
51 
Drug interactions 
Lapatinib is a major substrate for and inhibitor of CYP3A4 and an inhibitor of 
CYP2C8.  Ketoconazole, a CYP3A4 inhibitor, increases the AUC of lapatinib 3.6-


17 
11-C-0048 
fold relative to control, and the t1/2 increased 1.7-fold relative to control.50, 51 In 
contrast, carbamazepine, a CYP3A4 inducer, decreased the AUC of lapatinib by 
~75%.50, 51 
 
Maximum Clinically Achievable Concentration of Lapatinib  
Based on the available PK data for lapatinib, a dosing regimen of 500 mg twice daily 
provides the highest Cmax and Cmin without prohibitive GI toxicity.45  Calculating 
Cmax and Cmin for both 1,200 mg once daily and 500 mg twice daily, the maximally 
achievable concentration in humans for lapatinib is 4.07x10-6mol/L. This information is 
based on 
 
 
and the known molecular weight of lapatinib of 943.5.   
 
Lapatinib in Phase 2 and 3 Studies with Advanced or Metastatic Breast Cancer 
In the sentinel, randomized, open-label phase 2 study of lapatinib monotherapy as 
first-line treatment in patients with HER2-positive advanced or metastatic breast 
cancer, patients were randomized to receive oral lapatinib either as 1,500 mg QD (n = 
69) or 500 mg BID (n = 69).53 Overall, there was a 24% response rate (CR + PR) and 
a clinical benefit (CR, PR, + SD >24 weeks) of 31%, with no significant differences 
in these outcomes between treatment groups.  Most responses (32/33) occurred by 
week 12, with a median time to response of 7.9 weeks.  The responses were durable, 
with a median duration of response of 28.4 weeks and a 6-month PFS of 43%. This 
study showed that lapatinib in breast cancer has clinical efficacy as first-line 
treatment.53 
 


18 
11-C-0048 
In the international, multicenter, open label phase 3 trial leading to regulatory 
approval of lapatinib in HER2-positive metastatic breast cancer that is refractory to 
regimens including an anthracycline, a taxane, and trastuzumab, patients were 
randomly assigned in a 1:1 ratio to receive oral lapatinib 1,250 mg QD on an ongoing 
basis and oral capecitabine 2000 mg/m2 given in 2 divided doses on days 1 through 
14 of a 21-day cycle, or monotherapy with capecitabine 2,500 mg/m2 given in 2 
divided doses on days 1 through 14 of a 21-day cycle.54  The primary end point, TTP, 
was defined as the time from randomization to tumor progression or death related to 
breast cancer.  After independent review, the interim analysis of TTP met the 
prespecified criteria for early reporting based on the superiority of lapatinib + 
capecitabine relative to capecitabine monotherapy.54  There were 49 disease-
progression events in the combination therapy group and 72 in the monotherapy 
group, and the median TTP was 8.4 and 4.4 months, respectively.  The hazard ratio 
(HR) for TTP with combination therapy was 0.49 (95% CI, 0.34-0.71; P < 0.001). At 
the time of the interim analysis, there were no differences in OS between the groups, 
and 22% of patients in both groups had died. The updated analysis included 82 
disease-progression events with the combination of lapatinib + capecitabine and 102 
events with capecitabine monotherapy confirmed these findings.55 The median TTP 
for combination therapy was 6.2 months, compared with 4.3 months for capecitabine 
alone (HR = 0.57; 95% CI, 0.43-0.77; P < 0.001), indicating a 43% reduction in the 
relative risk of progression with the addition of lapatinib to capecitabine. Similarly, 
there was an improvement in PFS (HR = 0.55; 95% CI, 0.40-0.74; P < 0.001), 
indicating a 45% relative risk reduction in PFS with combination therapy. Although 
there was a reported improvement in OS with combination therapy (HR = 0.78), the 
difference did not reach statistical significance. Appendix A summarizes the outcome 
of clinical trials of lapatinib in advanced or metastatic breast cancer.49 
 
For phase II drugs against solid organ tumors, designs with (p1=targeted response 
rate; p0=low response rate) equal to (0.05; 0.20), (0.05; 0.25), or (0.10; 0.30) are most 
commonly used. Even when done in a genotype-directed fashion, molecular therapy 
trials have often only response rates of 25 – 30% in the metastatic setting when 
administering the agent to heavily pretreated patients. Additionally, as listed above, 
response rates of advanced or metastatic breast cancer to lapatinib have been reported 
in the 4.3 – 35.1% range (Appendix A). Thus, while p1 – p0 = 0.15 is reaching the 
smallest difference considered clinically interpretable, we are aiming to target 30% 
and hoping to rule out 10% as our response rate. 
 
 
Toxicity Profile of Lapatinib 
Similar to other tyrosine kinase inhibitors, lapatinib is well tolerated.  The most 
common clinical toxicities of all grades (occurring in ≥ 10%) associated with 
lapatinib in the sentinel phase 1 and 2 study of lapatinib monotherapy were diarrhea, 
rash, pruritus, and nausea (diarrhea (46%) and rash (32%)).45, 49, 54 Diarrhea events 
were mainly grade 1 or 2, as were rash events.49 The incidence of adverse events 
(AEs) considered by investigators to be related to lapatinib was equal between the 


19 
11-C-0048 
treatment regimens of 1,500 mg daily and 500 mg twice daily, affecting 71% of 
patients overall.60  These events were also mainly grade 1 or 2 in toxicity (60%); only 
9%, less than 1% of all patients, were reported to be grade 3, 4, and 5.  The most 
frequently reported AEs related to lapatinib monotherapy, including diarrhea (36%), 
rash (27%), pruritus (18%), and nausea (10%), are listed in Table 3. All other 
lapatinib-related AEs occurred in less than 10% of patients.53 
 
 
Table 3. Patients with drug-related adverse events that occurred in 10% of patients 
receiving lapatinib monotherapy (from Gomez HL. JCO 2008) 
 
Similar results were observed when lapatinib was given in combination with 
capecitabine where diarrhea (65%), hand-foot syndrome (53 %), nausea (44%), rash 
(29%), and fatigue (24%) occurred most commonly.54, 55 Discontinuation rates of 
lapatinib in both the combination and monotherapy group occurred in 14% of the 
cases and did not differ.55  Dose interruptions and adjustments due to AEs did also not 
differ between groups. Diarrhea and rash occurred more occurred more frequently in 
the combination-therapy group than in the monotherapy group (65% vs 34%, and 
29% vs 14%, respectively), however, the differences in both diarrhea and rash were 
the result of increases in grade 1 adverse events with no statistically significant 
difference in higher-grade toxicities. 
 
GI Toxicity 
In the sentinel phase 1 trial of lapatinib, the incidence of diarrhea has been found to 
increase at higher doses, not at higher serum concentrations, suggesting that this 
adverse effect is the result of unabsorbed drug.44 The development of rash did not 
appear to be dose or serum related.44, 45 


20 
11-C-0048 
 
In the twice daily dosing group, grade 3 diarrhea (total of 17%) was the limiting 
toxicity.60  None in the 500 mg twice daily group required dose reductions due to 
diarrhea. However, in the 900 mg twice daily and 750 mg twice daily group, 33 
percent of patients required dose modifications.60  The frequency of diarrhea as the 
most common dose-limiting toxicity (DLT) of lapatinib following administration 
once (QD) and twice (BID) daily doses is shown in Fig. 4 (from Burris HA. Clin 
Cancer Res 2009). 
 
Fig. 4 Grade 1, 2, and 3 diarrhea as the most common adverse event in relation to 
different doses and dosing schedules (from Burris HA. Clin Cancer Res 2009) 
 
In general, diarrhea events with lapatinib are in the majority of cases of grade 1 and 2 
severity.  No fatal lapatinib-associated diarrhea events have been reported.  Lapatinib-
related diarrhea occurs early usually within the first two weeks of treatment.60 The 
median duration of diarrhea with lapatinib was 5 days, with 85% of patients requiring 
no dose adjustment or interruption, and only 2% discontinuing therapy due to 
diarrhea.60 In general, severe diarrhea did not occur with lapatinib-containing 
regimens when proactive monitoring and appropriate intervention was instituted in a 
timely manner.  
 
Dermatologic Toxicity 
The second most frequently reported adverse events associated with lapatinib consist 
of dermatologic toxicities.  Similar to lapatinib-related diarrhea, these are most 
commonly toxicities of grade 1 and 2 severity.61  These include in decreasing order 
hand-foot syndrome (palmar plantar erythrodysesthesia), rash, hair disorder, dry skin, 
pruritus/urticaria, skin disorder, skin infection, and nail disorder.  In patients 


21 
11-C-0048 
receiving lapatinib monotherapy, 55% experienced grade 1 or 2 dermatologic events; 
no grade 4 events were observed.53 Rash was the most common dermatologic event 
(43%).  Dermatologic events typically developed early (within days 1-14), lasted a 
median of 29 days, and did not require any intervention or lapatinib dose reduction, 
interruption, or discontinuation.54, 61  
 
Cardiac Toxicity 
In a comprehensive review of 3,689 patients enrolled in phase 1-3 trials of lapatinib 
monotherapy and combination therapy in breast cancer a search for cardiotoxicity 
was performed by using either grade 3 or 4 toxicities according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) or 
asymptomatic decreases in LVEF >20% from baseline or below the institutional 
normal.62 The cardiac event rate was reported as 1.6% (n = 60); the event was not 
preceded by symptoms in 53 of these 60 patients.62  In 88% (n = 35) of the 40 patients 
the decrease in ventricular function improved or resolved spontaneously. The 
decrease was rarely severe (0.2%).  These preliminary data indicate no incremental 
risk of cardiac toxicity with the addition of lapatinib, although further studies of the 
cardiac tolerability of this combination are needed. 
 
Hepatic Toxicity 
Since lapatinib is mainly eliminated hepatically, dose adjustments are advised in 
patients with hepatic dysfunction.51 In a small study in patients with Child-Pugh class 
B and C liver impairment (excluded from this study), AUC after one single dose of 
100 mg lapatinib increased more than three-fold.50  Dose reductions to 500 mg or 750 
mg daily have been suggested.   
 
2.3 
Rationale 
Mutations of the Growth Factor Receptor Kinase 4 (ERBB4) are Common in 
Metastatic Melanoma 
One of the most promising aspects of cancer treatment is genotype-directed 
therapeutics targeted at constitutively activated signal transduction pathways.15  A 
recent high-throughput sequencing effort of the entire protein tyrosine kinase gene 
family in a large tumor bank of metastatic melanoma tissues identified several novel 
promising targets in this disease.63  Sequence analysis of 593 exons of 89 genes of 79 
melanoma samples (~ 12Mb) identified 19 genes with somatic mutations within the 
kinase domains of protein tyrosine kinases.63  In total, 19 percent of melanoma 
samples contained somatic gene mutations of the ERBB4 receptor, making it together 
with Braf, TP53, CDKN2A, and PTEN one of the most commonly mutated genes in 
melanoma. 
 
Increased activity of Erb receptors due to activating somatic gene mutations or 
amplifications of the HER2 gene has been found in several other histologies like 
breast, lung, and colon cancers, among others.64, 65  Targeted therapy with 
trastuzumab (Heceptin), erlotinib, or gefitinib against Erb or EGFR mediated cell-
signaling in breast, pancreas, or lung cancer, to name a few, has recently found FDA 


22 
11-C-0048 
approval and has now an established role in the treatment of these malignancies.66-69  
Mutated ERBB4 appears now to be a similarly attractive target for molecular therapy 
in melanoma: 
 
Mutations of ERBB4 are Oncogenic in Melanoma 
ERBB4 mutants show increased autophosphorylation and activation of the ERBB4 
receptor 
To show that mutations of ERBB4 identified in melanoma patients have increased 
kinase activity and increased activation of the ERBB4 receptor, wild type (WT) 
ERBB4 or seven mutants (E317K, E452K, E542K, R544W, E563K, E836K, E872K) 
found in the sequencing screen and shown in Fig. 4 were stably expressed in both 
HK293T cells and human melanoma cell lines. Compared to WT ERBB4 expressing 
cell lines, all the missense mutants showed a marked increase in total phosphorylation 
of the receptor, and increased tyrosine phosphorylation of the ERBB4 mutants 
correlated with increased kinase activity and activation of ERBB4. 
 
 
 
 
 
 
 
 
 
Fig. 5 Distribution of mutations in ERBB4 in metastatic melanoma. Red stars indicate 
ERBB4 mutants used in subsequent analysis (from Prickett TD. Nat Genet 2009) 
 
Mutated ERBB4 leads to increased activation of the Akt pathway 
ERBB4 is known to activate several downstream signaling pathways including the 
extracellular signal-regulated kinase 1 (ERK1) and ERK2 pathway and the AKT 
pathway. Both pathways are known to play pivotal roles in the process of malignant 
transformation in the development of various cancers including melanoma.21, 70 
Phosphoimmunoblot experiments in transfected melanoma cells demonstrated that the 
identified mutations in the ERBB4 receptor lead to activation of the Akt pathway in 
melanoma. Downstream signaling of mutated ERBB4 is nearly exclusively mediated 
via the Akt pathway with no effect on the MAPK pathway. 
Mutations of the ERBB4 receptor are oncogenic in melanoma 
To determine that the ERBB4 variants are transforming, NIH 3T3 cells were 
transiently transfected with vector, WT ERBB4, the seven constitutively active 
ERBB4 mutants described above, or oncogenic K-RasG12V. All ERBB4 mutants 
transformed NIH 3T3 cells more efficiently than WT ERBB4. Strikingly, the 
transformation ability of the ERBB4 mutations was similar to oncogenic K-Ras 
G12V, one of the most potent oncogenes. The transformation abilities of mutant 
E452K
E872K
*
*
*
ERBB4
I
II
III
IV
PTK
*
** *
Receptor L domain
Receptor L domain
GFR domain
GFR domain
29
502
331
206
974
634 718
L39F
Y111H
M313I
E317K
S341L
R393W
P409L
R491K
E542K
R544W
E563K
D609N
P700S
E836K
G936R
P1033S
R1174Q
S1246N
E452K
E872K
*
*
*
ERBB4
I
II
III
IV
PTK
*
** *
Receptor L domain
Receptor L domain
GFR domain
GFR domain
29
502
331
206
974
634 718
L39F
Y111H
M313I
E317K
S341L
R393W
P409L
R491K
E542K
R544W
E563K
D609N
P700S
E836K
G936R
P1033S
R1174Q
S1246N
E872K
*
*
*
ERBB4
I
II
III
IV
PTK
*
** *
Receptor L domain
Receptor L domain
GFR domain
GFR domain
29
502
331
206
974
634 718
L39F
Y111H
M313I
E317K
S341L
R393W
P409L
R491K
E542K
R544W
E563K
D609N
P700S
E836K
G936R
P1033S
R1174Q
S1246N


23 
11-C-0048 
ERBB4 are shown in Fig. 6 by significantly increased anchorage-independent growth 
of NIH 3T3 and melanoma SK-Mel-2 cells transfected with mutant ERBB4. 
 
 
 
 
 
 
 
 
 
 
 
Fig. 6 Mutant ERBB4 induces cell transformation and anchorage-independent growth 
in NIH3T3 and melanoma SK-Mel-2 cells (Prickett TD. Nat Genet 2009) 
 
In order to show that melanoma cells harboring endogenous ERBB4 mutations are 
dependent on ERBB4 signaling for proliferation, short hairpin RNA (shRNA) was 
used to stably knockdown ERBB4 protein levels in melanoma lines harboring either 
WT or mutant ERBB4. Three unique shRNA constructs targeting ERBB4 had 
minimal effect on the proliferation of cells expressing WT receptor but significantly 
reduced the growth of melanoma lines containing mutant ERBB4 (Fig. 7). Evaluation 
of the effects of ERBB4 knockdown on downstream signaling pathways revealed that 
down-regulation of ERBB4 in cells harboring mutant versions of the gene reduces 
levels of endogenous, phosphorylated Akt, but not of phosphorylated ERK.  
Vector
WT
E452K
E872K
E317K
R544W
E563K
E836K
Ras G V12
0
5000
10000
15000
20000
25000
Average number 
of foci
E542K
NIH 3T3 
Vector
WT
E452K
E872K
E317K
R544W
E563K
E836K
Ras G V12
0
5000
10000
15000
20000
25000
Average number 
of foci
E542K
NIH 3T3 
0
SK-Mel-2 ERBB4 pooled clones
Average number 
of foci
Vector
WT
E452K
E872K
E563K
50
100
150
200
250
300
350
400
450
0
SK-Mel-2 ERBB4 pooled clones
Average number 
of foci
Vector
WT
E452K
E872K
E563K
50
100
150
200
250
300
350
400
450


24 
11-C-0048 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fig. 7 Expression of mutant ERBB4 provides an essential cell survival signal in 
melanoma. Knockdown of endogenous, mutant ERBB4 with shRNA abolishes cell 
growth in metastatic melanoma (Prickett TD. Nat Genet 2009) 
 
In summary, mutant ERBB4 is essential for growth of melanoma cells harboring these 
mutations, and ‘oncogene addiction’ in these melanomas is mediated by activation of 
the Akt pathway. 
 
Lapatinib effectively inhibits ERBB4 mediated cell signaling in vitro and in vivo in 
metastatic melanoma 
Exposure of melanoma cells to lapatinib resulted in reduced cell proliferation to a 
significantly greater extent in cells containing ERBB4 mutations than in cells 
containing endogenous WT ERBB4 (Fig. 8). An IC50 calculation of this inhibition 
revealed that melanoma cells harboring ERBB4 mutations were 10-250 fold more 
0
5000
10000
15000
20000
25000
30000
35000
0
2
4
6
8
10
12
14
63T (E542K / E872K) shRNA clones
Days
Cell Number
0
5000
10000
15000
20000
25000
30000
35000
0
2
4
6
8
10
12
14
63T (E542K / E872K) shRNA clones
Days
Cell Number
0
1000
2000
3000
4000
5000
6000
7000
8000
9000
0
5
10
15
17T (E317K) shRNA clones
Days
Cell Number
0
1000
2000
3000
4000
5000
6000
7000
8000
9000
0
5
10
15
17T (E317K) shRNA clones
Days
Cell Number
31T (WT) shRNA clones
Days
0
2000
4000
6000
8000
10000
12000
0
2
4
6
8
10
12
14
16
18
31T (WT) shRNA clones
Days
0
2000
4000
6000
8000
10000
12000
0
2
4
6
8
10
12
14
16
18
control
shRNA #6
shRNA #7
shRNA #8
control
shRNA #6
shRNA #7
shRNA #8
Cell Number
0
10000
20000
30000
40000
50000
60000
70000
80000
0
2
4
6
8
10
12
14
16
18
2T (WT) shRNA clones
Days
Cell Number
0
10000
20000
30000
40000
50000
60000
70000
80000
0
2
4
6
8
10
12
14
16
18
2T (WT) shRNA clones
Cell Number
0
10000
20000
30000
40000
50000
60000
70000
80000
0
2
4
6
8
10
12
14
16
18
2T (WT) shRNA clones
Days
0
1000
2000
3000
4000
5000
6000
7000
8000
9000
0
2
4
6
8
10
12
14
7T (E452K) shRNA clones
Days
Cell Number
0
1000
2000
3000
4000
5000
6000
7000
8000
9000
0
2
4
6
8
10
12
14
7T (E452K) shRNA clones
Days
Cell Number


25 
11-C-0048 
sensitive to lapatinib than cells with WT receptor. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fig. 8 Melanoma lines expressing ERBB4 mutants are sensitive to ERBB4 inhibition by lapatinib. 
Representative dose response curves for ERBB4 WT and ERBB4 mutants, the inhibition of Akt 
signaling by lapatinib, and the induction of apoptosis by lapatinib in ERBB4 mutants is shown 
(Prickett TD. Nat Genet 2009) 
 
PI-Area
M1
M1
0
200
400
600
800
1000
0
60
120
180
240
300
Counts
12T (E563K)
31T (WT)
0
200
400
600
800
1000
M1
M1
PI-Area
Counts
0
70
140
210
280
350
Vehicle
Lapatinib
PI-Area
M1
M1
0
200
400
600
800
1000
0
60
120
180
240
300
Counts
12T (E563K)
31T (WT)
0
200
400
600
800
1000
M1
M1
PI-Area
Counts
0
70
140
210
280
350
Vehicle
Lapatinib
Cell line (mutation)
IC50 (nM)
Std Error 
(+/- nM)
68T (splice site)
131.8
1.97
49T (R393W)
259.6
3.27
12T (E563K)
324.6
4.87
17T (E317K)
513.8
6.36
7T (E452K)
1365
19.3
71T (L39F, S1246N)
1446
19.5
63T (M313I, E542K, E872K, R1174Q)
3213
40.5
31T (WT)
11370
157
93T (WT)
31860
523
2T (WT)
32980
861
39T (WT)
34050
661
1
2
3
4
5
0
50
100
Log [lapatinib] (nM)
% Survival
39T (WT)
31T (WT)
49T (R393W)
12T (E563K)
1
2
3
4
5
0
50
100
Log [lapatinib] (nM)
% Survival
39T (WT)
31T (WT)
49T (R393W)
12T (E563K)
39T (WT)
31T (WT)
49T (R393W)
12T (E563K)
vehicle
lapatinib
AKT
0
0.2
0.4
0.6
0.8
1
1.2
Fold  change
39T-WT
7T-E452K
63T-
E542K/E872K
17T-E317K
WT
MUTANT
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
39T-WT
31T-WT
7T-E452K
17T-E317K
WT
MUTANT
ERBB2
Fold change
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
39T-WT
31T-WT
7T-E452K
17T-E317K
WT
MUTANT
ERBB4
Fold change
63T-
E542K/E872K
63T-
E542K/E872K
vehicle
lapatinib
vehicle
lapatinib
AKT
0
0.2
0.4
0.6
0.8
1
1.2
0
0.2
0.4
0.6
0.8
1
1.2
Fold  change
39T-WT
7T-E452K
63T-
E542K/E872K
63T-
E542K/E872K
17T-E317K
WT
MUTANT
WT
MUTANT
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
39T-WT
31T-WT
7T-E452K
17T-E317K
WT
MUTANT
WT
MUTANT
ERBB2
Fold change
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
39T-WT
31T-WT
7T-E452K
17T-E317K
WT
MUTANT
WT
MUTANT
ERBB4
Fold change
63T-
E542K/E872K
63T-
E542K/E872K
63T-
E542K/E872K
63T-
E542K/E872K
WT
MUTANT
0
10
20
30
40
50
60
39T (WT)
2T (WT)
56T (R544W)
12T (E563K)
17T (E317K)
7T (E452K)
% Apoptotic cells
0hr
72hr
WT
MUTANT
0
10
20
30
40
50
60
39T (WT)
2T (WT)
56T (R544W)
12T (E563K)
17T (E317K)
7T (E452K)
% Apoptotic cells
0hr
72hr
0hr
72hr


26 
11-C-0048 
 
 
It must be noted that the observed reduced proliferation occurred in cells harboring 
BRAF, NRAS, ARAF or CRAF mutations in addition to the ERBB4 mutations 
reaffirming the ‘addictive oncogenic nature’ of ERBB4 mutations in melanoma.63 
Table 4 shows that sensitivity of melanomas harboring ERBB4 mutations to lapatinib 
was not impacted by the presence of concomitant BRAF or NRAS mutations as e.g. 
the most sensitive mutants (68T with IC50 value of 131.8nmol and 49T IC50 
259.6nmol; Fig 8) both harbored concomitant BRAFV600E mutations.  
 
 
Table 4 The presence of concomitant RAF and RAS mutations in melanoma 
 
samples harboring Erbb4 mutations. 
 
In this study, patients with melanoma harboring more than 2 mutations in the ERBB4 
gene will be excluded because of increased resistance to lapatinib due to synergy of 
activating mutations.  As the number of mutations that can activate ERBB4 is 
particularly large, due to the large and heterogenous number of residues that can lead 
to either stimulation of activating domains or abrogation of negative regulatory 
domains, the presence of multiple (>2) mutations has been found to be associated 
with increased autophosphorylation, receptor activation, downstream signaling, and 
lapatinib resistance (please see table in Figure 8 above).  
 
In summary, ERBB4 represents a near ideal target for personalized treatment of 
metastatic melanoma. Unlike the oncogene Ras, the near exclusive vertical signal 


27 
11-C-0048 
transduction of mutated ERBB4 in melanoma via the Akt pathway are ideal 
prerequisites for successful abolition of its oncogenic potential and for cancer 
treatment in this tumor in general. 
 
2.4 
Correlative Studies Background 
Genetic Fingerprinting of Melanoma Samples 
Response to lapatinib in patients with metastatic melanoma harboring ERBB4 
mutations is determined by  
 
(1) the intrinsic type of the individual ERBB4 mutation and its impact on receptor 
activation via mechanisms like increased ligand binding, increased receptor 
dimerization, increased ATP binding, and increased transphosphorylation of the 
paired receptor, and  
 
(2) extrinsically, by other genetic alterations of the tumor and their influence on 
aberrant cell signaling.39 
 
With respect to activating somatic mutations of the ERBB4 receptor, major oncogenic 
events in melanoma like activation of the MAPK kinase pathway through activating 
mutations in the BRAF kinase (present in more than 60% of melanomas), activation 
of the PI3K-Akt pathway through PTEN loss (20 – 50% of melanomas), or increased 
cell cycle progression via loss of the INK4A (p16) locus do not occur in an exclusive 
fashion and might therefore facilitate the activation of escape pathways following 
Erbb4 inhibition with lapatinib.14, 71 
 
Therefore, knowledge of other major genetic alterations in these melanoma samples 
will aid in 
1. Identifying tumors less responsive and/or resistant to lapatinib treatment 
2. The design of combination molecular therapy by targeting escape pathways, as 
the majority of these pathways are now amenable to pharmacological 
manipulation 
 
In addition to all 28 exons of ERBB4 (please see Appendix B for ERBB4 primers), 
exons of most common oncogenes / tumor suppressor genes affected most frequently 
by genetic alterations in cutaneous melanoma will be analyzed by Sanger sequencing 
(please see Section 5.4 and Appendices H-J). 
 
Pharmacokinetic Analysis of Patient Blood Samples 
In order to better characterize the lapatinib bioavailability when administered at the 
500 mg BID dose when taken one hour before or one hour after a major meal, PK 
samples will be collected.  PK analysis will be performed as per section 5.4.  
 


28 
11-C-0048 
 
3. 
PATIENT SELECTION 
 
3.1 
Eligibility Criteria 
 
3.1.1 Patients must have histologically confirmed stage IV cutaneous melanoma. 
 
3.1.2 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 > 
10 mm when measured by CT, MRI or caliper measurement by clinical exam; 
or > 20 mm when measured by chest x-ray. Lymph nodes must be > 15 mm in 
short axis when measured by CT or MRI.  See Section 10 for the evaluation of 
measurable disease. 
 
3.1.3 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 
which is not a small nucleotide polymorphism (SNP) as determined by 
sequence analysis of matched normal DNA from any specimen obtained from 
the individual 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 
 
3.1.4 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. 
 
3.1.5 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. 
 
3.1.6 Age >18 years.   
 
 
Note:  Because no dosing or adverse event data are currently available on the 
use of lapatinib in patients <18 years of age, children are excluded from this 
study but will be eligible for future pediatric single-agent trials, if applicable. 
 
3.1.7 Life expectancy of greater than 3 months. 
 


29 
11-C-0048 
3.1.8 ECOG performance status ≤1 (Karnofsky ≥70%; see Appendix C). 
 
3.1.9 Patients must have normal organ and marrow function as defined below: 
 
absolute neutrophil count 
>1,500/mcL 
 
platelets 
>75,000/mcL 
 
total bilirubin 
within normal institutional limits 
 
AST(SGOT)/ALT(SGPT) 
≤3 x institutional upper limit of normal 
 
creatinine 
less than or equal to institutional upper limit 
of normal 
 
OR 
 
creatinine clearance 
>60 mL/min/1.73 m2 for patients with 
 
creatinine levels above institutional normal. 
 
3.1.10 Patients must be willing to return to the Clinic for follow-up visits.  
 
3.1.11 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. 
 
3.1.12 Ability to understand and the willingness to sign the Informed Consent 
Document. 
 
3.1.13 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. 
 
3.2 
Exclusion Criteria 
 
3.2.1 Patients may not be currently receiving any other investigational agents. 
 
3.2.2 Patients may not have received prior treatment with tyrosine kinase inhibitors 
(e.g., lapatinib erlotinib, or gefitinib). 
 
3.2.3 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.  


30 
11-C-0048 
 
3.2.4 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) 
 
3.2.5 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. 
 
 
3.2.6 HIV-positive patients on antiretroviral therapy are excluded because most 
antiretrovirals are strong or moderate CYP3A4 inhibitors (please see 3.2.4 
above).  
 
3.2.7 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 
 
3.2.8 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. 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this 
trial.  Based on the nature of the disease and the primary patient population it affects, 
the planned accrual targets is shown in the table below: 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
1 
+ 
1 
= 
2 
Not Hispanic or Latino 
11 
+ 
12 
= 
23 
Ethnic Category: Total of all subjects 
12 
 
+ 
13 
 
= 
 
25 
Racial Category 
 
American Indian or Alaskan Native 
0 
+ 
0 
= 
 
Asian 
0 
+ 
0 
= 
 
Black or African American 
0 
+ 
0 
= 
 
Native Hawaiian or other Pacific Islander 
1 
+ 
1 
= 
2 
White 
11 
+ 
12 
= 
23 
Racial Category: Total of all subjects 
 
12 
+ 
13 
 
= 
25 
 
 
(A1 = A2) 
 
(B1 = B2) 
 
(C1 = C2) 
 


31 
11-C-0048 
 
 
3.4 
Research Eligibility Evaluation 
 
 
 
 
 
 
All Patients 
 
 
 
ERBB4 mutation screening 
Tumor tissue will be obtained for ERBB4 mutation analysis, which will take place at 
the NIH Clinical Molecular Profiling Core laboratory (Dr. P. Meltzer, NCI/NIH).  In 
addition, a blood sample or normal tissue adjacent to the tumor biopsy will be 
submitted with the tumor tissue specimen and used as matched normal control. 
Only patients with up to two ERBB4 somatic gene mutations on genomic sequence 
analysis of baseline biopsy will proceed to the treatment part of the trial. Appendix E 
contains the flowsheet with instructions for submission of tissue sample for ERBB4 
analysis by participating institutions.  Appendix B contains a list of the validated 
primers for all 28 ERBB4 exons. 
 
 
 
 
Patients with confirmed ERBB4 mutations 
 
 
 
To be completed within 4 weeks of treatment 
3.4.1 Complete history and physical examination  
 Height and weight, vital signs 
 ECOG performance score 
 Documentation of measurable disease (to be performed prior to enrollment 
in study) 
 Documentation of all prior therapies (e.g., hormonal, surgical, radio-
therapeutic and cytotoxic).   
 
3.4.2 Medication History  
 A complete medication history should be obtained prior to starting the 
study agents including over the counter medications, homeopathic 
remedies, vitamins, and alternative therapies. 
 
3.4.3 Imaging Studies  
 CT Scan, CT/PET scan, and/or other standard imaging method as 
determined at the time of the first evaluation (i.e., screening visit) to 
include oral and IV contrast of areas of known or suspected disease 
involvement.  This includes CT, CT/PET, or MRI of the brain. 
 Left Ventricular Ejection Fraction (LVEF) by ECHO. 
 
 
To be completed within 2 weeks of treatment: 
3.4.4 Laboratory Evaluation [baseline is to be obtained within 14 days prior to 
enrollment] 
 CBC with differential and platelet count 


32 
11-C-0048 
 Chem 14 Panel {Albumin, alkaline phosphatase, total bilirubin, Total CO2 
(bicarbonate), Urea nitrogen (BUN), calcium, chloride (Cl), creatinine, 
glucose, potassium(K), total protein, SGOT [AST], SGPT [ALT], 
sodium(Na)}    
 Urinalysis 
 PT/aPTT/fibrinogen or INR  
 Beta-HCG (serum or urine pregnancy test) for females of child bearing 
potential.  
 
4. 
REGISTRATION PROCEDURES 
 
4.1  
Participating Sites 
Patients will be registered by the PI designee or research nurse at the participating site 
within 2 weeks of the patient signing the screening consent by faxing a screening 
Eligibility Checklist with the appropriate sections completed to the Central 
Registration Office (CRO) at 301-480-0757.  Once it has been determined that the 
patient has the ERBB4 mutation in their tumor, a separate treatment consent and 
treatment eligibility checklist will be completed and faxed to the Principal 
Investigator, Udo Rudloff, M.D., Ph.D., or his designee for review (301-451-6933) 
prior to patients starting treatment.  The PI or his designee will review and fax the 
completed treatment eligibility checklist to the CRO at 301-480-0757 for registration 
on to the treatment phase of the protocol.  The CRO will fax confirmation of 
registration to the coordinating center and the site.  
4.2  
NCI 
Patients enrolled at the NCI Clinical Center will be screened under the Surgery 
Branch screening protocol 99-C-0128 “Evaluation for NCI Surgery Branch Clinical 
Research Protocols”. Registration of patients onto this study will take place within 24 
hours of the patient signing the 99-C-0128 consent by faxing a completed eligibility 
checklist to the Central Registration Office (CRO) at 301-480-0757.  Once it has been 
determined that the patient has the ERBB4 mutation in their tumor, the treatment 
consent for protocol 8786 ( NCI 11-C-0048) and treatment eligibility checklist will be 
completed and faxed to the Central Registration Office (CRO) at 301-480-0757.   
 
Except in very unusual circumstances, each participating institution will order 
DCTD-supplied agents directly from CTEP.  Agents may be ordered by a 
participating site only after the initial IRB approval for the site has been forwarded by 
the Coordinating Center to the CTEP PIO (PIO@ctep.nci.nih.gov). 
 
 
5. 
TREATMENT PLAN 
 
5.1 Lapatinib Administration 
Treatment will be administered on an outpatient basis.  Reported adverse events and 
potential risks are described in Section 7.  Appropriate dose modifications lapatinib 


33 
11-C-0048 
are described in Section 5.2 below.  No investigational or commercial agents or 
therapies other than those described below may be administered with the intent to 
treat the patient’s malignancy. 
Lapatinib will be administered as an oral dose of 500 mg twice daily (in the morning 
and evening).  All medications are given daily for 28 days, 28 days (4 weeks) equals 
one cycle.  The first course will consist of 28 days (one cycle).  All subsequent 
courses will consist of 2 cycles.  Up to 27 cycles may be administered (14 courses, 
approximately 2 years). 
 
Patients will be instructed to take the medications at the same time each day taken 
one hour before or after meals.  Patients will be advised not to consume grapefruit or 
grapefruit juice while taking the study medications.  The patient will be requested to 
maintain a medication diary of each dose of medication and any side effects and/or 
adverse events the patient may experience.  The medication diary will be returned to 
clinic staff at the end of each course. 
 
Prior to discharge from the clinic, the research nurse will review the following 
information with the patient:  
 The toxicities of each agent and how to treat/prevent them 
 The signs and symptoms to report to the study team 
 How to complete the medication self administration record (patient diary)(See 
Appendix F for lapatinib-specific medication diary). 
 Instructions to carefully observe for signs and symptoms of AEs 
 Potential risks regarding pregnancy and fetal exposure 
 Study agents should never be shared 
 
Patients will be dispensed 1 cycle of drug at a time (Section 5.3.7).  At each cycle 
prior to drug dispensing, the toxicity information as described in section 7 will be 
reviewed with the patient.   
 
5.2 
Dosing Delays/Modifications 
General guidelines for treatment modifications at the time of re-treatment:  
Adverse Events: All adverse events in this trial will be graded using the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 - a 
complete listing is available at the CTEP website: 
http://ctep.cancer.gov/forms/CTCAEv4.pdf.  
 
Dose adjustments will be made according to the guidelines below, with dose levels 
defined as follows: 
 
Dose Level (DL) 
Agent   Dose 
0 
Lapatinib 500 mg twice daily 
-1* 
Lapatinib 1000 mg once daily 


34 
11-C-0048 
-2* 
Lapatinib 750 mg once daily 
  * The Cmax for lapatinib is higher when administered at a BID dose.   
Please refer to Table 2 (background section) for specific values. 
 
Table 5 
Summary of dose holding/interruptions and dose de-escalation recommendations 
for lapatinib in case of lapatinib-related adverse events (graded according to NCI-CTCAE 
v4.0) 
General Adverse Events 
Action 
Non-hematological, Grade 1 or 2 
Continue lapatinib therapy at full dose prescribed. 
Apply maximum supportive care recommendations.  If 
prolonged duration of Grade 2 adverse event (≥7 days) 
is affecting quality of life, decrease dose to DL -1, if 
symptoms persist and continue to affect quality of life 
for ≥ 7 more days, a second dose reduction to DL -2 
will be allowed. 
Non-hematological, Grade 3 or 4 
(excluding cardiac and hepatobiliary 
events) 
Apply maximum supportive care recommendations. 
Hold lapatinib therapy until recovery to Grade  1 (up 
to 14 days).  
For NCI-CTCAE v4.0 Grade 3 or 4 interstitial 
pneumonitis or Grade 4 rash manifested as toxic 
epidermal necrolysis (e.g. Stevens-Johnson Syndrome 
etc) lapatinib must be permanently discontinued 
If recurrence of adverse event after drug hold/ 
interruptions is observed, and maximum supportive 
care measures applied, hold drug once again until 
recovery to Grade  1 (up to 14 days) and restart drug 
at DL-1.  If adverse event recurs, a second dose 
reduction to DL -2 will be allowed after symptoms 
recover to Grade  1. 
Non-hematological, Grade 3 or 4 
adverse events NOT resolved to 
Grade  1 within a maximum of 2 
weeks from last planned 
administration  
Action (discontinue or resume lapatinib therapy) in 
individual cases after discussions with the Sponsor. 
Up to 2 reductions (DL-1 and DL-2) will be 
considered after maximum supportive care 
recommendations are introduced. 
Cardiac Adverse Events 
 
Cardiac (Severity corresponding to 
NYHA criteria) 
Lapatinib therapy to be discontinued permanently in 
case of symptomatic NYHA class III and IV CHF. 
Lapatinib therapy to be held, continued, or resumed 
according to Figure 9 (please see Section 5.2.1 below) 
for patients with NYHA class I or II CHF. 
Hepatobiliary Adverse Events 
 
Grade 3 AST/ALT* and 
Grade 2 total bilirubin elevation 
Hold lapatinib for 2 weeks; restart drug at DL-1 if 
events resolved to ≤Grade 1.  
If Grade 3 events recur after dose reduction, then 
discontinue lapatinib.  


35 
11-C-0048 
Grade 2 AST/ALT or  
Grade 1 total bilirubin elevation 
Hold lapatinib for 2 weeks and restart drug at full dose 
if events resolved to ≤ Grade 1. 
Grade 4 events 
Discontinue lapatinib 
* retest within 3 days from the first occurrence and then weekly to determine if ALT elevation    
persists 
 
Note: In case of multiple short interruptions of dose due to either adverse events or drug supply 
or other reasons the sum of days without lapatinib treatment should not exceed 21 days in any 
90 day treatment period. 
 
 
 
5.2.1 Management of Cardiac Events 
Asymptomatic cardiac events: 
Subjects who have a ≥20% decrease in LVEF  relative to baseline, and the 
ejection fraction is below the institution's lower limit of normal, should have a 
repeat evaluation of ejection fraction 1-2 weeks later while still receiving 
investigational product. 
 If the repeat ejection fraction evaluation confirms a ≥20% decrease in 
LVEF, and the ejection fraction is below the institution's lower limit of 
normal, then lapatinib should be temporarily discontinued. 
 If the LVEF recovers during the next 3 weeks, after consultation and 
approval of the Sponsor, the subject may be restarted on lapatinib at a 
reduced dose. For such subjects, monitoring of LVEF will then be 
performed 2 weeks and 4 weeks after rechallenge, and then every 4 weeks 
thereafter. 
 If repeat ejection fraction evaluation still shows a decrease ≥20% in LVEF 
relative to baseline, and the value is below the institution's lower limit of 
normal, then lapatinib should be stopped. 
 
Symptomatic cardiac events: 
Lapatinib should be stopped. 
 
 


36 
11-C-0048 
 
5.3  
On Study Evaluations 
5.3.1 Day 1 (10 patients who live locally at any treating site) 
 
PK samples will be collected:  
 Pre-treatment (before start of lapatinib) 
 1h, 2h, 3h, 4h, 6h, 8h post 1st dose in the morning  
5.3.2 Day 14 after the start of therapy (± 5 days): 
 CBC with differential and platelet count  
 Chem 14 Panel {Albumin, alkaline phosphatase, total bilirubin, Total CO2 
(bicarbonate), Urea nitrogen (BUN), calcium, chloride (Cl), creatinine, 
glucose, potassium(K), total protein, SGOT [AST], SGPT [ALT], 
sodium(Na)}    
 Clinic visit or phone interview by Research Nurse for review of systems. 
 
5.3.3 At the end of Cycle 1 (after 28 days; ± 5 days): 
 Physical examination 
 CBC with differential and platelet count  
 Chem 14 Panel {Albumin, alkaline phosphatase, total bilirubin, Total CO2 
(bicarbonate), Urea nitrogen (BUN), calcium, chloride (Cl), creatinine, 
glucose, potassium(K), total protein, SGOT [AST], SGPT [ALT], 
sodium(Na)}    
 Toxicity assessment, review of patient diary, and medication 
reconciliation 
 Pregnancy counseling including the potential risk of fetal exposure, and 
verification of use of male and female contraception 
 CT or MRI scan with oral and IV contrast (the same studies as those done 
at initiation of treatment should be performed) 
 PK samples (patients who had PK samples performed prior to dose 1) - 
before 1st dose in the morning and 1h, 2h, 3h, 4h, 6h, 8h post morning 
dose. 
 
5.3.4 Days 14 of Cycle 2 and Cycle 3 (± 5 days): 
 CBC with differential and platelet count  
 Chem 14 Panel {Albumin, alkaline phosphatase, total bilirubin, Total CO2 
(bicarbonate), Urea nitrogen (BUN), calcium, chloride (Cl), creatinine, 
glucose, potassium(K), total protein, SGOT [AST], SGPT [ALT], 
sodium(Na)}    
 Phone interview by Research Nurse for review of systems. 
 
5.3.5 End of Course 2  Evaluation (end of Cycle 3, week 12; ± 5 days) and every 8 
weeks (one course) during treatment (± 2 weeks): 
 CT or MRI scan with oral and IV contrast (the same studies as those done 
at initiation of treatment should be performed) 
 History and physical examination  


37 
11-C-0048 
 Chem 14 Panel {Albumin, alkaline phosphatase, total bilirubin, Total CO2 
(bicarbonate), Urea nitrogen (BUN), calcium, chloride (Cl), creatinine, 
glucose, potassium(K), total protein, SGOT [AST], SGPT [ALT], 
sodium(Na)}    
 CBC with differential and platelet count 
 Toxicity assessment,  review of patient diary, and medication 
reconciliation 
 LVEF by ECHO (end of course 2 and every 2 courses (approx 16 weeks) 
thereafter 
 
Note: If clinically indicated (e.g. deterioration of performance status, increase in pain, 
change in relevant laboratory parameters) restaging studies (as noted above) may be 
done prior to the 2 month interval including repeat brain CT or MRI is warranted by 
clinical condition. 
 
 
5.3.6 Evaluation at the End of all Other Even Cycles (d28 of each cycle, +/- 5 days)  
 CBC with differential and platelet count 
 Chem 14 Panel {Albumin, alkaline phosphatase, total bilirubin, Total CO2 
(bicarbonate), Urea nitrogen (BUN), calcium, chloride (Cl), creatinine, 
glucose, potassium(K), total protein, SGOT [AST], SGPT [ALT], 
sodium(Na)}    
 Toxicity assessment, review of patient diary, and medication 
reconciliation, to be performed at clinic visit during week 4 of the first 
cycle of each course following course 1. 
 
 
5.3.7   Dispensing of medication 
After reviewing the most recent lab data and the patient diary (please see sections 
5.3.3, 5.3.5, and 5.3.6 above), and determining that the patient can continue with 
treatment, the physician or designee will contact the pharmacy and the investigational 
agent will be dispensed to the patient at the clinic visit.  Only enough lapatinib for 
one (1) cycle of therapy + one week to allow for  delays in appointment scheduling or 
travel may be provided to the patient each cycle.  Patients will be required to return 
any unused study drugs or empty bottles to the NIH or participating institution at each 
clinic visit. 
 
5.4 
Research Evaluations 
 
 
 
5.4.1 Pharmacokinetics 
PK samples will be collected, using a single 6 mL sodium heparing (green top) 
tube, from 10 patients who live locally at any of the treating sites and who agree 
to participate in the PK portion of the study. Blood will be drawn for PK analysis 
at the time points specified in Section 5.3.1 and 5.3.3 
 


38 
11-C-0048 
Determination of lapatinib concentration in all plasma samples as well as 
subsequent pharmacokinetic data analysis will be performed by the Clinical 
Pharmacology Program (CPP) (Dr. William Figg, MOB, CCR, NCI, 301-402-
3622).  Samples will be analyzed using a validated LC-MS-MS assay.  PK 
parameters derived from plasma concentrations may include peak Cmax, Tmax, 
AUC, CL and CL/F, Vd, and t1/2 
 
Please refer to Appendix G for collection, storage and shipment of samples. 
 
5.4.2 Biomarker development predicting response to lapatinib in patients with 
metastatic melanoma harboring ERBB4 mutations 
 
In this study, tumor biopsies will be obtained at the Coordinating Center (Surgery 
Branch/NCI) only to characterize the effects of lapatinib on the biology of the 
tumor cells.  For all patients, tumor biopsies will be optional. 
 
 
5.4.2.1 
Timing of biopsy 
Biopsies will be performed at the following times: 
• After consent, prior to treatment with lapatinib 
• At day 14 of cycle 1 (+/-5 days)  
 
 
• At day 28 of cycle 3 (+/-5 days)  
 
 
5.4.2.2 
Biopsy procedure 
At least 24 hours prior to the scheduled biopsy, the research nurse will contact the 
laboratory of Dr. Yardena Samuels, at 301-451-2628 notifying them of the 
procedure. 
 
Serial tumor biopsies will be obtained through Interventional Radiology by a 
percutaneous approach. Two core biopsies not less than 18-gauge in diameter and 
at least 1 cm in length will be obtained. Only percutaneous biopsies will be 
performed on patients with solid tumors. To minimize risk, serial biopsies will not 
be performed in deep organs of the chest and abdomen.  It is estimated that there 
will be between 2 to 5 million cells from each biopsy. If a site is deemed 
appropriate for biopsy with minimal risk to the participant by agreement between 
the investigators and Interventional Radiology, an attempt at biopsy will be made. 
The use of imaging to facilitate biopsies will be decided by members of the 
Interventional Radiology team and may include ultrasound, CT scan, or MRI. 
Should CT scan be needed for biopsy, the number of scans for each procedure 
will be limited to the minimum number needed to safely obtain a biopsy. Tumor 
biopsies and local anesthesia will be administered only if they are considered to 
be of low risk to the participant as determined by the investigators and 
Interventional Radiology. 
 
 
5.4.2.3  
Processing and Storage of the Biopsies 


39 
11-C-0048 
The biopsies will be cut into two parts in the operating room immediately after the 
procedure; the larger portion of the biopsies will be put into pre-labeled cryotubes 
and immediately put on dry ice, and the smaller portion will be fixed with 10% 
neutral buffered formalin overnight.  The samples will be immediately delivered 
to the Laboratory of Dr. Yardena Samuels in Bldg 50/Room 5140 and will be 
stored at a -80°C (frozen sample) or at room temperature (formalin fixed sample) 
until ready for analysis.  Formalin fixed samples will be paraffin-embedded at Dr. 
Samuels laboratory. 
 
5.4.2.4 
Studies 
Snap-frozen core-needle biopsies obtained from patients pre- and post treatment 
with lapatinib will be utilized to make cell lysates for the analysis of the changes 
in protein levels and phosphorylation status of the ERBB4 and Akt pathways: 
 
 
5.4.2.4.1  
DNA Sequencing 
RAF and RAS isoforms will be sequenced by Sanger sequencing on the ABI 3730 
using the forward, reverse, and sequencing primers (Appendix H) as detailed in 
SOP listed in Appendix I. Of the BRAF gene only exon 15 containing the V600E 
hotspot will be sequenced. Additionally, all exons of the CDKN2A gene 
(INK/p16) and TP53 will be determined on all biopsies using the sequencing 
primers listed in Appendix J.  
 
 
5.4.2.4.2 
Genetic markers predicting response to lapatinib in 
melanoma harboring activating ERBB4 mutations 
Genomic DNA extracted from patients tissues and used for ERBB4 mutation 
analysis will be sequenced for the presence of concomitant oncogene mutations in 
the RAF / RAS family and the tumor suppressor genes INK4/p16 and TP53 as 
outlined in section 5.4.2.4.1 above. The association of response to lapatinib (PR 
as defined by RECIST) and presence of concomitant activating oncogene 
mutations or loss of tumor suppressor function will be examined in a Fisher’s 
exact test design: 
 
 
 
 
PR, CR – response to 
lapatinib 
PD – progression of 
disease 
          Presence of mutation 
 
 
         Wild type – no concomitant 
mutation 
 
 
 
Validation of any statistically significant association will require a larger follow-
up study. 
 
 


40 
11-C-0048 
5.4.2.4.3 
Correlative Protein Expression Studies 
Tissue obtained at follow-up biopsies (outlined below) will be collected, stored, 
and in the future analyzed by quantitative Western Blotting for phosphoprotein 
expression of pERBB4, pAKT, and pERK. Phospho- and total protein expressions 
will be compared to baseline levels, and changes will be correlated using the 
Fischer’s exact test design for response to lapatinib. The development and 
translation into clinically applicable IHC testing will need to await larger studies. 
 
Immunoprecipitation and protein blotting. Melanoma tissue from core needle 
biopsies will be gently washed three times in PBS and then lysed using 0.5–1.0 
mL 1% NP-40 lysis buffer (1% Nonidet P-40, 50 mM Tris-HCl pH 7.5, 150 mM 
NaCl, 1× EDTA-free Complete Protease Inhibitor tablet (Roche), 1 μM sodium 
orthovanadate, 1 mM sodium fluoride and 0.1% β-mercaptoethanol) for 20 min 
on ice. Extracts are centrifuged for 10 min at 20,000g at 4 °C. Five hundred 
microliters of supernatant will be immunoprecipitated overnight using 20 μL of 
anti-ERBB4–conjugated agarose beads (Santa Cruz Biotechnology). The 
immunoprecipitates will be washed and subject to SDS-PAGE and protein 
blotting. Primary antibodies used in our analysis are anti-ERBB4 (Santa Cruz 
Biotechnology), anti–P-ERBB4(Y1162) (Abgent), anti–P-ERBB4(Y1284) (Cell 
Signaling), anti-PY20 (Zymed-Invitrogen), anti–P-ERK1/2 (T202/Y204), anti-
ERK1/2, anti–P-AKT (S473), anti-AKT (Cell Signaling), and anti–α-tubulin 
(Calbiochem–EMD Biosciences). 
 
Immunoblot quantification analysis. Scanned films from protein blot analysis 
of SDS-PAGE will be analyzed using ImageJ (National Institutes of Health, 
Bethesda, Maryland, USA). Individual bands will be quantified and plots 
generated to determine the intensities in each band. The data are exported to 
Microsoft Excel and analyzed further for the ratio of phosphoprotein to total 
protein. 
 
5.5 
General Concomitant Medication and Supportive Care Guidelines 
Because there is a potential for interaction of lapatinib with other concomitantly 
administered drugs through the cytochrome P450 system, the case report form must 
capture the concurrent use of all other drugs, over-the-counter medications, or 
alternative therapies.  The Principal Investigator should be alerted if the patient is 
taking any agent known to affect or with the potential to affect selected CYP450 
isoenzymes. 
 
Either the Principal Investigator or an Associate Investigator should be notified of any 
change in the patient’s therapy, if a change is indicated.  All effort should be made to 
give only medications that are clearly indicated for a specific medical purpose. Other 
anti-tumor therapy will not be permitted while the patient is on study. 
 
Patients may be admitted as necessary to manage issues related to study medication 
or disease process. Anti-emetic and anti-diarrheal medications will be administered as 


41 
11-C-0048 
appropriate.  Guidelines for Management of Gastrointestinal Adverse Events can be 
found in Appendix K of this protocol. 
 
5.6 
Duration of Therapy 
In the absence of treatment delays due to adverse event(s), treatment may continue for 
up to 2 years (27 cycles), or until patients meet off treatment criteria as described in 
Section 5.8. 
 
5.7 
Follow-Up Evaluations 
After completion of therapy, patients will be followed every three months during the 
first 2 years, every 4 months during the third year and as clinically indicated after 
that.  After three years, patients who are continuing to respond will be contacted by 
telephone annually to determine disease status. 
At each clinic visit the patient will undergo the following evaluation: 
 History and physical examination  
 Laboratory evaluations 
 Chem 14 Panel {Albumin, alkaline phosphatase, total bilirubin, Total CO2 
(bicarbonate), Urea nitrogen (BUN), calcium, chloride (Cl), creatinine, glucose, 
potassium(K), total protein, SGOT [AST], SGPT [ALT], sodium(Na)}    
 CBC with differential and platelet count 
 Imaging Studies 
 
5.8 
Off Treatment Criteria 
 Disease progression 
 Intercurrent illness that prevents further administration of treatment 
 Unacceptable adverse event(s) 
 Pregnancy 
 Patient decides to withdraw from treatment 
 Patient must start on a drug with potential CYP3A4 interaction 
 General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator 
 
5.9 
Off Study Criteria 
Patients will be taken off study for the following: 
 The patient voluntarily withdraws 
 There is significant noncompliance 
 General or specific changes in the patient’s condition render continued 
participation the patient unacceptable for further follow up in the judgment of 
the investigator. 
 Disease Progression 
 
Note : Prior to being taken off study, all patients will be followed for 30 days or until 
all adverse events have resolved to grade 2 or less following the last dose of 


42 
11-C-0048 
medication. In the event of a hepatobiliary event, patients will be followed until 
events have resolved to grade 1 or less following the last dose of medication. 
 
 
 
6. 
DATA COLLECTION, MONITORING, AND REPORTING 
 
6.1. 
Data Collection 
 
Data will be prospectively collected and entered into the database at least once every 
two weeks.  The NCI C3D database will be used for this study. The responsible 
investigator is Dr. Udo Rudloff.   
 
Complete records must be maintained on each patient.  These will consist of the 
hospital chart with any supplementary information obtained from outside laboratories, 
radiology reports, or physician’s records.  These records will serve as the primary 
source material that forms the basis for the research record.  All relevant data will 
also be entered into the NCI C3D database from which formal analyses are done.  The 
primary source documentation will assure the following: on study information, 
including patient eligibility data and patient history; and off-study summary sheets, 
including a final assessment by the treating physician. All data will be kept secure. 
Personal identifiers will not be used when collecting and storing data. An enrollment 
log will be maintained in the regulatory binder/file which is the only location of 
personal identifiers with unique subject identification number. 
 
Laboratory data collected from outside of the NIH Clinical Center will be entered into 
C3D manually.  Training will be provided to the participating institutions by the NIH. 
 
Data will be submitted to the CTEP/CDUS every three months via the NCI C3D 
database.  
 
6.2 
 Data Reporting 
 
 
 
6.2.1 Method 
This study will be monitored by the Clinical Data Update System (CDUS) version 
3.0.  Cumulative CDUS data will be submitted quarterly to CTEP by electronic 
means.  Reports are due January 31, April 30, July 31, and October 31.  
Instructions for submitting data using the CDUS can be found on the CTEP Web 
site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/cdus.htm).   
 
Note:  All adverse events that have occurred on the study, including those 
reported through AdEERS, must be reported via CDUS. 
 
 
 
6.2.2 Responsibility for Submissions 


43 
11-C-0048 
Participating institutions are responsible for submitting CDUS data and/or data 
forms to the Coordinating Center quarterly by January 10, April 10, July 10, 
October 10 to allow time for Coordinating Center compilation, Principal 
Investigator review, and timely submission to CTEP (see Section 11.1.).   
 
The Coordinating Center is responsible for compiling and submitting CDUS data 
to CTEP for all participants and for providing the data to the Principal 
Investigator for review.   
 
 
6.3 
Data and Safety Monitoring Plan 
 
The principal investigator will review all serious adverse events and will 
monitor the data and toxicities to identify trends monthly. The principal investigator 
will be responsible for revising the protocol as needed to maintain safety. The NCI 
IRB will review submitted adverse events monthly to also evaluate trends and will 
require a follow up plan from the principal investigator whenever a trend is identified.   
 
A CCR Safety Monitoring Committee will monitor toxicity trends on this study on at 
least an annual basis and report any trends to the NCI IRB and Principal Investigator. 
 
The principal investigator will review accrual to both the screening and enrollment 
phases of the trial every 12 months.  If fewer participants than anticipated are enrolling in 
the treatment phase, the reasons for lack of enrolment will be reviewed and discussed 
with the Sponsor. 
 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) 
will determine whether the event requires expedited (via AdEERS) reporting in addition to 
routine reporting.   


44 
11-C-0048 
 
7.1  Comprehensive Adverse Events and Potential Risks List (CAEPR) 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Lapatinib (GW572016, NSC 727989) 
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Agent Specific Adverse Event List 
(ASAEL), appears in a separate column and is identified with bold and italicized text. This subset of AEs 
(ASAEL) contains events that are considered 'expected' for expedited reporting purposes only. Refer to 
the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.info.nih.gov/protocolDevelopment/default.htm#adverse_events_adeers  for further clarification. 
Frequency is provided based on 1890 patients. Below is the CAEPR for Lapatinib (GW572016). 
1 
Version 2.4, January 6, 2010 
 
 Adverse Events with Possible  
 Relationship to Lapatinib (GW572016) 
 (CTCAE 4.0 Term) 
[n= 1890] 
 
 
 
 EXPECTED AEs FOR 
ADEERS REPORTING  
 
Agent Specific Adverse 
Event List 
(ASAEL) 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
Expected 
CARDIAC DISORDERS 
  
 
 
Left ventricular systolic 
dysfunction 
 Left ventricular systolic 
dysfunction 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal distension 
 
 Abdominal distension 
 
Abdominal pain 
 
 Abdominal pain 
Diarrhea 
 
 
 Diarrhea 
 
Dyspepsia 
 
 Dyspepsia 
 
Flatulence 
 
 Flatulence 
 
Gastrointestinal disorders – 
Other (Mucositis/stomatitis – 
Select) 
 
 Gastrointestinal disorders – 
Other (Mucositis/stomatitis 
– Select) 
Nausea 
 
 
 Nausea 
 
Vomiting 
 
 Vomiting 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Fatigue 
 
 Fatigue 
 
Flu like symptoms 
 
 Flu like symptoms 
HEPATOBILIARY DISORDERS 
  
 
 
Hepatic failure 
 Hepatic failure 
IMMUNE SYSTEM DISORDERS 
  
 
 
Allergic reaction 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
 Alanine aminotransferase 
increased 
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase 
increased 
 
Blood bilirubin increased 
 
 Blood bilirubin increased 
 
 
Electrocardiogram QT 
 Electrocardiogram QT 


45 
11-C-0048 
 
 
corrected interval prolonged 
corrected interval prolonged 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia 
 
Dehydration 
 
 Dehydration 
NERVOUS SYSTEM DISORDERS 
  
 
Dysgeusia 
 
 Dysgeusia 
 
Headache 
 
 Headache 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
 
Pneumonitis 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Nail loss 
 
  
 
Pruritus 
 
 Pruritus 
 
Rash acneiform 
 
 Rash acneiform 
Rash maculo-papular 
 
 
 Rash maculo-papular 
VASCULAR DISORDERS 
  
 
Flushing 
 
 Flushing 
 
1 
 This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
Also reported on Lapatinib (GW572016) trials but with the relationship to Lapatinib (GW572016) 
still undetermined: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Anemia; Febrile neutropenia 
CARDIAC DISORDERS - Atrial fibrillation; Restrictive cardiomyopathy 
EYE DISORDERS - Blurred vision 
GASTROINTESTINAL DISORDERS - Constipation; Dysphagia; Gastritis; Gastrointestinal disorders – 
Other (Hemorrhage, GI – Select); Gastrointestinal disorders – Other (Obstruction, GI – Select) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema limbs; Fever; Pain 
INFECTIONS AND INFESTATIONS – Infections and infestations – Other (Infection – Select) 
INVESTIGATIONS - Alkaline phosphatase increased; Creatinine increased; Lymphocyte count 
decreased; Neutrophil count decreased; Platelet count decreased; Weight loss; White blood cell 
decreased 
METABOLISM AND NUTRITION DISORDERS - Hyperglycemia; Hypoalbuminemia; Hypoglycemia; 
Hypokalemia; Hyponatremia; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Back pain; Myalgia 
NERVOUS SYSTEM DISORDERS - Cerebrospinal fluid leakage; Depressed level of consciousness; 
Dizziness; Intracranial hemorrhage 
PSYCHIATRIC DISORDERS - Insomnia 
RENAL AND URINARY DISORDERS - Acute kidney injury 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Cough; Dyspnea; Epistaxis; Pleural 
effusion 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Palmar-plantar 
erythrodysesthesia syndrome; Skin and subcutaneous tissue disorders - Other (seborrheic dermatitis); 
Urticaria 
VASCULAR DISORDERS - Hypotension; Thromboembolic event; Vascular disorders - Other 
(hypovolemia) 
 
 
Note: Lapatinib (GW572016) in combination with other agents could cause an exacerbation of any 


46 
11-C-0048 
adverse event currently known to be caused by the other agent, or the combination may result in events 
never previously associated with either agent. 
 
7.2  
Adverse Event Characteristics  
 
 CTCAE term (AE description) and grade:  The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be utilized for AE reporting.  All appropriate 
treatment areas should have access to a copy of the CTCAE version 4.0.  A copy 
of the CTCAE version 4.0 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.   
 
 “Expectedness”:  AEs can be ‘Unexpected’ or ‘Expected’ (see Section 7.1 
above) for expedited reporting purposes only.  ‘Expected’ AEs (the ASAEL) are 
bold and italicized in the CAEPR (Section 7.1). 
 
 Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3 Expedited Adverse Event Reporting 
 
7.3.1 Expedited AE reporting for this study must use AdEERS (Adverse Event 
Expedited Reporting System), accessed via the CTEP home page 
(http://ctep.cancer.gov).  The reporting procedures to be followed are 
presented in the “CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements” which can be downloaded from the CTEP home page 
(http://ctep.cancer.gov).  These requirements are briefly outlined in the table 
below (Section 7.3.3). 
 
In the rare event when Internet connectivity is disrupted a 24-hour notification 
is to be made to NCI by telephone at 301-897-7497.  An electronic report 
MUST be submitted immediately upon re-establishment of internet 
connection.  Please note that all paper AdEERS forms have been removed 
from the CTEP website and will no longer be accepted.   
 
7.3.2 AdEERS is programmed for automatic electronic distribution of reports to the 
following individuals:  Study Coordinator of the Lead Organization, Principal 
Investigator, and the local treating physician.  AdEERS provides a copy 
feature for other e-mail recipients.  
 
7.3.3 Expedited Reporting Guidelines – AdEERS Reporting Requirements for 
Adverse Events that occur within 30 Days1 of the Last Dose of the 


47 
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Investigational Agent on Phase 2 and 3 Trials 
 
Phase 2 and 3 Trials 
 
Grade 1 
Grade 2 
Grade 2 
Grade 3 
Grade 3 
Grades 
4 & 52 
Grades 
4 & 52 
Unexpected 
and 
Expected 
Unex-
pected 
Expected 
Unexpected 
Expected 
Unex- 
pected 
Expected 
with 
Hospitali-
zation 
without 
Hospitali- 
zation 
with 
Hospitali- 
zation 
without 
Hospitali- 
zation 
Unrelated 
Unlikely 
Not 
Required 
Not 
Required 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
10 
Calendar 
Days 
10 
Calendar 
Days 
Possible 
Probable 
Definite 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
10 
Calendar 
Days 
10 
Calendar 
Days 
10 
Calendar 
Days 
Not 
Required 
24-Hour; 
5 Calendar 
Days 
10 
Calendar 
Days 
1 
Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after the last 
dose of treatment with an agent under a CTEP IND require reporting as follows: 
AdEERS 24-hour notification followed by complete report within 5 calendar days for: 
 
Grade 4 and Grade 5 unexpected events  
AdEERS 10 calendar day report: 
 
Grade 3 unexpected events with hospitalization or prolongation of hospitalization 
 
Grade 5 expected events 
2 
Although an AdEERS 24-hour notification is not required for death clearly related to progressive disease, a full report is 
required as outlined in the table. 
 
 
 
 
 
 
December 15, 2004 
 
Note:  All deaths on study require both routine and expedited reporting 
regardless of causality.  Attribution to treatment or other cause must be 
provided. 
 
 Expedited AE reporting timelines defined: 
¾ “24 hours; 5 calendar days” – The investigator must initially report 
the AE via AdEERS within 24 hours of learning of the event 
followed by a complete AdEERS report within 5 calendar days of 
the initial 24-hour report. 
¾ “10 calendar days” - A complete AdEERS report on the AE must 
be submitted within 10 calendar days of the investigator learning 
of the event.  
 
 Any medical event equivalent to CTCAE grade 3, 4, or 5 that 
precipitates hospitalization (or prolongation of existing hospitalization) 
must be reported regardless of attribution and designation as expected 
or unexpected with the exception of any events identified as protocol-
specific expedited adverse event reporting exclusions.   
 
 Any event that results in persistent or significant 
disabilities/incapacities, congenital anomalies, or birth defects must be 
reported via AdEERS if the event occurs following treatment with an 
agent under a CTEP IND. 
 


48 
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Use the NCI protocol number and the protocol-specific patient ID 
assigned during trial registration on all reports. 
 
 
 
 
7.3.4 Protocol-Specific Expedited Adverse Event Reporting Exclusions 
 
For this protocol only, certain AEs/grades are exceptions to the Expedited 
Reporting Guidelines and do not require expedited reporting (i.e., AdEERS).  
The following AEs must be reported through the routine reporting mechanism 
(Section 7.4): 
 
o 
Grade 2 or greater pain with or without hospitalization 
o 
Events related to vascular access devices with or without 
hospitalization 
o 
Grade 2 or greater lab abnormalities with or without hospitalization 
that do not support a reportable adverse event 
 
7.3.5 Additional Protocol-Specific Expedited Reporting Requirements 
 
  Cardiac Events 
Cardiac dysfunction will be reported as an SAE and will be defined as any 
signs or symptoms of deterioration in left ventricular cardiac function that are 
Grade 3 (NCI CTCAE) or a ≥20% decrease in LVEF relative to baseline 
which is below the institution's lower limit of normal.  See section 5.2.1 for 
additional information regarding cardiac event reporting. 
Note: Refer to NCI CTCAE grading of left ventricular cardiac function. 
 
   Pulmonary Events 
If a patient develops symptoms suggestive of interstitial pneumonitis, adult 
respiratory distress syndrome (ARDS), or non-cardiogenic pulmonary edema, 
lapatinib therapy should be interrupted and a thorough evaluation performed.  
If NCI-CTCAE v4.0 Grade 3 or 4 pneumonitis or pulmonary fibrosis is 
confirmed (and the relationship to lapatinib cannot be excluded), lapatinib 
must be permanently discontinued.  All incidences of interstitial lung disease/ 
interstitial pneumonitis regardless of grade will be reported as serious adverse 
events (SAEs). 
 
 
7.3.6 
Expedited Reporting of Adverse Events and Deaths to the IRB 
 
Participating sites will report expedited adverse events to CTEP and the 
coordinating center via AdEERs.  Each institution and the coordinating 
center will submit the events to their IRB of record per established 
institutional guidelines.  
 
At the Coordinating Center (NCI) the protocol PI will report adverse 
events to the NCI-IRB as per guidelines described in Section 7.6 below. 


49 
11-C-0048 
 
 
 
 
7.3.7 Expedited Reporting of  Deaths on Study and Adverse Events to GSK 
 
 
 
 
 
A copy of all AdEERS reports submitted to CTEP will also be submitted by 
fax by each participating institution (with a copy to the coordinating center) to 
the following individuals at GSK: 
 
Yasir Naagarwala, MD 
Yasir.x.nagarwala@gsk.com 
Phone: 610-917-6068 
Fax: 610-917-6715 
 
Michael Arbushites 
Michael.2.arbushites@gsk.com 
Phone: 610-917-4039 
Fax: 610-917-6715 
 
7.4 Routine Data Reporting 
 
All Adverse Events must be reported in routine study data submissions.  AEs 
reported through AdEERS must also be reported in routine study data 
submissions. 
 
Data will be captured in the NCI C3D web based electronic reporting system.   This 
study will utilize the CTCAE version 4.0 for toxicity and Adverse Event reporting.  A 
copy of the CTCAE version 4.0 can be downloaded from the CTEP home page 
(http://ctep.cancer.gov).  All appropriate treatment areas should have access to a copy 
of the CTCAE version 4.0. 
 
7.4.1 All laboratory evaluation will be kept in the source documents.  Only the 
following laboratory values that are drawn outside of the NIH Clinical Center will be 
entered in C3D: 
 On study and at each the beginning of each cycle: 
o ALT, AST, Bilirubin, Creatinine, 
o ANC, hemoglobin, platelets  
 At any time during the study: 
o Any grade 3 - 4  value of the above  
o Any grade 2 or greater lab abnormality that supports the diagnosis of a 
reportable adverse event 
 
7.4.2  The following concomitant medications will be reported in the source 
documents only and will not be captured in C3D: 
 PRN and one time medications 
 Medications prescribed for a short period to treat an acute symptom (e.g. a 
course of antibiotics for a sinus infection.) 


50 
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7.5 Secondary AML/MDS 
 
AML/MDS events are now to be reported via AdEERS (in addition to your routine AR 
reporting mechanisms).  In CTCAE v4.0, the event (s) may be reported as either: 
1. Leukemia secondary to oncology chemotherapy, 
2. Myelodysplastic syndrome,  
3. Treatment related secondary malignancy.  
 
For more information, please refer to: 
http://ctep.info.nih.gov/protocolDevelopment/electronic_applications/adeers.htm 
 
7.6 NCI-IRB Adverse Event Reporting 
7.6.1  NCI-IRB Expedited Reporting of Adverse Events, Unanticipated Problems, and 
Deaths 
At the Coordinating Center (NCI) the Protocol PI will report to the NCI-IRB: 
 All unexpected serious adverse events that are possibly, probably, or definitely 
related to the research  
 All deaths, except deaths due to progressive disease  
 All Protocol Violations or Deviations 
 All Unanticipated Problems 
Reports must be received by the NCI-IRB within 7 working days of PI awareness via 
iRIS. 
7.6.2  NCI-IRB Requirements for PI Reporting of Adverse Events at Continuing 
Review 
The protocol PI will report to the NCI-IRB:  
 All Grade 2 unexpected events that are possibly, probably or definitely related to 
the research;  
 All Grade 3 and 4 events that are possibly, probably or definitely related to the 
research;  
 All Grade 5 events regardless of attribution;  
 All Serious Events regardless of attribution.  
NOTE: Grade 1 events are not required to be reported.  
7.6.3  NCI-IRB Reporting of IND Safety Reports 
Only IND Safety Reports that require a sponsor recommended change to the protocol 
or the consent form or in the opinion of the PI increases risks to study participants 
will need to be reported to the NCI IRB. 


51 
11-C-0048 
 
8. 
PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with lapatinib can be found in 
Section 7.1.   
 
8.1 
Lapatinib (NSC 727989)   
 
Chemical Name:  N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-
(methylsulfonyl)ethyl]amino}methyl)-2 furyl]-4-quinazolinamine 
 
Other Names:      GW572016, Tykerb® 
 
Molecular Formula: C29H26ClFN4O4S(C7H8O3S)2H2O 
 
Molecular Weight:  943.48 
 
Approximate solubility:  0.007 mg/mL in water and  0.001 mg/mL in 0.1 N HCl at 
25°C.   
 
Mode of Action: Dual inhibitor of epidermal growth factor receptor (EGFR or 
ErbB1) and ErbB2 tyrosine kinases.  
 
How Supplied: 
Lapatinib is supplied by the NCI/DCTD as 250 mg oval, biconvex, 
orange film-coated tablets with one side plain and the opposite side debossed with 
either FG HLS or GS XJG. The tablets contain 405 mg of lapatinib ditosylate 
monohydrate, equivalent to 250 mg lapatinib free base per tablet. The tablets are 
packaged into HDPE bottles with child-resistant closures containing 90 tablets per 
container.  
 
Excipients present in the tablet include: Microcrystalline cellulose, povidone, sodium 
starch glycolate, and magnesium stearate. 
 
The film-coat contains:  Hydroxypropyl methylcellulose, titanium dioxide, 
macrogel/PEG 400, Polysorbate 80, FD&C Yellow No. 6, and FCF aluminum lake. 
  
Storage: Store intact bottles at controlled room temperature (15°C-30°C).  Protect 
from light. 
 
Stability: Shelf life surveillance studies of the intact bottle are on-going.  Current 
data indicates lapatinib is stable for at least 36 months at controlled room temperature 
(15°C - 30°C). 
 
Route of Administration:  Oral, taken one hour before or after meals.  
 


52 
11-C-0048 
Method of Administration:  
Whenever possible, administer whole tablets.  Lapatinib tablets have not been 
deliberately formulated to be dispersible tablets; however, in circumstances where 
dosing of whole tablets is not possible, see procedure below.  Tablet crushing is not 
recommended.  
 
For patients unable to swallow tablets, a suspension preparation in water or Kool-Aid 
can be made using the following procedure: 
 
1. Prepare Lemonade or Tropical Punch Kool-Aid as directed on package. 
2. Place 2 or 4 ounces of water or Kool-Aid in a glass container, then add the 
required number of lapatinib tablets for dose (up to six tablets per 2 to 4 ounces) to 
the container. 
3. Cover the container, let it stand for 5 minutes, and then stir the mixture 
intermittently for 15 minutes or until it is fully dispersed. 
4. Stir the container for 5 seconds then administer. 
5. Rinse the container with 2 ounces of water or Kool-Aid and repeat the 
administration process.  
 
(The lemonade mixture appears somewhat like orange juice whereas the tropical 
punch mixture appears like carrot juice.) 
 
 
Potential Drug Interactions:   
In vitro studies with human liver microsomes indicate that lapatinib is metabolized by 
CYP3A4 and CYP3A5, and to a lesser extent CYP2C19 and CYP2C8.  Co-
administration of lapatinib with potent or moderate CYP3A4 inhibitors (including 
grapefruit juice) and all CYP3A4 inducers is prohibited.  Assess risk/benefit before 
co-administering lapatinib with weak CYP3A4 inhibitors.  CYP3A4 inhibitors may 
decrease lapatinib metabolism (increasing levels); while CYP3A4 inducers may 
increase lapatinib metabolism  (decreasing levels).   
 
In human subjects, lapatanib inhibited CYP3A4 and CYP2C8 at clinically relevant 
concentrations. Avoid co-administration of lapatinib with drugs that are substrates of 
CYP3A4 or CYP2C8 and have narrow therapeutic windows.    
 
Lapatinib potentially interacts with warfarin and quinazoline derivatives to increase 
INR and bleeding.  Collect INR/PT determinations more frequently (e.g. weekly for 
the first month and weekly for a minimum of 2 weeks following lapatinib 
discontinuation). 
 
8.2 
Availability 
 
Lapatinib is an investigational agent supplied to investigators by the Division of 
Cancer Treatment and Diagnosis (DCTD), NCI. 


53 
11-C-0048 
 
Lapatinib is provided to the NCI under a Collaborative Agreement between the 
Pharmaceutical Collaborator and the DCTD, NCI (see Section 12.3). 
 
8.3 
Agent Ordering 
 
NCI-supplied agents may be requested by the Principal Investigator (or their 
authorized designee) at each participating institution.  Pharmaceutical Management 
Branch (PMB) policy requires that agent be shipped directly to the institution where 
the patient is to be treated.  PMB does not permit the transfer of agents between 
institutions (unless prior approval from PMB is obtained.)  The CTEP assigned 
protocol number must be used for ordering all CTEP supplied investigational agents.  
The responsible investigator at each participating institution must be registered with 
CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of 
Investigator), Curriculum Vitae, Supplemental Investigator Data Form (IDF), and 
Financial Disclosure Form (FDF).  If there are several participating investigators at 
one institution, CTEP supplied investigational agents for the study should be ordered 
under the name of one lead investigator at that institution. 
 
Agent may be requested by completing a Clinical Drug Request (NIH-986) and 
faxing it to the Pharmaceutical Management Branch at (301) 480-4612.  For 
questions about drug orders, transfers, returns, or accountability call (301) 496-5725 
Monday through Friday between 8:30 am and 4:30 pm (ET) or email 
PMBAfterHours@mail.nih.gov anytime. 
 
8.4 
Agent Accountability 
 
Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the inventory and disposition of all 
agents received from DCTD using the NCI Drug Accountability Record Form 
(DARF).  (See the CTEP home page at http://ctep.cancer.gov for the Procedures for 
Drug Accountability and Storage and to obtain a copy of the DARF and Clinical Drug 
Request form.) 
 
 
 
 
 
 


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11-C-0048 
9. 
STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 4 weeks prior to administration of protocol 
therapy, unless otherwise indicated.  Assessment may be performed more frequently as 
clinically indicated. 
 
 
 
 
 
Course 1 
Course 2 
Course 3-14 
 
 
Pre- 
Study 
Cy 1, 
d1 
Cy 1,  
d14 
Cy 1, 
d 28 
Cy 2,  
d 14 
Cy 2, 
d 28 
Cy 3,  
d 14 
Cy 3, 
d 28 
1st Cy 
(even) 
d 28h 
2nd Cy 
(odd) 
d 28i 
Off 
Study
e 
Lapatiniba 
 
X------------------------------------------------------------------------------X 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Erbb4 mutation screen 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
Performance status 
X 
 
 
 
 
 
 
 
 
 
X 
CBC w/diff, pltsj 
X 
X------------------------------------------------------------------------------X 
 
Serum chemistryb,j 
X 
X------------------------------------------------------------------------------X 
 
Urinalysisj 
X 
 
 
 
 
 
 
 
 
 
 
B-HCGc,j 
X 
 
 
 
 
 
 
 
 
 
 
PT/aPTT/fibrinogen or 
INR j 
X 
 
 
 
 
 
 
 
 
 
 
ECHO 
X 
 
 
 
 
 
 
X 
 
Xf 
 
Radiologic evaluation 
X 
 
 
X 
 
 
 
X 
 
X 
 
Adverse event eval 
 
X------------------------------------------------------------------------------X 
 
Tumor measurements 
X 
 
 
X 
 
 
 
X 
 
X 
 
Tumor biopsyd 
X 
 
X 
 
 
 
 
X 
 
 
 
PKg 
X 
X 
 
X 
 
 
 
 
 
 
 
a: 
Lapatinib: Dose as assigned; route/schedule. 
b: 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, 
potassium, total protein, SGOT[AST], SGPT[ALT], sodium. 
c: 
Serum or urine pregnancy test (women of childbearing potential). 
d:     Biopsy optional 
e: 
Off-study evaluation. 
f:       Every other course 
g       On 10 patients only 
h       1st cycle of each course (cycles 4, 6, 8, 10, 12, and 14) 
I       2nd cycle of each course (cycles 5, 7, 9, 11 and 13) 
j      These baseline tests are to be conducted within 14 days prior to administration of lapatinib. 


55 
11-C-0048 
10. MEASUREMENT OF EFFECT 
10.1 
Antitumor Effect – Solid Tumors 
For the purposes of this study, patients should be re-evaluated for response after 
completion of the first cycle, after completion of the 3rd cycle and every 8 weeks 
thereafter (± 2 weeks).  In addition to a baseline scan, confirmatory scans should also 
be obtained 8 weeks following initial documentation of objective response. 
 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors 
(RECIST) guideline (version 1.1).72  Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant 
lymph nodes are used in the RECIST criteria. 
 
 
 
10.1.1 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of 
their first treatment with lapatinib. 
 
Evaluable for objective response.  Only those patients who have measurable 
disease present at baseline, have received at least one cycles of therapy, and have 
had their disease re-evaluated will be considered evaluable for response.  These 
patients will have their response classified according to the definitions stated 
below.  (Note:  Patients who exhibit objective disease progression prior to the end 
of cycle 1 will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at 
baseline that are evaluable but do not meet the definitions of measurable disease, 
have received at least one cycle of therapy, and have had their disease re-
evaluated will be considered evaluable for non-target disease.  The response 
assessment is based on the presence, absence, or unequivocal progression of the 
lesions.  
 
 
 
10.1.2 Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter for non-nodal 
lesions and short axis for nodal lesions to be recorded) as >20 mm by chest x-ray, 
as >10 mm with CT scan, or >10 mm with calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area are not be 
considered measurable 
 
Malignant lymph nodes.  To be considered pathologically enlarged and 


56 
11-C-0048 
measurable, a lymph node must be >15 mm in short axis when assessed by CT 
scan (CT scan slice thickness recommended to be no greater than 5 mm).73  At 
baseline and in follow-up, only the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small 
lesions (longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 
mm short axis), are considered non-measurable disease.  Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple 
cysts should not be considered as malignant lesions (neither measurable nor non-
measurable) since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ 
and 5 lesions in total, representative of all involved organs, should be identified as 
target lesions and recorded and measured at baseline.  Target lesions should be 
selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend 
themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in 
which circumstance the next largest lesion which can be measured reproducibly 
should be selected.  A sum of the diameters (longest for non-nodal lesions, short 
axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters.  If lymph nodes are to be included in the sum, then only 
the short axis is added into the sum.  The baseline sum diameters will be used as 
reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any 
measurable lesions over and above the 5 target lesions should be identified as 
non-target lesions and should also be recorded at baseline.  Measurements of 
these lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow-up.  
 
 
 
10.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to 


57 
11-C-0048 
the beginning of treatment and never more than 4 weeks before the beginning of 
the treatment. 
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination 
unless the lesion(s) being followed cannot be imaged but are assessable by 
clinical exam. 
 
Clinical lesions  Clinical lesions will only be considered measurable when they 
are superficial (e.g., skin nodules and palpable lymph nodes) and 10 mm 
diameter as assessed using calipers (e.g., skin nodules).  In the case of skin 
lesions, documentation by color photography, including a ruler to estimate the 
size of the lesion, is recommended.  
 
Conventional CT and MRI  This guideline has defined measurability of lesions on 
CT scan based on the assumption that CT slice thickness is 5 mm or less.  If CT 
scans have slice thickness greater than 5 mm, the minimum size for a measurable 
lesion should be twice the slice thickness.  MRI is also acceptable.  Ideally, the 
same type of scanner should be used and the image acquisition protocol should be 
followed as closely as possible to prior scans.  Body scans should be performed 
with breath-hold scanning techniques, if possible. 
 
PET-CT  At present, the low dose or attenuation correction CT portion of a 
combined PET-CT is not always of optimal diagnostic CT quality for use with 
RECIST measurements.  However, if the site can document that the CT 
performed as part of a PET-CT is of identical diagnostic quality to a diagnostic 
CT (with IV and oral contrast), then the CT portion of the PET-CT can be used 
for RECIST measurements and can be used interchangeably with conventional 
CT in accurately measuring cancer lesions over time.  Note, however, that the 
PET portion of the CT introduces additional data which may bias an investigator 
if it is not routinely or serially performed.   
 
Ultrasound, Endoscopy, Laparoscopy, or Tumor markers  cannot be used for 
disease evaluation in this study.  
 
FDG-PET  is an optional imaging modality in this study. Results from FDG-PET 
scans which are obtained in the routine care of patients may be captured and 
recorded including SUV measurements. FDG-PET cannot substitute for above 
imaging for disease evaluation.  
 
 
 
10.1.4 Response Criteria 
 
 
 
 
10.1.4.1 
Evaluation of Target Lesions72 
 


58 
11-C-0048 
Complete Response (CR): 
Disappearance of all target lesions.  Any 
pathological lymph nodes (whether target or 
non-target) must have reduction in short axis 
to <10 mm. 
 
Partial Response (PR): 
At least a 30% decrease in the sum of the 
diameters of target lesions, taking as 
reference the baseline sum diameters. 
 
Progressive Disease (PD): 
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).  In addition to the 
relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 
5 mm.  (Note:  the appearance of one or 
more new lesions is also considered 
progressions). 
 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for 
PR nor sufficient increase to qualify for PD, 
taking as reference the smallest sum 
diameters while on study. 
 
 
 
 
10.1.4.2 
Evaluation of Non-Target Lesions72 
 
Complete Response (CR): 
Disappearance of all non-target lesions and 
normalization of tumor marker level.  All 
lymph nodes must be non-pathological in 
size (<10 mm short axis). 
 
Note:  If tumor markers are initially above 
the upper normal limit, they must normalize 
for a patient to be considered in complete 
clinical response. 
 
Non-CR/Non-PD: 
Persistence of one or more non-target 
lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
 
Progressive Disease (PD): 
Appearance of one or more new lesions 
and/or unequivocal progression of existing 
non-target lesions.  Unequivocal 
progression should not normally trump 


59 
11-C-0048 
target lesion status.  It must be 
representative of overall disease status 
change, not a single lesion increase.     
 
Although a clear progression of “non-target” 
lesions only is exceptional, the opinion of 
the treating physician should prevail in such 
circumstances, and the progression status 
should be confirmed at a later time by the 
review panel (or Principal Investigator). 
 
 
 
 
10.1.4.3 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of 
the treatment until disease progression/recurrence (taking as reference for 
progressive disease the smallest measurements recorded since the 
treatment started).  The patient's best response assignment will depend on 
the achievement of both measurement and confirmation criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-
CR/Non-PD 
No 
PR 
 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-
CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-
CR/Non-
PD/not 
evaluated 
No 
SD 
documented at least once >4 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a new 
lesion.72 
** 
required in this non-randomized trials with response as primary endpoint 
*** 
On discretion of the Principal Investigator, unequivocal progression in non-target 
lesions may be accepted as disease progression. 
 
Note: Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should 
be reported as “symptomatic deterioration.”  Every effort should be made to 
document the objective progression even after discontinuation of treatment. 
 
 


60 
11-C-0048 
 
 
 
 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease  
 
 
 
10.1.5 Duration of Response 
Duration of overall response:  The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements recorded 
since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are 
first met for CR until the first date that progressive disease is objectively 
documented.  
 
Duration of stable disease:  Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the 
smallest measurements recorded since the treatment started, including the baseline 
measurements.  
 
 
 
10.1.6 Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of 
progression or death, whichever occurs first. 
 
10.2 
Antitumor Effect – Hematologic Tumors 
 
N/A 
 
11. 
REGULATORY CONSIDERATIONS 
 
11.1 
CTEP Multicenter Guidelines 
This protocol will adhere to the policies and requirements of the CTEP Multicenter 
Guidelines.  The specific responsibilities of the Principal Investigator and the 
Coordinating Center (Study Coordinator) and the procedures for auditing are 


61 
11-C-0048 
presented in Appendix L. 
 
 The Principal Investigator/Coordinating Center is responsible for distributing 
all IND Action Letters or Safety Reports received from CTEP to all 
participating institutions for submission to their individual IRBs for action as 
required. 
 
 Except in very unusual circumstances, each participating institution will order 
DCTD-supplied agents directly from CTEP.  Agents may be ordered by a 
participating site only after the initial IRB approval for the site has been 
forwarded by the Coordinating Center to the CTEP PIO 
(PIO@ctep.nci.nih.gov) except for Group studies. 
 
11.2 
Collaborative Agreements Language 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to 
the NCI under a Collaborative Agreement (CRADA, Agent-CRADA, CTA, CSA) 
between the Pharmaceutical Company(ies) (hereinafter referred to as 
“Collaborator(s)”) and the NCI Division of Cancer Treatment and Diagnosis.  
Therefore, the following obligations/guidelines, in addition to the provisions in the 
“Intellectual Property Option to Collaborator” (http://ctep.cancer.gov/industry) 
contained within the terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor 
can Agent(s) be transferred or licensed to any party not participating in the 
clinical study.  Collaborator(s) data for Agent(s) are confidential and proprietary 
to Collaborator(s) and shall be maintained as such by the investigators.  The 
protocol documents for studies utilizing investigational Agents contain 
confidential information and should not be shared or distributed without the 
permission of the NCI.  If a copy of this protocol is requested by a patient or 
patient’s family member participating on the study, the individual should sign a 
confidentiality agreement.  A suitable model agreement can be downloaded from: 
http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in 
combination with (an)other investigational Agent(s), each the subject of different 
collaborative agreements , the access to and use of data by each Collaborator shall 
be as follows (data pertaining to such combination use shall hereinafter be 
referred to as “Multi-Party Data”. ): 
 
a. NCI will provide all Collaborators with prior written notice regarding the 
existence and nature of any agreements governing their collaboration with 
NIH, the design of the proposed combination protocol, and the existence of 
any obligations that would tend to restrict NCI's participation in the proposed 
combination protocol. 


62 
11-C-0048 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the 
clinical trial by any other Collaborator solely to the extent necessary to allow 
said other Collaborator to develop, obtain regulatory approval or 
commercialize its own investigational Agent. 
c. Any Collaborator having the right to use the Multi-Party Data from these trials 
must agree in writing prior to the commencement of the trials that it will use 
the Multi-Party Data solely for development, regulatory approval, and 
commercialization of its own investigational Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available exclusively to Collaborator(s), the NCI, and 
the FDA, as appropriate and unless additional disclosure is required by law or 
court order.  Additionally, all Clinical Data and Results and Raw Data will be 
collected, used, and disclosed consistent with all applicable federal statutes and 
regulations for the protection of human subjects including, if applicable, the 
Standards for Privacy of Individually Identifiable Health Information set forth in 
45 CFR Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be 
sent to the NCI, who will then notify the appropriate investigators (Group Chair 
for Cooperative Group studies, or PI for other studies) of Collaborator's wish to 
contact them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance 
with the guidelines and policies of the responsible Data Monitoring Committee 
(DMC), if there is a DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to 
CTEP by the Group office for Cooperative Group studies or by the principal 
investigator for non-Cooperative Group studies for immediate delivery to 
Collaborator(s) for advisory review and comment prior to submission for 
publication.  Collaborator(s) will have 30 days from the date of receipt for review.  
Collaborator shall have the right to request that publication be delayed for up to 
an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are 
protected.  Copies of abstracts must be provided to CTEP for forwarding to 
Collaborator(s) for courtesy review as soon as possible and preferably at least 
three (3) days prior to submission, but in any case, prior to presentation at the 
meeting or publication in the proceedings.  Press releases and other media 
presentations must also be forwarded to CTEP prior to release.  Copies of any 
manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Regulatory Affairs Branch, CTEP, DCTD, NCI 
Executive Plaza North, Suite 7111 


63 
11-C-0048 
Bethesda, Maryland  20892 
FAX 301-402-1584 
Email: ncicteppubs@mail.nih.gov  
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No 
publication, manuscript or other form of public disclosure shall contain any of 
Collaborator’s confidential/ proprietary information. 
 
12. 
STATISTICAL CONSIDERATIONS 
 
12.1 
Study Design/Endpoints 
 
This is a phase 2 trial in patients with measurable stage IV melanoma harboring 
ERBB4 mutations treated with the tyrosine kinase inhibitor lapatinib.  All patients 
eligible for treatment will undergo formal response evaluation after 1 and 3 cycles of 
therapy and every 2 cycles after that. 
 
Screening 
The prevalence of metastatic cutaneous melanoma patients harboring no more than 
two ERBB4 mutations is 17%. If this were to apply to the screening population and if 
180 patients were screened, there is an 88.9% probability of identifying at least 25 
patients with an ERBB4 mutation. 
 
Treatment 
The primary objective of this trial is to determine if lapatinib monotherapy is able to 
produce adequate numbers of clinical responses in patients with metastatic melanoma 
harboring ERBB4 mutations.  If so, this regimen will be considered for use in 
subsequent studies, to determine its role in this disease. 
 
The study will be conducted using a phase 2 MinMax design.74  The objective of the 
trial will be to determine whether, this novel agent 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). Using alpha=0.10 (probability of accepting a poor 
agent) and beta=0.10 (probability of rejecting a good agent), initially 16 evaluable 
patients will be enrolled in the study. If 0 to 1 of 16 patients respond (PR +CR), then 
no further patients will be enrolled.  If 2 or more of the  first 16 evaluable patients 
enrolled have a clinical response, then accrual will continue until a total of 25 
evaluable patients have been enrolled. If 2 to 4 of the 25 have a clinical response, then 
this will be considered inadequate for further investigation of this regimen. If 5 or 
more of 25 respond, then this will warrant further investigation in a subsequent trial.  
Under the null hypothesis (10% response rate), the probability of early termination is 
51%.  If a DLT is seen in the first three patients, dose de-escalation will occur as 
described in section 3.3. 
 
A variety of secondary evaluations will be performed, corresponding to the secondary 


64 
11-C-0048 
objectives listed. In all cases, the evaluations will be done with exploratory intent, and 
will be performed using non-parametric tests and descriptive statistics on however 
many samples are available. If the study terminates after only 16 patients then no 
further patients will be enrolled to obtain biologic endpoint data. 
 
12.2 
Sample Size/Accrual Rate 
 
The accrual ceiling will be set at 180 patients to be screened for the presence of 
ERBB4 mutations to allow for treatment of up to 28 patients, which would include up 
to 3 inevaluable patients and based on the calculation described above (Section 12.1).  
It is expected that 1-3 patients per month will be treated on this trial.  Allowing for 
treatment with this agent over a two year period with follow up, it is expected that the 
trial will be completed in approximately 3-5 years. 
 
12.3 
Stratification Factors 
 
N/A 
 
12.4 
Analysis of Secondary Endpoints 
 
Progression-free survival will be calculated using the Kaplan-Meier method. 
 
Toxicity data will be obtained, and if there are 5 or more patients who experience 
Grade 3 or greater toxicity attributable to the agent, then comparisons between this 
cohort and patients who tolerated the same course of lapatinib without toxicity across 
grades of toxicity with respect to outcome (response) and clinicopathological 
parameters (age, sex, type of visceral involvement) may be done using a Kruskal-
Wallis test. Otherwise, toxicities will be tabulated and described. 
 
The association of response to lapatinib (PR as defined by RECIST) and presence of 
concomitant activating oncogene mutations or loss of tumor suppressor function will 
be examined in a Fischer’s exact test. 
 
Comparisons between the pERBB4 : total ERBB4 and phospho Akt : total Akt ratio 
will be made by subtracting pre-treatment from posttreatment levels and determining 
the statistical significance of the difference using a Fischer’s exact test. Similarly, 
pErk and pSTAT levels will be evaluated for a change from baseline levels.  These 
measures will all be evaluated with exploratory intent, and findings will be reported 
without formal adjustment for multiple comparisons, but in the 
context of a study with multiple exploratory analyses performed. 
 
12.5 
Reporting and Exclusions 
12.5.1 Evaluation of toxicity – All patients will be evaluable for toxicity from the time of 
their first treatment with lapatinib. 
 


65 
11-C-0048 
12.5.2 Evaluation of response – All patients included in the treatment portion of the 
study must be assessed for response to treatment, even if there are major protocol 
treatment deviations or if they are ineligible.  Each patient will be assigned one of 
the following categories:  1) complete response, 2) partial response, 3) stable 
disease, 4) progressive disease, 5) early death from malignant disease, 6) early 
death from toxicity, 7) early death because of other cause, or 9) unknown (not 
assessable, insufficient data).  [Note:  By arbitrary convention, category 9 usually 
designates the “unknown” status of any type of data in a clinical database.] 
 
All of the patients who met the eligibility criteria (with the possible exception of 
those who received no study medication) should be included in the main analysis 
of the response rate.  Patients in response categories 4-9 should be considered to 
have a treatment failure (disease progression).  Thus, an incorrect treatment 
schedule or drug administration does not result in exclusion from the analysis of 
the response rate.  Precise definitions for categories 4-9 will be protocol specific.  
All conclusions should be based on all eligible patients.  Subanalyses may then be 
performed on the basis of a subset of patients, excluding those for whom major 
protocol deviations have been identified (e.g., early death due to other reasons, 
early discontinuation of treatment, major protocol violations, etc.).  However, 
these subanalyses may not serve as the basis for drawing conclusions concerning 
treatment efficacy, and the reasons for excluding patients from the analysis should 
be clearly reported.   
 
13. HUMAN SUBJECTS PROTECTION 
13.1 
Rationale for Subjects Protection 
 Selection based on gender, ethnicity, and race: Subjects from both genders and all 
racial/ethnic groups are eligible for this study if they meet the eligibility criteria.  
To date, there is no information which suggests that differences in drug 
metabolism or disease response would be expected in any one patient group. 
Efforts will be made to extend accrual to a representative population, but in this 
preliminary study, a balance must be struck between patient safety considerations 
and limitations on the number of patients exposed to potentially toxic treatments 
on the one hand and the need to explore gender and ethnic aspects of clinical 
research on the other.  Prior toxicologic and clinical evaluations have not 
specifically assessed effects on juvenile animals.  Therefore, this study will not 
include patients < 18 years of age.  This is a Phase II trial designed to define the 
response rate, characterize the side effect profile, and assess several biological 
endpoints.   
 
13.2 
Evaluation of Benefits and Risks/Discomforts 
Potential benefits to subjects expected from the trial: As a result of participating in 
this trial, patients will receive evaluation and treatment of their tumor.  This protocol 
may or may not be helpful for a specific patient, but the results may help the 
investigators learn about the administration of lapatinib on a continuing basis.  The 


66 
11-C-0048 
potential for this research treatment to offer control of the disease is unknown; 
however, based on information to date, the possibility of an effect on the progression 
of disease exists.  Benefit cannot be promised nor can the chance of benefit be 
accurately predicted. 
 
13.3 
Consent and Assent Processes and Documents 
The investigational nature and objectives of this trial, the procedures and treatments 
involved and their attendant risks and discomforts, potential benefits and potential 
alternative therapies will be carefully explained to the patient or the patient’s 
surrogate, and a signed informed consent document will be obtained by the PI, AI or 
clinical staff fellow.  Moreover, any experimental invasive procedure will require a 
separate consent form. 
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Desmond RA, Soong SJ. Epidemiology of malignant melanoma. Surg Clin North Am 
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Tsao H, Atkins MB, Sober AJ. Management of cutaneous melanoma. N Engl J Med 
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Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, Abrams J, Sznol M, 
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Bellett RE, Mastrangelo MJ, Laucius JF, Bodurtha AJ. Randomized prospective trial of 
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Middleton MR, Grob JJ, Aaronson N, Fierlbeck G, Tilgen W, Seiter S, Gore M, Aamdal 
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APPENDIX A:  CLINICAL TRIALS OF LAPATINIB IN BREAST CANCER 
 
Clinical Trials of Lapatinib in Patients with Advanced or Metastatic Breast Cancera 
 
Authors 
Patient Population 
No. 
Treatment 
Regimens 
Response 
Burstein et al.[73] 
  Phase II 
  International 
  OL  
 
 
Cohort A: HER2-positive MBC 
refractory to an anthracycline, a 
taxane, capacitabine, and 
trastuzumab 
 
Cohort B: HER2-negative 
MBC refractory to an 
anthracycline, a taxane, 
and capecitabine 
 
140 
 
 
 
 
 
89 
Lapatinib 
1,500 mg QD 
Response RR: 4.3%; clinical 
benefit: 5.7%;  
median TTP: 9.1 wk; median PFS: 9.1 wk; 
median survival: 29.4 wk 
 
No objective responses; 
median TTP: 7.6 wk; 
median PFS: 7.6 wk; 
median survival: 18.6 wk 
Blackwell et al.[74] 
  Phase II 
  MC, OL 
HER2-positive MBC refractory 
to trastuzumab 
78 
Lapatinib 
1,500mg QD 
PR: 7.7%; clinical benefit: 21.8% 
Iwata et al.[75] 
  Phase II 
  MC, OL 
HER2-positive MBC refractory 
to an anthracycline, a taxane, 
capecitabine, and 
trastuzumab 
45 
Lapatinib 
1,500mg QD 
Clinical benefit: 33.3% 
Gomez et al.[76] 
  Phase II 
  MC, R, OL 
First-line treatment of HER2-
positive advanced breast cancer 
or MBC 
138 
Lapatinib 
1,500mg QD 
(n=69) or 
Lapatinib 
500mg BID 
(n=69) 
RR: 24%; clinical benefit: 31%; PFS at 6 
mo: 43%; no difference in clinical activity 
between doses 
Geyer et al.[77] and 
Cameron et al.[78] 
  Phase III 
  MC, R, OL 
HER2-positive locally advanced 
breast cancer or MBC that had 
progressed with regimens 
including an anthracycline, a 
taxane, and trastuzumab 
399 
Lapatinib 
1,250mg QD + 
capacitabine 
1,000 mg/m2 
PO BID on days 
1-14 of a 21-day 
cycle or 
Capacitabine 
1,250mg/m2 PO 
BID on days 1-
14 of a 21-day 
cycle 
Median TTP: 6.2 mo (combination) vs  4.3 
mo (capacitabine alone) (HR=0.57; 95% CI, 
0.43-0.77; p<0.001); improved PFS with 
combination vs capacitabine alone 
(HR=0.55; 95% CI, 0.4-0.74; p<0.001) 
DiLeo et al.[79] 
  Phase III 
  MC, R, DB, PC 
First-line therapy of HER2-
negative or unknown advanced 
breast cancer or MBC 
580 
Lapatinib 
1,500mg QD + 
paclitaxel 
175mg/m2 IV 
q3wk or 
Placebo + 
paclitaxel 
175mg/m2 IV 
q3wk 
RR: 35.1% vs 25.3%, combination vs 
paclitaxel monotherapy, respectively 
(p=0.008); clinical benefit: 40.5% vs 31.9% 
(p=0.025); no difference in TTP or OS 
afrom Medina PJ, Goodin S. Clin Ther 2008 


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APPENDIX B:  ERBB4 PRIMERS 
 
GENE Exon 
Primer Name 
Non M13 tagged Forward Primer 
Primer Name 
Non M13 tagged Reverse Primer 
ERBB4 1b 
ERBB4-X1b-F 
GGGGATATGCCATTTGGAC 
ERBB4-X1b-R 
CGGAGTGCCAGAAGGAAC 
ERBB4 2 
ERBB4-X2-F 
AGAACTGGGATAGGCTTGTGG 
ERBB4-X2-R 
TTCCAGGTATCAGCACACAGG 
ERBB4 3b 
ERBB4-X3b-F 
GGCAACTGTTTGTGTCTTTTCA 
ERBB4-X3b-R 
AAGCATATTTGCCATTTTGGA 
ERBB4 4b 
ERBB4-X4b-F 
TTCATCAACAAGCAGTTTGACA 
ERBB4-X4b-R 
TCGCCACATAGGGTAGAACA 
ERBB4 5 
ERBB4-X5-F 
AAATCCTCATAAAGGAGCAGGAG 
ERBB4-X5-R 
CCAAAGCAAATCAACCACAAG 
ERBB4 6 
ERBB4-X6-F 
TGAATTGAGTCAAAGACAGGGTG 
ERBB4-X6-R 
GGAATGACTTTGAGGAGGGC 
ERBB4 7b 
ERBB4-X7b-F 
TGAAAGTAATATTTGCTGTGTTGC 
ERBB4-X7b-R 
TTCTTTTGATTTCAAATAATGACCT 
ERBB4 8b 
ERBB4-X8b-F 
TGTTTTGAGCTTGTTTGCTGA 
ERBB4-X8b-R 
AAACCTTGTTATATAGGCCCAGTTC 
ERBB4 9b 
ERBB4-X9b-F 
TTGGCCAAAAATAAGTTTCTCAA 
ERBB4-X9b-R 
CACTTTGTAAAATAACTTGCACAAAAA 
ERBB4 10b 
ERBB4-X10b-F 
AAATTTGGCTACATCTCTTCTTGA 
ERBB4-X10b-R 
AAATTATATTGTTCATAGCGCAACA 
ERBB4 11 
ERBB4-X11-F 
CCTTTCTCACTTCCCAACTTTC 
ERBB4-X11-R 
TACCTCACACCATCATCGGAG 
ERBB4 12b 
ERBB4-X12b-F 
TTTTCTCACTTCCCCCTCCT 
ERBB4-X12b-R 
TCCAAAGAAGAATGGGAAAAA 
ERBB4 13b 
ERBB4-X13b-F 
TCCCCTTGATTTTGGTGTTT 
ERBB4-X13b-R 
ATGAGGTGAAGGCAACCCTA 
ERBB4 14 
ERBB4-X14-F 
TGATGCTCCTGGCACATAGAG 
ERBB4-X14-R 
CCCATGGCATCCTGTAAGTAG 
ERBB4 15 
ERBB4-X15-F 
TCTTAGAGGAAGATTTGCCACC 
ERBB4-X15-R 
CATTTCAGAGATGGTACCAGGG 
ERBB4 16 
ERBB4-X16-F 
GCTTCCCATGTTCTTCCTCC 
ERBB4-X16-R 
AAGTAAGAAAGTTGGCTTGAGAAGG 
ERBB4 17 
ERBB4-X17-F 
TGTGGATAATGTCTTGTACAACTGC 
ERBB4-X17-R 
TTCACAAGCTTTGTTTAACGGAC 
ERBB4 18b 
ERBB4-X18b-F 
TTCTTCTTTCCGCTTTGCAG 
ERBB4-X18b-R 
TCCATTGGCTATTATTTTCTAAACA 
ERBB4 19b 
ERBB4-X19b-F 
TGTAACAGGTGCTAAATAAACATTTG 
ERBB4-X19b-R 
TGATTGCCTGGGTGTCTGTA 
ERBB4 20b 
ERBB4-X20b-F 
TTGAGTTGAAATCATGGTATTGC 
ERBB4-X20b-R 
TTCCATAGAAATTGACAGGCACT 
ERBB4 21b 
ERBB4-X21b-F 
GGGAAAACCTGGGCATTAAC 
ERBB4-X21b-R 
TCAAGCAAGATTGCTCTCAAAA 
ERBB4 22 
ERBB4-X22-F 
AGGCCAGCCCAAAGACTC 
ERBB4-X22-R 
TAACTGCTTTAGGAAATTAGGCTTATC 
ERBB4 23b 
ERBB4-X23b-F 
TTGGTGTTTGGATTGACCTG 
ERBB4-X23b-R 
TGATGGTGATAACATTATTTTGCAG 
ERBB4 24 
ERBB4-X24-F 
GAGTCGTTTCTTTCACTAGCTTGC 
ERBB4-X24-R 
TGTTTGTGGTCCTTTCCACAG 
ERBB4 25b 
ERBB4-X25b-F 
TGTGTCTGATGGGCAATCTT 
ERBB4-X25b-R 
TTATTTTGAAATGTTAGTGCTTATGAA 
ERBB4 26b 
ERBB4-X26b-F 
CCATCATTCCATTTTTCTTTCC 
ERBB4-X26b-R 
AAGCAAAGACCGAAAATCCT 
ERBB4 27b 
ERBB4-X27b-F 
ACAACGCCTTCTCTCCACAT 
ERBB4-X27b-R 
AATGGCGATCGTTTCTGAAT 
ERBB4 28_1b ERBB4-X28_1b-F TTTTCCAGAAACTAGAGGTTAGCTG 
ERBB4-X28_1b-R GGTAGTCTGGGTGCTGAAGG 
ERBB4 28_2b ERBB4-X28_2b-F AGGCCGAGGATGAGTATGTG 
ERBB4-X28_2b-R GGAAATTGGAGCAGGTGTGT 
 


75 
11-C-0048 
APPENDIX C:  PERFORMANCE STATUS CRITERIA  
 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 


76 
11-C-0048 
 
APPENDIX D:  List of drugs that may have potential CYP3A4 interactions 
 
List of drugs that may have potential CYP3A4 interactions (source: ctep.cancer.gov) 
[Updated on May 1, 2007] 
 
When drugs classified as ‘substrates’ are co-administered with lapatinib there is the potential for 
higher concentrations of the ‘substrate’. When lapatinib is co-administered with compounds 
classified as ‘inhibitors’, increased plasma concentrations of lapatinib is the potential outcome. 
The co-administration of ‘inducers’ would potentially lower plasma lapatinib concentrations. 
Only major substrates and effective inducers are listed. 
 
CYP3A4 Substrates 
Albuterol 
Alfentanil 
Alprazolam 
Amiodarone 
Amlodipine 
Amprenavir 
Aprepitant 
Aripiprazole 
Atazanavir 
Atorvastatin 
Benzphetamine 
Bisoprolol 
Bortezomib 
Bosentan 
Bromazepam 
Bromocriptine 
Budesonide 
Buprenorphine 
Buspirone 
Busulfan 
Carbamazepine 
Cerivastatin 
Chlordiazepoxide 
Chloroquine 
Chlorpheniramine 
Cilostazol 
Cisapride 
Citalopram 
Clarithromycin 
Clobazam 
Clonazepam 
Clorazepate 
Cocaine 
Colchicine 
Conivaptan 
Cyclophosphamide 
Cyclosporine 
Dantrolene 
Dapsone 
Dasatinib (1) 
Delavirdine 
Diazepam 
Dihydroergotamine  
Diltiazem  
Disopyramide  
Docetaxel 
Doxepin 
Doxorubicin 
Doxycycline 
Efavirenz 
Eletriptan 
Enalapril 
Eplerenone 
Ergoloid mesylates 
Ergonovine 
Ergotamine 
Erythromycin 
Escitalopram 
Estradiol 
Estrogens, conj., synthetic 
Estrogens, conj., equine 
Estrogens, conj., esterified 
Estrone 
Estropipate 
Ethinyl estradiol 
Ethosuximide 
Etoposide 
Exemestane 
Felbamate 
Felodipine 
Fentanyl 
Flurazepam 
Flutamide 
Fluticasone 
Fosamprenavir 
Gefitinib 
Haloperidol 
Ifosfamide 
Imatinib 
Indinavir 
Irinotecan 
Isosorbide 
Isosorbide dinitrate 
Isosorbide mononitrate 
Isradipine  
Itraconazole 
Ketamine  
Ketoconazole 
Lansoprazole 
Letrozole 
Levonorgestrel 
Lidocaine 
Losartan 
Lovastatin 
Medroxyprogesterone 
Mefloquine 
Mestranol 
Methadone 
Methylergonovine 
Methysergide 
Miconazole 
Midazolam 
Miglustat 
Mirtazapine 
Modafinil 
Montelukast 
Moricizine 
Nateglinide 
Nefazodone 
Nelfinavir 
Nevirapine 
Nicardipine 
Nifedipine 
Nimodipine 
Nisoldipine 
Norethindrone 
Norgestrel 
Ondansetron 
Paclitaxel 
Pergolide 
Phencyclidine 
Pimozide 
Pipotiazine 
Primaquine 
Progesterone 
Quetiapine 
Quinidine 
Rabeprazole  
Ranolazine 
Repaglinide 
Rifabutin 
Ritonavir 
Salmeterol 
Saquinavir 
Sibutramine 
Sildenafil 
Simvastatin 
Sirolimus 
Spiramycin 
Sufentanil 
Sunitinib 
Tacrolimus 
Tamoxifen 
Tamsulosin 
Telithromycin 
Teniposide 
Tetracycline 
Theophylline 
Tiagabine 
Ticlopidine 
Tipranavir 
Tolterodine 
Toremifene 
Trazodone 
Triazolam 
Trimethoprim 
Trimipramine 
Troleandomycin 
Vardenafil 
Venlafaxine 
Verapamil 
Vinblastine 
Vincristine 
Vinorelbine 
Zolpidem 
Zonisamide 
Zopiclone 
 
 


77 
11-C-0048 
CYP3A4 Inhibitors 
Acetominophen 
Acetazolamide 
Amiodarone 
Amlodipine 
Amprenavir 
Anastrozole 
Aprepitant 
Atazanavir 
Atorvastatin 
Azelastine 
Azithromycin 
Betamethasone 
Bortezomib 
Bromocriptine 
Caffeine 
Cerivastatin 
Chloramphenicol 
Chlorzoxazone 
Cimetidine 
Ciprofloxacin 
Cisapride 
Clarithromycin 
Clemastine 
Clofazimine 
Clotrimazole 
Clozapine 
Cocaine 
Conivaptan 
Cyclophosphamide 
Cyclosporine 
Danazol 
Dasatinib (1) 
Delavirdine 
Desipramine 
Dexmedetomidine 
Diazepam 
Diclofenac 
Dihydroergotamine 
Diltiazem 
Disulfiram 
Docetaxel 
Doxorubicin 
Doxycycline 
Drospirenone 
Efavirenz 
Enoxacin 
Entacapone 
Ergotamine 
Erythromycin 
Ethinyl estradiol 
Etoposide 
Felodipine 
Fentanyl 
Fluconazole 
Fluoxetine 
Fluvastatin 
Fluvoxamine 
Fosamprenavir 
Glyburide 
Grapefruit juice (2) 
Haloperidol 
Hydralazine 
Ifosfamide 
Imatinib 
Indinavir 
Irbesartan 
Isoniazid 
Isradipine 
Itraconazole 
Ketoconazole 
Lansoprazole 
Lidocaine 
Lomustine 
Losartan  
Lovastatin 
Mefloquine 
Mestranol 
Methadone 
Methimazole 
Methoxsalen 
Methylprednisolone 
Metronidazole 
Miconazole 
Midazolam 
Mifepristone 
Mirtazapine 
Mitoxantrone 
Modafinil 
Nefazodone 
Nelfinavir 
Nevirapine 
Nicardipine 
Nifedipine 
Nisoldipine 
Nizatidine 
Norfloxacin 
Olanzapine 
Omeprazole 
Orphenadrine 
Oxybutynin 
Paroxetine 
Pentamidine 
Pergolide 
Phencyclidine 
Pilocarpine 
Pimozide 
Pravastatin 
Prednisolone 
Primaquine 
Progesterone 
Propofol  
Propoxyphene 
Quinidine 
Quinine 
Quinupristin 
Rabeprazole 
Ranolazine 
Risperidone 
Ritonavir 
Saquinavir 
Selegiline 
Sertraline 
Sildenafil 
Sirolimus 
Sulconazole 
Tacrolimus 
Tamoxifen 
Telithromycin 
Teniposide 
Testosterone 
Tetracycline 
Ticlopidine 
Tranylcypromine 
Trazodone 
Troleandomycin 
Valproic acid 
Venlafaxine 
Verapamil 
Vinblastine 
Vincristine 
Vinorelbine 
Voriconazole 
Zafirlukast 
Ziprasidone 
 
CYP3A4 Inducers 
Aminoglutethimide 
Carbamazepine 
Fosphenytoin 
Nafcillin  
Nevirapine 
Oxcarbazepine 
Pentobarbital 
Phenobarbital  
Phenytoin 
Primidone 
Rifabutin 
Rifampin  
Rifapentine 
St. John’s wort (3) 
 
Note: Adapted from Cytochrome P450 Enzymes: Substrates, Inhibitors, and Inducers. In: Lacy 
CF, Armstrong LL, Goldman MP, Lance LL eds. Drug Information Handbook 15TH ed. Hudson, 
OH; LexiComp Inc. 2007: 1899-1912.   
Only major substrates and effective inducers are listed.   
Additional information for drug interactions with cytochrome P450 isoenzymes can be found at 
http://medicine.iupui.edu/flockhart/. 
 
(1)   Investigator’s Brochure: Dasatinib (BMS 354825). Bristol-Myers Squibb. October 2006. 
(2)  Malhotra et al. (2001). Clin Pharmacol Ther. 69:14-23. 
(3)  Mathijssen et al. (2002). J Natl Cancer Inst. 94:1247-1249. 
      Frye et al. (2004). Clin Pharmacol Ther. 76:323-329. 


78 
11-C-0048 
APPENDIX E:  LAPATINIB SCREENING SCHEMA 
 
New Patient
Identified
Patient consented to screening phase of protocol
Site Study personnel complete eligibility check list and
fax to CRO
NCI CRO notifies Site, PI, and NCI research
RN of patient enrollment
Tissue obtained
Paraffin block (preferable) or 10 unstained
slides + one H&E stained slide sent => Fedex
to NCI Study Cordinator
NCI Study Coordinator notified that sample has
been sent
NCI Study Coordinator enters request in CMPC database
Dr Meltzer’s lab performs ERBB4 assay {takes about 2
weeks} and uploads results into CMPC site
NCI Study Coordinator receives notification of results via e-mail and
notifies treating team of results
If results are + site will consent patient on treatment protocol and send
eligibility documents to NCI research RN for review
NCR research RN will review eligibility documents with PI and
register patient with CRO to treatment arm of protocol
CRO will notify site and NCI staff of registration
to treatment arm
Patient receives
treatment.
Lapitinib Screening Schema
Participating Sites


79 
11-C-0048 
 
APPENDIX F:  Patient Medication Diary 
 
 


80 
11-C-0048 
APPENDIX G:  Laboratory Methodology for Pharmacokinetics Studies 
 
Laboratory Methodology 
 
Pharmacokinetic Studies 
Pharmacokinetics of lapatinib 
Venous blood samples should be collected in a 6-ml sodium heparin (green top) tube at the 
following time points: 
 Pre-treatment (before start of lapatinib) 
 1h, 2h, 3h, 4h, 6h, 8h post 1st dose in the morning (up to pre evening dose) 
 Day 28 (± 5 days) – before 1st dose in the morning and 1h, 2h, 3h, 4h, 6h, 
8h post morning dose (up to pre-evening dose). 
 
For samples collected at the Surgery Branch, NCI, immediately place specimens on wet ice and 
refrigerate. The date and exact time of each blood draw should be recorded on the sample tube 
and the PK sheet. Please page 102-11964 (Gareth Peters or alternate tech) for immediate pick-up. 
(Contact the Clinical Pharmacology Program (CPP) processing group in 10/5A09 at 301-594-
6131 or 301-402-3622 with any questions).  
 
Instructions for Specimen Processing and Shipping (collaborating institutions) 
  
Specimen Processing 
1.      Draw specimen in 6ml Na Heparin tube (green top) 
2.      Place blood tubes on wet ice immediately after draw - keep cold (4C) until aliquots are 
placed in the freezer. 
3.      Process samples within one hour of draw whenever possible. 
4.      Spin at   2400rpm (1250g) for 5min at 4C 
5.      After centrifugation, split each Na heparin tube sample into 2 aliquots and store aliquots in 
cryovials (ex. Nunc 375418). 
6.      Store at -80 C 
7.      Provide the date and time of draw both on the frozen tube and PK sheet. Provide patient’s 
assigned study code and protocol number on PK sheet. Put patient study code and protocol 
number on tubes to link them to PK sheet.  
8.      Do not allow samples to thaw once frozen. 
  
Specimen Shipping 
1.       Place samples in a cardboard sample box with an absorbent strip (ex. Saf-T-Pak #STP-152 
250ml absorbent) 
2.       Place sample box and PK sheet in a ziplock bag (ex. Lab Guard # SBL2X810B)  
3.       Package specimen bag with dry ice inside an insulated shipper (ex. Saf-T-Pak #STP-300 
Category A shipping overpak). 
Note: Any shipping packaging approved for a Category A substance is acceptable; dry ice is 
considered a hazardous material and thus must be handled by appropriately trained individuals. 
4.       Ship via FedEx Priority Overnight to: 
William Figg 


81 
11-C-0048 
National Cancer Institute 
9000 Rockville Pike 
Bldg 10 Rm 5A01 
Bethesda, MD 20892 
Tel: 301-402-3622 
5.       Ship only on Mon-Wed. Do not ship the day before a federal holiday. 
6.       Send PK sheets with shipment. 
7.       If shipping samples for more than one pt, separate out patient specimens in separate 
ziplock bags. 
8.      Notify me via email (comptok@mail.nih.gov) or fax (301 402-8606) on the date of 
shipment. Provide contact information for the person in charge of shipping at that institute as 
well as the number of samples shipped. 
 
Sample Data Collection 
All samples sent to the Clinical Pharmacology Program (CPP) will be barcoded, with data 
entered and stored in the Patient Sample Data Management System (PSDMS) utilized by the 
CPP. This is a secure program, with access to the PSDM System limited to defined CPP 
personnel, who are issued individual user accounts. Installation of PSDMS is limited to 
computers specified by Dr. Figg. These computers all have a password restricted login screen. 
All CPP personnel with access to patient information annually complete the NIH online 
Protection of Human Subjects course.  
 
PSDMS creates a unique barcode ID for every sample and sample box, which cannot be traced 
back to patients without PSDMS access. The data recorded for each sample includes the patient 
ID, name, trial name/protocol number, time drawn, cycle time point, dose, material type, as well 
as box and freezer location. Patient demographics associated with the clinical center patient 
number are provided in the system. For each sample, there are notes associated with the 
processing method (delay in sample processing, storage conditions on the ward, etc.). 
 
Sample Storage and Destruction 
Barcoded samples are stored in barcoded boxes in a locked freezer at either -20 or -80 C 
according to stability requirements.  These freezers are located onsite in the CPP and offsite at 
NCI Frederick Central Repository Services (Fisher Bioservices) in Frederick, MD. Visitors to the 
laboratory are required to be accompanied by laboratory staff at all times.  
 
Access to stored clinical samples is restricted. Samples will be stored until requested by a 
researcher named on the protocol. All requests are monitored and tracked in the PSDM System. 
All researchers are required to sign a form stating that the samples are only to be used for 
research purposes associated with this trial (as per the IRB approved protocol) and that any 
unused samples must be returned to the CPP. It is the responsibility of the NCI Principal 
Investigator to ensure that the samples requested are being used in a manner consistent with IRB 
approval. 
 
Following completion of this study, samples will remain in storage as detailed above. Access to 
these samples will only be granted following IRB approval of an additional protocol, granting 


82 
11-C-0048 
the rights to use the material.  
 
If, at any time, a patient withdraws from the study and does not wish for their existing samples to 
be utilized, the individual must provide a written request. Following receipt of this request, the 
samples will be destroyed (or returned to the patient, if so requested), and reported as such to the 
IRB. Any samples lost (in transit or by a researcher) or destroyed due to unknown sample 
integrity (i.e. broken freezer allows for extensive sample thawing, etc.) will be reported as such 
to the IRB. 
 
Sample barcodes are linked to patient demographics and limited clinical information. This 
information will only be provided to investigators listed on this protocol, via registered use of the 
PSDMS. It is critical that the sample remains linked to patient information such as race, age, 
dates of diagnosis and death, and histological information about the tumor, in order to correlate 
genotype with these variables. 
 


83 
11-C-0048 
 
APPENDIX H: Primers used for PCR amplification and sequencing of RAS and Raf 
isoforms 
 
  
 


84 
11-C-0048 
 
APPENDIX I:  SOP - DNA PCR and Sequencing Assays Using the ABI 3730 
 
Standard Operating Procedure 
 
Clinical Molecular Profiling Core 
Genetics Branch, CCR, NCI 
50 South Drive, MSC 8000 
Building 50, Room 5140 
Bethesda MD 20892-8000 
CLIA # 21D1092530 
 
DNA PCR and Sequencing Assays Using the ABI 3730 
 
Overview: This standard operating procedure describes the technical details of Sanger 
sequencing of an extant DNA sample produced using the laboratory’s CLIA certified 
protocol. The procedure for DNA extraction from anatomic pathology specimens for clinical 
testing is described elsewhere. Details regarding the Sanger assay sensitivity, specificity, and 
validation for particular mutations being tested for are also provided elsewhere. 
 
Workflow: 
 
1) DNA analytes are pipetted into a 96-well plate in a pre-PCR environment where the DNA 
is safe from contamination. 
2) Perform polymerase chain reaction (PCR) using the selected CLIA-certified test primers. 
3) Purify amplified DNA in preparation for sequencing reaction. 
4) Run the sequencing reactions in order to produce uniform peak heights, optimize the 
signal balance, and produce long reads. 
5) Perform second purification to remove any unincorporated dye terminators. 
6) Set up the Applied Biosystems 3730 DNA Analyzer, and set the program for the selected 
plates. 
7) Run the 3730 DNA Analyzer and analyze the DNA sequence data using the software 
program Variant Reporter™. 
 
Reagents & Supplies: 
 
A. Components of Applied Biosystems Mix: 
 
 
1. 2X AmpliTaq Gold Master Mix (Applied Biosystems Cat. # 4327059) 
 
 
2. Ultra Pure Glycerol (Invitrogen Cat. # 15514-011) 
 
 
B. PCR: 
1.  
5-10 ng/ l DNA 
2. 
Selected 0.6 m Primers (diluted from 100 μM Primers) 


85 
11-C-0048 
3.   
Water, ultra pure, unfiltered, deionized by reverse osmosis, endotoxin 
tested, one liter (Quality Biological, Inc. Cat #: 118-162-131) 
4.  
2X AmpliTaq Gold Master Mix (Applied Biosystems Cat. # 4327059) 
 
 
5.  
Ultra Pure Glycerol (Invitrogen Cat. # 15514-011) 
 
 
C. 
PCR Purification: 
1. 
Exo-Sap It (USB Cat. # 78205)   
 
 
D. 
Sequencing Reaction: 
1. 
Ultra pure deionized H2O (Quality Biological, Inc., Cat. # 118-162-131) 
2. 
BigDye® Terminator v3.1 Cycle Sequencing Kit (Applied Biosystems Cat. 
# 4337456) 
3. 
Hi-DiTM Formamide (Applied Biosystems Cat. # 4311320) 
4. 
BigDye® Terminator v1.1, v3.1 5X Sequencing Buffer (Applied 
Biosystems Cat. # 4336699) 
 
E. 
Purification: 
1. 
 BigDye XTerminator Purification Kit (Applied Biosystems, Cat. # 
4376484) 
F. 
General Supplies: 
1. 
MicroAmp® 96-well Reaction Plate (Applied Biosystems Cat. # N801-
0531) 
2. 
MicroAmp® Optical Adhesive Film (Applied Biosystems Cat. # 4311971) 
 
Equipment: 
A. ABI 3730 (Applied Biosystems Cat. # 4373905/4364619/4364620) 
B. SORVALL Legend RT Plus Centrifuge (Thermo Scientific Cat. # 75004373) 
C. Thermo Savant DNA 120 SpeedVac® 
D. Alpha Innotech FluorChem® 8900 
E. PTC-225 DNA Engine Tetrad Thermal Cycler (BioRad {formerly MJ Research} Cat. # 
PTC-0225) 
F. Illumina High-Speed Microplate Shaker (VWR International, catalog # 13500-890). 
 
Assay Procedure: 
For DNA extraction and primer design, please see the relevant SOPs. 
 
I. PCR Reaction: 
 
Protocol: 
1) Add three uL of PCR Primer set (0.6 uM) into each well. Dry down primer plates. 
2) Add the PCR Master Mix. Mix with corresponding DNA to primer plates 
3) Follow recipes in Excel Spreadsheet (see file on CMPC shared folder named 
“3730_Meltzer_Template_96well(current).xls”) 


86 
11-C-0048 
 
n=
16
n=1
Stock
Unit
Final
(uL) 160
10
2
X
1
X
Amplitaq Gold PCR Master Mix, Lot # ____________________
(uL) 0
0
0.6
uM
0.24
uM
RSA primers, diluted 50%, robot disp 3ul -dried down,
(uL) 16
1
10
ng/ul
10
ng
Template DNA (5ng/ul) - robot dispensed 2ul
(uL) 51.2
3.2
50
%
8
%
Glycerol (Invitgoren only), Made ___/___/___ by _____________
(uL) 92.8
5.8
H2O
(uL) 320
20
 
 
4)  Select “VSEQR” on the DNA Engine Tetrad / PTC-225 Peltier Thermal Cycler. 
 
PCR Cycling
vseqr
96
5 min
40 cycles
94
30 sec
60
45 sec
Thermal cycler used
72
45 sec
___________________
72
10 min
10
Hold
 
 
5) Run a 1-2% Agarose Gel (See 1-2% Agarose Gel Electrophoresis protocol) 
 
 
II. PCR Purification Protocol: 
 
Exo-Sap-IT Protocol: 
 
1) Add 2-4 uL of ExoSap-It enzyme reagent to each PCR well. 
2) Perform the reaction using a thermocycler under the following conditions: 
 
 
37 
30 min 
 
 
80 
15 min 
 
 
10 
hold 
 
 
 
 
III. ABI Sequencing Reaction: 
(See Applied Biosystems Variant seqr protocol). 
 
1) In 96 well reaction trays, add 2 μL each of the PCR amplicons into the appropriate wells. 
2) Spin down the plates to get rid of bubbles. 
3) Add 8 uL of sequencing mix as noted below. 
 
n= 
100 
n=1 
0 
Unit 
Final 
 
 
 
 
(uL) 
160 
1.6 
2.5 
X 
0.4 
X 
Big Dye 3.1, Lot # 
______________ 
(uL) 
120 
1.2 
5 
X 
0.6 
X 
Big Dye Sequencing Buffer 
(uL) 
32 
0.32 
10 
uM 
320 
nM 
M13 for OR M13 Rev primer,  
 
0 
2 
 
 
 
 
ExoSAP- treated PCR product 
(uL) 
488 
4.88 
 
 
 
 
H2O 
 
 


87 
11-C-0048 
 
800 
10 
 
 
 
 
 
 
 
 
 
4) Cover and place in the DNA Engine Tetrad / PTC-225 Peltier Thermal Cycler and select 
the program “m13seq” using the following conditions: 
 
Cycle Sequencing 
  
m13seq 
  
 
96 
1 min 
25 cycles 
 
96 
10 sec 
  
 
50 
5 sec 
  
 
60 
4 min 
  
  
10 
Hold 
 
Label a new set of 96 well plates before proceeding to the Qiagen DyeEx 96 Kit Protocol. 
 
IV. Sequencing Reaction Purification: 
 
Protocol: 
The sequencing reactions can be purified using the BigDye XTerminator Kit from Applied 
Biosystems.   
 
1. Add 45μL of SAM solution directly to each sequencing reaction well (heat SAM solution 
to 37°C if precipitates are present).  
2.  Vortex well to resuspend BigDye Xterminator Beads and add 10μL to each reaction well.   
3.  Seal plate with foil and vortex at 1800rpm for 30 minutes on an Illumina High-Speed 
Microplate Shaker. 
4.  Centrifuge the plate at 1000 xg for 2 minutes.   
5.  The plate is now ready to be loaded onto the 3730 DNA Analyzer.  Check that the 
instrument protocol is set to BDx-FastSeq50_Pop7_v3_Z to ensure proper capillary 
height during injection. 
 
V. Quick Guide to Applied Biosystems 3730 DNA Analyzer: 
 
1. Turn on the 3730 DNA Analyzer instrument. 
2. Log into the Applied Biosystems computer that is connected to the 3730 DNA Analyzer 
hardware using the following information: 
   Username: Administrator 
    
Password: MeltzerLab 
3. Run Applied Biosystems Software (Foundations 3730 Data Collection program). 
Go to Plate Manager and enter File name.  The file name should include: [Gene]_[gene 
section or region]_[sample ID]_[PI] _[plate ID]_[F or R]_[date run] (denoting F for 
forward primer and R for reverse primer). 
4. At Run Scheduler add the files in the order in which you would like the plates to be run. 
The bottom plate will be run first. 
5. Clean out all trays labeled Buffer, Water, and Waste by rinsing with water.  Refill 
deionized water up to the black lines in the Water and Waste trays. Add 1X 3730 Applied 


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Biosystems buffer (after diluting original 10X concentration) into tray labeled Buffer. 
Place tray back into the 3730 DNA Analyzer. 
6. If bubbles are present in the capillary tubes, you MUST run Bubble Wizard to remove 
bubbles. Sample plates must be loaded in the In tray to run this program. If a bubble is 
present and the Bubble Wizard is not run, the capillary tubes can be damaged. 
7. Change Sequencing Buffer in small glass jar next to the DNA polymer and fill the jar to 
the red line. 
8. Close doors, and turn off lights (if turned on) by pushing the button with the light bulb on 
the left side of the 3730 DNA Analyzer instrument. The light should be green on the 
outside of the 3730 DNA Analyzer. If the computer is ready to run, a green Play button 
should be highlighted on the computer in the program under Run Scheduler. Click to run. 
9. Discard plates after they have been run. 
 
VI. DNA Analysis Using Variant Reporter: 
 
1. Open and import all files. 
2. Import the associated reference sequence file. 
3. Click ‘Analyze button.’ 
4. Click on Variant Review tab for visual chromatogram analysis of all samples. 
5. Save sequencing project in the following format: PI_CMPC study ID_Gene name_date of 
sequencing. 
 
 
VII. Resulting Reads: 
Ultimately, the scoring is the judgment of the technician and director reviewing the results. There 
are standard quality control measures, but we only read sequence that is well above the level of 
these cutoffs - in other words, we are reading in the best part of reads. Generally, we strive for 
bidirectional reads. On those occasions when the complexity of the sequence on one end is just 
so low that getting one of the directions to work is really difficult, but the other strand can be 
sequenced quite well, a judgment call will be made by the CLIA director as to whether to accept 
the current results, to rerun the sample, or report out with a caveat that the results are suspect.  
 
A failed read needs to be repeated if that exon has been shown in other cancer patients to contain 
a possible mutation. Questionable reads should also be repeated if there is a known hotspot. 
Instead of “questionable” we will use the term “lower quality” or LQ. 
 
We will rely upon the software to correctly call all negative bases but a few spot checks (~6) will 
be performed by the technician as a QC measure. However, the CLIA laboratory director or his 
designate will visually review any mutations prior to reporting the results to the clinician. In 
general, we will not do validation of mutations; that can be kicked back to the investigator. For 
some projects, validation might be important, but due to limited resources we will discuss on a 
case by case basis, first internally, and then with the investigator, if appropriate. In general, good 
quality bidirectional sequence is definitive. Result reporting nomenclature will be guided by the 
Update on Nomenclature for Human Gene Mutations, Ad Hoc Committee on Mutation 
Nomenclatures1. 


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VIII. Quality Control: 
PCR quality control: 
QC data tracking will be documented via the PCR Amplicon Quality Control Data Tracking 
form. 
1. Positive controls: No external positive control (PC) is necessary for this assay, rather 
the amplification of the patient DNA is proof that the PCR reagents and method are 
functioning correctly. 
2. Negative controls: No template controls (NTC) should be run for each primer set 
used in the assay for each run. These are to control against contamination of the 
reagents or reaction environment from foreign DNA or amplicons. A positive NTC 
rules out against the use of that primer reaction in the assay and must subsequently be 
repeated after making use of fresh reagents and cleaning the work area with 10% 
bleach. 
3. Gel electrophoresis: All NTCs and a random sampling of the patient amplicons will 
be run on an agarose gel to show that there is no contamination and to confirm that 
the reagents and PCR method is working as expected.  
Acceptable limits: no band for NTCs and visible bands of the expected size for patient 
amplicons. Results will not be reported out if controls do not pass QC. 
 
 
DNA sequencing quality control: 
The Quality Number generated by Variant Reporter is a numerical scale (ranging from 0-99) 
that is used in order to compare the quality of the sample sequence with the GenBank 
reference sequence. Generally, the Quality Number for the sample sequence should be 5 or 
above in order to make an accurate comparison with the GenBank reference sequence. 
However, sometimes a case may occur where the forward or reverse sequence may be of low 
quality, while its corresponding forward or reverse sequence may be above a quality number 
of 5 and satisfactory. In this case, use the higher quality sequence to compare with the 
reference sequence. Every so often, a region of the higher quality sequence may be 
unreadable. When this occurs, look at the same region of the sequence in the reverse 
direction. If that region is clear, then review that particular region and continue analysis, but 
if that region is also unreadable then that sample sequence should be marked as Failure. 
Ultimately, however, the Quality Number is only a guide and the final determination of 
sequence quality is the technician’s. The test read should also be compared to the normal 
sequence generated during the validation stage of the test. 
 
IX. Troubleshooting and Corrective Actions: 
1. If plate is loaded incorrectly into the ABI 3700, look for two problems: (1) Is the white 
lid snapped tightly onto the plate holder (2) Are the capillary needles still straight? 
Solution (1) is to readjust the lid for the plate holder. Solution (2) is to shut off the ABI 
3700 and seek technical support to readjust capillary needles. 


90 
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2. If error has occurred overnight then fix the error and either run same plate again or rerun 
Dye-Ex clean up using the saved plate from the sequencing reaction. 
 
X. References 
1. Cotton, RGH. Update on Nomenclature for Human Gene Mutations. Human Mutation 
(1996), 8:197-202. 
2. Patrick C. Ma, Maria S. Tretiakova, Alexander C. MacKinnon, Nithya Ramnath, Candace 
Johnson, Sascha Dietrich, Tanguy Seiwert, James G. Christensen, Ramasamy 
Jagadeeswaran, Thomas Krausz, Everett E. Vokes, Aliya N. Husain, Ravi Salgia, 
Expression and mutational analysis of MET in human solid cancers. Genes, 
Chromosomes and Cancer (2008), 47 (12); 1025-1037. 
3. Fluorescent DNA Sequencing on the ABI 3730/3730xl. Mayo Clinic: Department of 
Laboratory Medicine and Pathology Molecular Genetics Laboratory, Rochester, MN 55905. 
4. Fluorescence-based Dideoxy Sequencing - ABI Prism BigDye Terminator Cycle 
Sequencing Kit. Division of Laboratory Medicine, Clinical Center, NIH, Bethesda 20892 


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DNA PCR and Sequencing Assays Using the ABI 3730 
SOP Revision Tracking Sheet 
 
 
 
Prepared by: Robert Chang, BS, and Marbin Pineda, MS, Daniel C Edelman, PhD 
 
 
 
Date 
 
By 
Signature 
Comments 
 
Adopted 
 
 
Jonathan K. Killian, MD, 
PhD 
 
Original SOP for CLIA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
vised 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discontinued: 
 
 
 
 
 
 
 
 
 


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APPENDIX J:  Primers for CDKN2A and TP53 genes 
 
Coding 
Exon # 
Genomic position 
Forward 
primer - 
Relative 
position
† 
Forward primer sequence§ 
Reverse 
primer - 
Relative 
position
‡ 
Reverse primer sequence§ 
1 
chr9:21964676-21964826 
-114 
M13-
AGCACCGGAGGAAGAAAGAG 
66 
AGCGCTACCTGATTCCAATTC 
2 
chr9:21960900-21961207 
-73 
M13-
GGGCTCTACACAAGCTTCCTTTC 
67 
CCGGGCTGAACTTTCTGTG 
3 
chr9:21958227-21958241 
-294 
TCTTCTTGCAACCCTGCG 
59 
M13-GGCAGTTGTGGCCCTGTAG 
1 
chr9:21984137-21984453 
-101 
ATCTTGGAGGTCCGGGTG 
69 
M13-
CCTGGGCTAGAGACGAATTATC 
2 
chr9:21961001-21961207 
-72 
M13-
GGCTCTACACAAGCTTCCTTTC 
60 
CTATGCGGGCATGGTTACTG 
1 
chr17:7520563-7520637 
-74 
M13-
AGGGTTGGAAGTGTCTCATGC 
139 
AGCCCAACCCTTGTCCTTAC 
2 
chr17:7520424-7520446 
-179 
M13-
CAGTCAGATCCTAGCGTCGAG 
120 
AAATCATCCATTGCTTGGGAC 
3 
chr17:7520036-7520315 
-117 
ACGTTCTGGTAAGGACAAGGG 
69 
M13-
GAGGAATCCCAAAGTTCCAAAC 
4 
chr17:7519095-7519279 
-154 
AAGCTCCTGAGGTGTAGACGC 
69 
M13-
GGGCCAGACCTAAGAGCAATC 
5 
chr17:7518901-7519014 
-98 
M13-CTGCTCAGATAGCGATGGTG 
169 
AGGCCCTTAGCCTCTGTAAGC 
6 
chr17:7518223-7518333 
-286 
CATCCTGGCTAACGGTGAAAC 
70 
M13-
AGAAATCGGTAAGAGGTGGGC 
7 
chr17:7517743-7517880 
-92 
GTTGGGAGTAGATGGAGCCTG 
81 
M13-
TTGGGCAGTGCTAGGAAAGAG 
8 
chr17:7517577-7517651 
-107 
M13-
GGAGCACTAAGCGAGGTAAGC 
110 
TTGTCTTTGAGGCATCACTGC 
9 
chr17:7514651-7514758 
-222 
ATTGCACCATTGCACTCCC 
81 
M13-
AGCTGCCTTTGACCATGAAG 
10 
chr17:7513651-7513733 
-124 
M13-CCATCTTGATTTGAATTCCCG 
76 
ATTGCAAGCAAGGGTTCAAAG 
 


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APPENDIX K:  Guidelines for Management of Gastrointestinal Adverse Events 
 
 
If GI adverse events are not appropriately managed, they may be associated with the 
development of dehydration.  Management of gastrointestinal adverse events is discussed in 
detail below. 
 
Nausea, vomiting, or both 
 
In subjects who have emesis and are unable to retain lapatinib, every attempt should be made to 
obtain control of nausea and vomiting.  A dose may be repeated if tablets can be visually found 
after the vomiting episode. 
 
Diarrhea 
 
These broad general management principles are recommended to proactively try and avoid more 
serious complications by active management of diarrhea syndrome.  Guidelines such as these 
should never replace sound clinical judgment.  Experience thus far suggests that when lapatinib 
is used as monotherapy, uncomplicated Grade 1 or 2 diarrhea is most prevalent.  These general 
management principles do not address comprehensive management of more serious or protracted 
diarrhea syndromes. 
 
Common clinical sense with the onset of uncomplicated Grade 1-2 diarrhea: stop all lactose 
containing products: drink 8-10 large glasses of clear liquids a day; eat frequent small meals; for 
Grade 2 diarrhea hold cytotoxic chemotherapy, and consider a dose reduction of lapatinib 
(discuss with Sponsor); administer standard doses of loperamide: initial dose 4 mg followed by 2 
mg every 4 hours or after every unformed stool.  It is suggested to continue loperamide until the 
subject is free from diarrhea for 12 hours. 
 
For Grade 3 or 4 diarrhea or Grade 1 or 2 with complicating features (severe cramping, severe 
nausea/vomiting, decreased performance status, fever, sepsis, Grade 3 or 4 neutropenia, frank 
bleeding, dehydration) use intravenous fluids as appropriate, consider hospital administration. 
Use prophylactic antibiotics as needed (example fluoroquinolones) especially if diarrhea is 
persistent beyond 24 hours or there is a fever or Grade 3-4 neutropenia, hold both cytotoxic 
chemotherapy and lapatinib and discuss with medical monitor. 
 
Treatment of gastrointestinal adverse events 
 
Diarrhea can be debilitating, and on rare occasions, it is potentially life-threatening.  Based on 
experience with lapatinib alone or in combination with taxanes and/or trastuzumab, diarrhea 
should be managed proactively to avoid complications or worsening of the patient’s condition. 
Guidelines developed by an American Society of Clinical Oncology (ASCO) panel for treating 
chemotherapy-induced diarrhea are abstracted below.  
Pharmacological approaches include the following: 
Loperamide, administered as an initial 4-mg dose, followed by 2-mg doses every  


94 
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4 hours. This dose and regimen are moderately effective. 
Clonidine, non-steroidal anti-inflammatory drugs, and the serotonin antagonist cyproheptadine 
have been shown to be effective in controlling diarrhea associated with inflammation of the 
bowel. 
The synthetic octapeptide, octreotide, has been shown to be effective in the control of diarrhea 
induced by fluoropyrimidine-based chemotherapy regimens when administered as an escalating 
dose by continuous infusion or subcutaneous injection. Octreotide can be administered at doses 
ranging from 100 μg twice daily to 500 μg 3 times daily, with a maximum-tolerated dose of 
2000 μg 3 times daily in a 5-day regimen. 


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APPENDIX L:  CTEP MULTICENTER GUIDELINES 
 
 
If an institution wishes to collaborate with other participating institutions in performing a CTEP 
sponsored research protocol, then the following guidelines must be followed. 
 
Responsibility of the Protocol Chair  
 The Protocol Chair will be the single liaison with the CTEP Protocol and Information 
Office (PIO).  The Protocol Chair is responsible for the coordination, development, 
submission, and approval of the protocol as well as its subsequent amendments.  The 
protocol must not be rewritten or modified by anyone other than the Protocol Chair.  
There will be only one version of the protocol, and each participating institution will use 
that document.  The Protocol Chair is responsible for assuring that all participating 
institutions are using the correct version of the protocol. 
 The Protocol Chair is responsible for the overall conduct of the study at all participating 
institutions and for monitoring its progress.  All reporting requirements to CTEP are the 
responsibility of the Protocol Chair.  
 The Protocol Chair is responsible for the timely review of Adverse Events (AE) to assure 
safety of the patients. 
 The Protocol Chair will be responsible for the review of and timely submission of data 
for study analysis. 
 
Responsibilities of the Coordinating Center 
 Each participating institution will have an appropriate assurance on file with the Office 
for Human Research Protection (OHRP), NIH.  The Coordinating Center is responsible 
for assuring that each participating institution has an OHRP assurance and must maintain 
copies of IRB approvals from each participating site.  
 Prior to the activation of the protocol at each participating institution, an OHRP form 310 
(documentation of IRB approval) must be submitted to the CTEP PIO. 
 The Coordinating Center is responsible for central patient registration.  The Coordinating 
Center is responsible for assuring that IRB approval has been obtained at each 
participating site prior to the first patient registration from that site. 
 The Coordinating Center is responsible for the preparation of all submitted data for 
review by the Protocol Chair. 
 The Coordinating Center will maintain documentation of AE reports.  There are two 
options for AE reporting: (1) participating institutions may report directly to CTEP with a 
copy to the Coordinating Center, or (2) participating institutions report to the 
Coordinating Center who in turn report to CTEP.  The Coordinating Center will submit 
AE reports to the Protocol Chair for timely review. 
 Audits may be accomplished in one of two ways:  (1) source documents and research 
records for selected patients are brought from participating sites to the Coordinating 
Center for audit, or (2) selected patient records may be audited on-site at participating 
sites.  If the NCI chooses to have an audit at the Coordinating Center, then the 
Coordinating Center is responsible for having all source documents, research records, all 
IRB approval documents, NCI Drug Accountability Record forms, patient registration 


96 
11-C-0048 
lists, response assessments scans, x-rays, etc. available for the audit. 
 
Inclusion of Multicenter Guidelines in the Protocol 
 The protocol must include the following minimum information:  
¾ The title page must include the name and address of each participating institution and 
the name, telephone number and e-mail address of the responsible investigator at each 
participating institution. 
¾ The Coordinating Center must be designated on the title page. 
¾ Central registration of patients is required.  The procedures for registration must be 
stated in the protocol. 
¾ Data collection forms should be of a common format.  Sample forms should be 
submitted with the protocol.  The frequency and timing of data submission forms to 
the Coordinating Center should be stated. 
¾ Describe how AEs will be reported from the participating institutions, either directly 
to CTEP or through the Coordinating Center. 
¾ Describe how Safety Reports and Action Letters from CTEP will be distributed to 
participating institutions.  
 
Agent Ordering 
 Except in very unusual circumstances, each participating institution will order DCTD-
supplied agents directly from CTEP.  Agents may be ordered by a participating site only 
after the initial IRB approval for the site has been forwarded by the Coordinating Center 
to the CTEP PIO.  
 
 
 
 

ICF_001.pdf: 
 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
   MEDICAL RECORD 
               •  Adult Patient or     •  Parent, for Minor Patient 
 
 
INSTITUTE: 
National Cancer Institute 
 
 
STUDY NUMBER: 
11-C-0048 
PRINCIPAL INVESTIGATOR:  Udo Rudloff, M.D., Ph.D 
 
 
STUDY TITLE: 
A Phase II Study of Lapatinib for the Treatment of Stage IV Melanoma Harboring ERBB4 
Mutations 
 
 
Continuing Review Approved by the IRB on 06/25/12 
Amendment Approved by the IRB on 02/10/12 (D) 
 
 
 
Date Posted to Web:  08/04/12 
Standard 
 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY 
 
•   Adult Patient or    •   Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent (1) 
 
INTRODUCTION 
 
We invite you to take part in a research study at the National Institutes of Health (NIH). 
 
First, we want you to know that: 
 
Taking part in NIH research is entirely voluntary. 
 
 
You may choose not to take part, or you may withdraw from the study at any time.  In either case, you will not 
lose any benefits to which you are otherwise entitled.  However, to receive care at the NIH, you must be taking 
part in a study or be under evaluation for study participation. 
 
 
You may receive no benefit from taking part.  The research may give us knowledge that may help people in the 
future. 
 
Second, some people have personal, religious or ethical beliefs that may limit the kinds of medical or research treatments 
they would want to receive (such as blood transfusions).  If you have such beliefs, please discuss them with your NIH 
doctors or research team before you agree to the study. 
 
Now we will describe this research study.  Before you decide to take part, please take as much time as you need to ask 
any questions and discuss this study with anyone at NIH, or with family, friends or your personal physician or other 
health professional. 
 
Why is this Study being done? 
 
We have studied samples of melanoma tumors in the laboratory and have discovered that tumor cells from approximately 
20% of melanoma patients contain a specific mutation (change) of a gene involved in making a protein called ERBB4 and 
changes in this gene have been associated with cancer.  Lapatinib is a small molecule (drug) that is currently approved by 
the Food and Drug Administration (FDA) for the treatment of breast cancer.   In the laboratory, lapatinib has been shown 
to significantly slow the growth of melanoma cells that contain this specific ERBB4 gene mutation.  
 
Why are you being asked to take part in this study? 
 
You have been diagnosed with metastatic melanoma and the only standard treatment available at this time that has been 
shown to cure melanoma in a small percentage of patients (about 5%) is aldesleukin (IL-2).  A genetic analysis of your 


  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER:        11-C-0048 
CONTINUATION:  page  2  of  11  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
tumor has demonstrated that your tumor contains the specific gene mutation we are studying and we want to test the 
effects lapatinib has on your cancer. 
 
How many people will take part in this Study? 
 
Up to 28 patients in several centers across the country may be enrolled in this study.  The NIH Clinical Center will be the 
coordinating center for the study. 
 
Description of Research Study 
 
The purpose of this study is to determine if lapatinib can cause your tumor to shrink and to see how much lapatinib is in 
your blood after you have taken the lapatinib tablets (pharmacokinetics).  We also want to measure how long the agent is 
able to keep your tumor from progressing.  If you have a tumor that is easy to biopsy, we will ask you to have a biopsy 
after you have been taking the tablets for 2 weeks and again after you have taken the tablets for 12 weeks.  This is to 
see if we can find genetic changes in your tumor. You may refuse to have biopsy and still participate in this study. 
 
What will happen if you take part in this research study? 
 
Before you begin the study 
Prior to receiving the experimental treatment with lapatinib you will undergo many tests. These include imaging 
procedures, an EKG, and laboratory tests.   
 
If you are a woman, you will undergo a pregnancy test.  Women who are breast feeding or pregnant may not participate 
in this study because of the unknown effect on a fetus or nursing baby.  We also ask that you practice an effective form 
of birth control while on this trial from at least 10-14 days prior to receiving the therapy, and for 4 months after being 
treated on this trial.  Effective birth control methods include use of one of the following: abstinence, intrauterine device 
(IUD); hormonal (birth control pills, injections, implants); tubal ligation; cervical cap; or partner’s vasectomy.  If you think 
that you might be pregnant at any time during this trial, you should notify their doctor immediately. 
 
During the study 
Once we determine that you are eligible for treatment you will be given a 28-day supply of lapatinib in the form of a 
tablet.  Each tablet contains 250 mg of the drug and you need to take 4 tablets a day; two tablets in the morning, 
approximately one hour before or after breakfast and 2 tablets in the evening, approximately one hour before or after 
dinner. The tablets should be taken approximately 10-12 hours apart, for a total of 1000 mg each day.  You should not 
consume grapefruit or grapefruit juice while taking the study medications, as grapefruit may increase the risks for side 
effects. You should also discuss with your doctor all other medications you are currently taking, including herbal 
medicines, as some of these medicines may also interact with lapatinib in a harmful way. 
 
You will be asked to keep a diary of the medicine that you are given and any side effects you may have during the study. 
 
After the first 2 weeks, and every 2-4 weeks after that for the first 12 weeks, you will have laboratory tests repeated 
either at the NIH clinic or at home, to make sure you are tolerating the drug.  If you do the tests at home, you will need 
to fax the results of the tests to Carole Webb, R.N. at 301-451-6933.  After 4 weeks (28 days = 1 treatment cycle) you 
will return to the clinic for full evaluation and in addition to the laboratory tests, you will have scans repeated to 
determine if lapatinib is causing your disease to shrink or be controlled.  If your disease has not progressed, you will 
continue to receive a new lapatinib supply every 28 days for up to 2 years (27 cycles).  You will be asked to return to the 


  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER:        11-C-0048 
CONTINUATION:  page  3  of  11  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
clinic at the end of every treatment cycle (4 weeks) for repeat labs and review of your medication diary.  On certain visits 
(at the end of the first treatment cycle and every 2 cycles after that) you will also have repeat scans to evaluate your 
disease and to confirm that your tumor has not progressed. 
 
Pharmacokinetics 
Up to 10 patients, who live close by the NIH clinical center, may be asked to have blood drawn to measure the amount of 
lapatinib in their blood circulation.  The decision to participate in this part of the research is optional, and no matter what 
you decide to do, it will not affect your care. If you agree to participate in this part of the study, you will have blood 
drawn before you take your morning tablets and 1, 2, 3, 4, 6, and 8 hours after your morning tablets on the day you start 
taking the tablets and again when you return for your follow up visit in about 4 weeks.   
 
Please read the sentence below and think about your choice. After reading the sentence, circle and initial the answer that 
is right for you.  
 
I agree to participate in the pharmacokinetics portion of this study which is for research purposes only.  
 
Yes              No               Initials_________ 
 
Follow up and Evaluation 
If your cancer continues to be better or stable after 27 cycles of therapy, you will be followed at the NIH every three 
months during the first 2 years, every 4 months during the third year and as clinically indicated after that. 
If we find that your tumor is growing during lapatinib therapy, we will ask you to stop taking the drug and remove you 
from study.  We will look for other investigational therapies you may be eligible for, or refer you back to the care of your 
local physician.   
 
Study Chart 
 
The treatment is given over 4-week periods of time called cycles.  The 4-week treatment cycle will be repeated as long as 
you are tolerating the medication and your cancer is either stable or getting better.  Each cycle is numbered in 
consecutive order.  The chart below shows what will happen during cycle 1 and future cycles.  This schedule indicates 
what will happen to you after you sign the consent and start the study. 


  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER:        11-C-0048 
CONTINUATION:  page  4  of  11  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
 
Day 
What to do and what w ill happen to you 
Before starting study 
• 
Complete history and physical examination 
• 
CT or other imaging studies 
• 
Laboratory tests 
• 
Echocardiogram 
• 
Pregnancy test ( if female)  
• 
Evaluation of ERBB4 status 
Cycle 1 (Days 1-28) 
• 
Take lapatinib tablets twice a day   
• 
Complete medication and side effects diary 
• 
On day 14 (± 5 days), repeat laboratory tests (may be 
done at home or at the NIH) and have biopsy 
(optional) 
• 
PK studies  
Prior to initiation of Cycle 2 
• 
Physical examination 
• 
CT or other imaging studies as indicated 
• 
Laboratory tests 
• 
Review medication diary with research nurse  
Cycles 2 and 3  
• 
Take lapatinib by mouth every 12 hours (± 1 hour) and 
record in medication diary 
• 
On days 14 and 28 of cycle 2 and day 14 or cycle 3 (± 
5 days), repeat laboratory tests (may be done at home 
or at the NIH) 
Prior to initiation of Cycle 4 
• 
Physical examination 
• 
CT or other imaging studies as indicated 
• 
Laboratory tests 
• 
Review medication diary with research nurse  
• 
Repeat biopsy (optional) 
Cycle 4 through Cycle 27 
• 
Take lapatinib by mouth every 12 hours (± 1 hour) and 
record in medication diary 
At the end of every cycle: 
• 
Physical examination 
• 
Laboratory tests 
• 
Review of medication diary with research nurse  
At the completion of every 2nd Cycle 
( disease restaging) 
• 
Physical examination 
• 
CT or other imaging studies as indicated 
• 
Laboratory tests 
• 
Review medication diary with research nurse  
Follow-up 
• 
Physical examination 
• 
CT or other imaging studies as indicated 
• 
Laboratory tests 
 
 


  
CONTINUATION SHEET for either: 
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NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER:        11-C-0048 
CONTINUATION:  page  5  of  11  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
Optional Biopsy  
 
When tumor tissue is easily accessible and can be easily biopsied, we would like to request two additional biopsies, one 
after 2 weeks of therapy and one after 12 weeks of therapy.  Biopsies are usually performed in the interventional 
radiology department using a CT imaging to locate the tumor.  The biopsy to be performed is exclusively for research 
purposes and will not benefit you (refer to page 3).  It might help other people in the future.  Even if you sign "yes" to 
have the biopsy you can change your mind at any time.  Please read the sentence below and think about your choice. 
After reading the sentence, circle and initial the answer that is right for you. The decision to participate in this part of the 
research is optional, and no matter what you decide to do, it will not affect your care. If you agree to have a tumor 
biopsy for research purposes, you will return to the NIH around 14 days after you start taking lapatinib (± 5 days) and 
again around 84 days after you start taking lapatinib (12 weeks, ± 5 days).  Depending on the procedure, we may ask 
you to stay overnight to make sure you are ok. 
 
I agree to have the tumor biopsy for the research tests in this study.  
 
Yes              No               Initials_________ 
 
Optional Studies  
 
We would like to keep some of the tissue, blood, and urine that are collected for future research.  These specimens will 
be identified by a number and not your name.  The use of your specimens will be for research purposes only and will not 
benefit you.  It is also possible that the stored specimens may never be used.  Results of research done on your 
specimens will not be available to you or your doctor.  It might help people who have cancer and other diseases in the 
future.   
 
If you decide now that your tissue, blood, and urine can be kept for research, you can change your mind at any time. 
Just contact us and let us know that you do not want us to use your tissue, blood, and urine.  Then any tissue, blood, 
and urine that remain will be destroyed.  
 
Please read each sentence below and think about your choice. After reading each sentence, circle and initial the answer 
that is right for you.  No matter what you decide to do, it will not affect your care. 
 
1. My tissue, blood, and urine specimens may be kept for use in research to learn about, prevent, or treat cancer.  
 
Yes              No               Initials_________ 
 
2. My specimens may be kept for use in research to learn about, prevent or treat other health problems (for example: 
diabetes, Alzheimer's disease, or heart disease).  
 
Yes              No               Initials_________ 
 
3. Someone may contact me in the future to ask permission to use my specimen(s) in new research not included in this 
consent.  
 
Yes              No               Initials_________ 
 


  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER:        11-C-0048 
CONTINUATION:  page  6  of  11  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
Alternative Approaches or Treatments 
 
Other options for treatment of your cancer include: 
• 
standard therapies 
• 
experimental vaccines;  
• 
experimental chemotherapies or biotherapies (such as ipilimumab or tremelimumab);  
• 
other combination therapies; or 
• 
getting no treatment; getting comfort care, also called palliative care. This type of care helps reduce pain, 
tiredness, appetite problems, and other problems caused by cancer. It does not treat the cancer directly, but 
instead tries to improve how you feel. Comfort care tries to keep you as active and comfortable as possible. 
 
Risks or Discomforts of Participation  
 
The primary risks involved in this study result from receiving lapatinib. Other possible risks relate to the biopsies.  If new 
toxicities arise during the course of this study that are not in this consent, we will inform you of them. 
 
Risk Profile of Lapatinib (CAEPR version 2.4, January 6, 2010) 
 
Likely: 
• 
Diarrhea 
• 
Nausea or the urge to vomit 
• 
Skin rash with the presence of macules (flat discolored area) and papules (raised bump) 
 
Less likely: 
• 
Swelling or feeling of fullness and tightness in the abdomen (belly) 
• 
Belly pain 
• 
Heartburn 
• 
Excess passing of gas 
• 
Irritation or sores somewhere in the lining of the gastrointestinal tract 
• 
Vomiting 
• 
Fatigue or tiredness 
• 
Flu-type symptoms (including body aches, fever, chills, tiredness, loss of appetite, cough) 
• 
Increased blood level of a liver enzyme (ALT/SGPT) 
• 
Increased blood level of a liver enzyme (AST/SGOT) 
• 
Increased blood level of a liver pigment (bilirubin) often a sign of liver problems 
• 
Loss of appetite 
• 
Dehydration (when your body does not have as much water and fluid as it should) 
• 
Taste changes 
• 
Headache or head pain 
• 
Loss of some or all of the finger or toenails 
• 
Itching 
• 
Acne 
• 
Sudden reddening of the face and/or neck 
 


  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER:        11-C-0048 
CONTINUATION:  page  7  of  11  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
Rare but Serious: 
• 
Decrease in heart's ability to pump blood during the "active" phase of the heartbeat (systole) 
• 
Liver failure 
• 
Abnormal reaction of the body to substances, called allergens, that are contacted through the skin, inhaled into 
the lungs, swallowed, or injected (allergic reaction) 
• 
Abnormal electrical conduction within the heart 
• 
Inflammation (swelling and redness) of the lungs 
 
Biopsy risks 
The risks of a biopsy include bruising and discomfort at the biopsy site and rarely bleeding and infection.  The biopsy may 
be performed using CT imaging to locate the tumor.  If this is the case, you will receive additional radiation from the CT 
scan.  This radiation exposure is not necessary for your medical care and is for research purposes only.  The total 
amount of radiation you will receive in this study is from one or two CT scans. The NIH Radiation Safety Committee has 
reviewed the use of radiation in this research study and has approved this use as involving minimal risk and necessary to 
obtain the research information desired. 
 
Using the standard way of describing radiation dose, from participating in this study, the most radiation you will receive 
will be a total of 1.2  rem to your  kidneys.  All other parts of your body will receive smaller amounts of radiation.  
Although each organ will receive a different dose, the amount of radiation exposure you will receive from this study is 
equal to a uniform whole-body exposure of  0.29  rem.  This calculated value is known as the “effective dose” and is used 
to relate the dose received by each organ to a single value.    The amount of radiation you will receive in this study is 
below the dose guideline established by the NIH Radiation Safety Committee for research subjects.  This guideline is an 
effective dose of 5 rem (or 5,000 mrem) received per year. 
 
For comparison, the average person in the United States receives a radiation exposure of 0.3 rem (or 300 mrem) per year 
from natural background sources, such as from the sun, outer space, and from radioactive materials that are found 
naturally in the earth’s air and soil.  The dose that you will receive from participation in this research study is about the 
same amount you would normally receive in one year from these natural sources.  If you would like more information 
about radiation and examples of exposure levels from other sources, please ask the investigator for a copy of the 
pamphlet called, An Introduction to Radiation for NIH Research Subjects. 
 
Please tell your doctor if you have taken part in other research studies or received any medical care at the NIH or other 
places or hospitals that used radiation.  This way we can make sure that you will not receive too much radiation.  
Consider x-rays taken in radiology departments, cardiac catheterization, and fluoroscopy as well as nuclear medicine 
scans in which radioactive materials were injected into your body. 
 
Potential Benefits of Participation 
 
Are there benefits to taking part in this study? 
 
The aim of this study is to see if this experimental treatment will cause your tumors to shrink.  We hope that you will get 
personal medical benefit from taking part in this study, but we cannot be certain.  These potential benefits could include 
shrinking of your tumor or lessening of your symptoms, such as pain, that are caused by the cancer.  Because there is 
not much information about the drug’s effect on your cancer, we do not know if you will benefit from taking part in this 
study, although the knowledge gained from this study may help others in the future who have cancer.   
 


  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER:        11-C-0048 
CONTINUATION:  page  8  of  11  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
It is possible that the information obtained from your participation in this study may become valuable for commercial 
research and development purposes (including patentable inventions), which may be of significant benefit to society, the 
sponsor of this study, individual researchers, or other third parties.  You will not receive direct financial benefit from such 
research and development. 
 
Research Subject’s Rights 
 
The NCI Cancer Therapy Evaluation Program (CTEP) is the sponsor of this study. Your records may be reviewed by NIH 
organizations including the NCI and by organizations outside the National Institutes of Health, such as qualified 
representatives of the pharmaceutical collaborator that supplies the drugs for the study and representatives of the US 
Food and Drug Administration. Every effort will be made to protect your privacy in any recording or reporting of this 
information.  
 
What are the costs of taking part in this study?  
 
If you choose to take part in the study, the following will apply, in keeping with the NIH policy: 
• 
You will receive study treatment at no charge to you. This may include surgery, medicines, 
laboratory testing, x-rays or scans done at the Clinical Center, National Institutes of Health 
(NIH), or arranged for you by the research team to be done outside the Clinical Center, NIH if 
the study related treatment is not available at the NIH.  
• 
Even though it probably won’t happen, it is possible that the manufacturer may not continue to 
provide the lapatinib to the NCI/CTEP for some reason.  If this would occur, other possible 
options are:  
1. You might be able to get the lapatinib from the manufacturer or your pharmacy but you or 
your insurance company may have to pay for it.  
2. If there is no lapatinib available at all, no one will be able to get more and the study would 
close. 
If a problem with getting lapatinib occurs, your study doctor will talk to you about these 
options. 
• 
There are limited funds available to cover the cost of some tests and procedures performed 
outside the Clinical Center, NIH.  You may have to pay for these costs even if they are not 
covered by your insurance company. 
• 
Medicines that are not part of the study treatment will not be provided or paid for by the Clinical 
Center, NIH. 
• 
Once you have completed taking part in the study, medical care will no longer be provided by 
the Clinical Center, NIH. 
 
Stopping Therapy 
 
Your doctor may decide to stop your therapy for the following reasons: 
 
• 
if he/she believes that it is in your best interest 
• 
if your disease progresses during treatment 
• 
if you have side effects from the treatment that your doctor thinks are too severe 
• 
if new information shows that another treatment would be better for you 
 


  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER:        11-C-0048 
CONTINUATION:  page  9  of  11  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
In this case, you will be informed of the reason therapy is being stopped. 
 
You can stop taking part in the study at any time. However, if you decide to stop taking part in the study, we would like 
you to talk to the study doctor and your regular doctor first. 
 
Conflict of Interest 
 
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts of interest.  The 
following link contains details on this process http://ethics.od.nih.gov/procedures/COI-Protocol-Review-Guide.pdf.  You 
may ask your research team for a copy of the Protocol Review Guide or for more information.  Members of the research 
team who do not work for NIH are expected to follow these guidelines but they do not need to report their personal 
finances to the NIH. 
 
Members of the research team working on this study may have up to $15,000 of stock in the companies that make 
products used in this study.  This is allowed under federal rules and is not a conflict of interest.  


 
  
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
   MEDICAL RECORD 
•  Adult Patient or    •  Parent, for Minor Patient 
 
STUDY NUMBER: 
11-C-0048 
CONTINUATION:  page  10  of  11  pages 
 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY (Continuation Sheet) 
 
•  Adult Patient or   •  Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
OTHER PERTINENT INFORMATION 
 
1. Confidentiality.  When results of an NIH research study are reported in medical journals or at scientific meetings, 
the people who take part are not named and identified.  In most cases, the NIH will not release any information about 
your research involvement without your written permission.  However, if you sign a release of information form, for 
example, for an insurance company, the NIH will give the insurance company information from your medical record.  This 
information might affect (either favorably or unfavorably) the willingness of the insurance company to sell you insurance. 
 
The Federal Privacy Act protects the confidentiality of your NIH medical records.  However, you should know that the Act 
allows release of some information from your medical record without your permission, for example, if it is required by the 
Food and Drug Administration (FDA), members of Congress, law enforcement officials, qualified representatives of the 
pharmaceutical collaborator or authorized hospital accreditation organizations. 
 
2. Policy Regarding Research-Related Injuries.  The Clinical Center will provide short-term medical care for any 
injury resulting from your participation in research here.  In general, no long-term medical care or financial compensation 
for research-related injuries will be provided by the National Institutes of Health, the Clinical Center, or the Federal 
Government.  However, you have the right to pursue legal remedy if you believe that your injury justifies such action. 
 
3. Payments.  The amount of payment to research volunteers is guided by the National Institutes of Health policies.  In 
general, patients are not paid for taking part in research studies at the National Institutes of Health.  Reimbursement of 
travel and subsistence will be offered consistent with NIH guidelines. 
 
4. Problems or Questions If you have any problems or questions about this study, or about your rights as a 
research participant, or about any research-related injury, contact the Principal Investigator: Udo Rudloff, M.D., Ph.D. 
Building 10, Room 4-5950, Telephone:  (301) 496-3098. If you have any questions about the use of your tissue for 
future research studies, you may also contact the Office of the Clinical Director at 301-496-4251. 
 
You may also call the Clinical Center Patient Representative at (301) 496-2626. 
 
5. Consent Document.  Please keep a copy of this document in case you want to read it again.


 
  
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
   MEDICAL RECORD 
•  Adult Patient or    •  Parent, for Minor Patient 
 
STUDY NUMBER: 
11-C-0048 
CONTINUATION:  page  11  of  11  pages 
 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY (Continuation Sheet) 
 
•  Adult Patient or   •  Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
 
 
 
 
COMPLETE APPROPRIATE ITEM(S) BELOW: 
 
A. Adult Patient’s Consent 
B. Parent’s Permission for Minor Patient. 
I have read the explanation about this study and have been given the 
opportunity to discuss it and to ask questions.  I hereby consent to take 
part in this study. 
I have read the explanation about this study and have been given the 
opportunity to discuss it and to ask questions.  I hereby give permission 
for my child to take part in this study.   
(Attach NIH 2514-2, Minor’s Assent, if applicable.) 
 
  
 
 
  
 
Signature of Adult Patient/Legal Representative 
Date 
 
 
 
 
Print Name 
Signature of Parent(s)/Guardian 
Date 
 
 
 
 
Print Name 
 
 
C. Child’s Verbal Assent (If Applicable) 
The information in the above consent was described to my child and my child agrees to participate in the study. 
 
 
  
 
 
Signature of Parent(s)/Guardian 
Date 
 
 
 
 
Print Name 
 
 
 
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE  
FROM JUNE 25, 2012 THROUGH JUNE 24, 2013. 
 
 
 
  
 
 
  
 
Signature of Investigator 
Date 
 
 
 
 
Print Name 
Signature of Witness 
Date 
 
 
 
 
Print Name