Clinical trial NCT01873833
Conditions: HER2-positive Breast Cancer Recurrent Breast Cancer Stage IV Breast Cancer
Sponsor: University of Southern California
Start date: 2013-07-29; Completion date: 2021-03-02
Enrollment: 10 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well capecitabine, cyclophosphamide, lapatinib ditosylate, and trastuzumab work in treating patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. Drugs used in chemotherapy, such as capecitabine and cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving capecitabine and cyclophosphamide daily may kill more tumor cells. Lapatinib ditosylate may stop the growth of tumor cells by blocking some of the enzymes needed for growth. Monoclonal antibodies, such as trastuzumab, can block tumor growth in different ways. Some block the ability of the tumor to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Giving capecitabine, cyclophosphamide, lapatinib ditosylate, and trastuzumab together may be an effective treatment for breast cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To estimate the progression free survival (PFS).

SECONDARY OBJECTIVES:

I. To evaluate the overall response rate (ORR).

II. To evaluate the clinical benefit rate (CBR; complete response, partial response, and stable disease for \>= 24 weeks).

III. To estimate the overall survival (OS).

IV. To assess the safety and tolerability.

OUTLINE:

Patients receive capecitabine orally (PO) once daily (QD), cyclophosphamide PO QD, and lapatinib ditosylate PO QD on days 1-21 and trastuzumab intravenously (IV) on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year.

Arms: arm 1: Patients receive capecitabine by mouth (PO) every day (QD), cyclophosphamide PO QD, and lapatinib ditosylate PO QD on days 1-21 and trastuzumab IV on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: capecitabine intervention 2: cyclophosphamide intervention 3: lapatinib ditosylate intervention 4: trastuzumab intervention 5: laboratory biomarker analysis
Intervention descriptions: intervention 1: Given PO intervention 2: Given PO intervention 3: Given PO intervention 4: Given IV intervention 5: Correlative studies

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Local Protocol #: 1B-12-10 
Protocol Title: Phase II Trial of Metronomic Capecitabine and 
Cyclophosphamide with Lapatinib and Trastuzumab in Patients 
with HER2 Positive Metastatic Breast Cancer Who Have 
Progressed on a Previous Trastuzumab-Based Regimen 
Protocol version date: 12/1/2015 
 
ClinicalTrialsgov #: NCT01873833 
 
 


UNIVERSITY OF SOUTHERN CALIFORNIA/KENNETH NORRIS, JR.
COMPREHENSIVE CANCER CENTER AND HOSPITAL 
 
 
1B-12-10 
Phase II Trial of Metronomic Capecitabine and Cyclophosphamide with Lapatinib and 
Trastuzumab in Patients with HER2 Positive Metastatic Breast Cancer Who Have Progressed 
on a Previous Trastuzumab-Based Regimen 
 
 
 
Principal Investigator: 
 Darcy Spicer, MD  
 
University of Southern California 
1441 Eastlake Avenue, Suite 3440 
Los Angeles, CA 90033 
(T) – 323.865.3904 
(F) – 323.865.0061 
(E) – dspicer@med.usc.edu 
 
Co-Investigator(s): 
 
 
Biostatistician: 
Richard Sposto, PhD 
Department of Preventive Medicine / Biostatistics Cancer Core 
 
Lingyun Ji, MS 
Department of Preventive Medicine / Biostatistics Cancer Core 
 
 
 
Study Contact: 
 
 
 
 
Study Drugs: 
Capecitabine (Xeloda®) 
Cyclophosphamide (Cytoxan®) 
Lapatinib (Tykerb®) 
Trastuzumab (Herceptin®) 
 
IND Number: 
N/A 
 
IND Holder Name: 
N/A 
 
Funding Source: 
Novartis Pharmaceuticals Corporation 
John Sabo, Clinical Research Scientist 
Novartis Pharmaceuticals Corporation 
One Health Plaza, Bldg. 345-2104B 
East Hanover, NJ  07936-1080  
(T) – 862-778-2982 
(E) –john.sabo@novartis.com 
 
 
CONFIDENTIAL 
This material is the property of the University Of southern California/ Norris Comprehensive Cancer Center. Do not disclose or use except as authorized in writing by 
the study sponsor. 


UNIVERSITY OF SOUTHERN CALIFORNIA/KENNETH NORRIS, JR.
COMPREHENSIVE CANCER CENTER AND HOSPITAL 
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the study sponsor. 
 
 
 
 
Initial version: 
18 January 2013 
Amended: 
03 September 2014 
 
01 December 2015 
 
Research Office: 
CLINICAL INVESTIGATIONS SUPPORT OFFICE (CISO) 
1441 Eastlake Avenue, Room 7310E 
Los Angeles, California 90089-9177 
(T) – 323.865.0451 
(E) – ciso.clinical@med.usc.edu 


UNIVERSITY OF SOUTHERN CALIFORNIA/KENNETH NORRIS, JR.
COMPREHENSIVE CANCER CENTER AND HOSPITAL 
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the study sponsor. 
 
 
 
SIGNATURE PAGE 
 
 
 
The signature below constitutes the approval of this protocol and the attachments, and provides the necessary 
assurances that this trial will be conducted according to all stipulations of the protocol, including all statements 
regarding confidentiality, and according to local legal and regulatory requirements and applicable U.S. federal 
regulations and ICH guidelines. 
 
 
 
 
Principal Investigator (PI) Name:   
 
(Please Print) 
 
 
 
PI Signature: 
 
(Please Sign) 
 
 
Institutional Name: 
 
Date: 
          /           /                   
M   M 
D    D 
Y 
Y     Y     Y 


UNIVERSITY OF SOUTHERN CALIFORNIA/KENNETH NORRIS, JR.
COMPREHENSIVE CANCER CENTER AND HOSPITAL 
5.0 
STUDY PROCEDURES................................................................................................................ 28
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the study sponsor. 
 
 
 
CONTENTS 
 
 
SIGNATURE PAGE .................................................................................................................................III 
CONTENTS........................................................................................................................................... IV 
LIST OF ABBREVIATIONS ......................................................................................................................VII 
LIST OF TABLES ..................................................................................................................................VIII 
STUDY SUMMARY................................................................................................................................. IX 
1.0     BACKGROUND AND HYPOTHESES ................................................................................................ 1 
 
1.1 
Metronomic Chemotherapy ....................................................................................... 1 
1.2 
Metronomic Chemotherapy in Metastatic Breast Cancer ........................................ 1 
1.3 
HER2 Targeted Therapies in Breast Cancer ............................................................. 2 
1.4 
HER2 Targeted Therapy with Anti-Angiogenic Therapies ....................................... 3 
1.5 
Metronomic Chemotherapy Combined with Targeted Therapy .............................. 4 
1.6 
Hypothesis .................................................................................................................. 6 
 
2.0     OBJECTIVES AND PURPOSE ........................................................................................................ 6 
 
2.1 
Primary Objective ....................................................................................................... 7 
2.2 
Secondary Objectives ................................................................................................ 7 
 
3.0     SELECTION AND WITHDRAWAL OF PARTICIPANTS ........................................................................ 7 
 
3.1 
Inclusion Criteria ........................................................................................................ 7 
3.2 
Exclusion Criteria ....................................................................................................... 8 
 
4.0     TREATMENT PLAN ...................................................................................................................... 9 
 
4.1 
Treatment Dosage and Administration ..................................................................... 9 
4.2 
Toxicities and Specific Management Guidlines ..................................................... 10 
 
4.2.1 UNACCEPTABLE TOXICITIES .............................................................................. 10 
4.2.2 SPECIFIC SYMPTOM MANAGEMENT – CARDIAC AND RESPRIATORY EVENTS ......... 10 
4.2.3 SPECIFIC SYMPTOM MANAGEMENT – DIARRHEA ................................................. 11 
4.2.4 SPECIFIC MANAGEMENT GUIDANCE – HEPATOTOXICITY ...................................... 18 
4.2.5 SPECIFIC MANAGEMENT GUIDANCE – SKIN DISORDERS ...................................... 21 
 
4.3 
Toxicity Related Dose Reduction Guidelines ......................................................... 22 
 
4.3.1 HEMATOLOGIC TOXICITIES ................................................................................ 23 
4.3.2 NON-HEMATOLOGIC TOXICITIES ........................................................................ 24 
 
4.4 
Dose Adjustment ...................................................................................................... 24 
 
4.5.1 DOSE ADJUSTMENT LEVELS FOR CAPECITABINE................................................. 24 
4.4.2 DOSE ADJUSTMENT LEVELS FOR CYCLOPHOSPHAMIDE....................................... 25 
4.4.3 DOSE ADJUSTMENT LEVELS FOR LAPATINIB ....................................................... 25 
4.4.4 DOSE ADJUSTMENT GUIDELINES FOR TRASTUZUMAB.......................................... 25 
4.4.5 OFF-TREATMENT .............................................................................................. 25 
4.4.6 MISSED DOSE OF ORAL MEDICATIONS ............................................................... 25 
 
4.5 
Concomitant Medications ........................................................................................ 26 
4.6 
Duration of Therapy ................................................................................................. 27 
4.7 
Removal of Patients from Protocol Therapy .......................................................... 28 
4.8 
Duration of Follow-Up .............................................................................................. 28 


UNIVERSITY OF SOUTHERN CALIFORNIA/KENNETH NORRIS, JR.
COMPREHENSIVE CANCER CENTER AND HOSPITAL 
 
MEASUREMENT OF EFFECT ....................................................................................................... 29
6.0 
10.2 
Institutional Review Board (IRB) Approval and Consent Process ........................ 41
 
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the study sponsor. 
 
 
 
6.1 
Methods of Measurement ........................................................................................ 30 
 
6.1.1 BASELINE DOCUMENTATION OF “TARGET” AND “NON-TARGET” LESIONS ............... 30 
 
6.2 
Response Criteria..................................................................................................... 30 
 
6.2.1 EVALUATION OF TARGET LESIONS ...................................................................... 31 
6.2.2 EVALUATION OF NON-TARGET LESIONS .............................................................. 31 
6.2.3 EVALUATION OF BEST OVERALL RESPONSE......................................................... 31 
 
6.3 
Confirmation ............................................................................................................. 32 
 
6.3.1 DURATION OF OVERALL RESPONSE .................................................................... 32 
6.3.2 DURATION OF STABLE DISEASE ......................................................................... 33 
6.3.3 PROGRESSION-FREE SURVIVAL......................................................................... 33 
6.3.4 OVERALL SURVIVAL .......................................................................................... 33 
 
7.0 
ADVERSE EVENTS..................................................................................................................... 33 
 
7.1 
ADVERSE EVENT MONITORING...................................................................................... 33 
7.2 
DEFINITIONS ................................................................................................................ 33 
 
7.2.1 
DEFINITION OF ADVERSE EVENT......................................................................... 33 
7.2.2 
SEVERITY OF ADVERSE EVENTS......................................................................... 34 
7.2.3 
SERIOUS ADVERSE EVENTS............................................................................... 34 
 
7.3 
STEPS TO DETERMINE IF AN ADVERSE EVENT REQUIRES EXPEDITED REPORTING ........... 35 
7.4 
REPORTING REQUIREMENTS FOR ADVERSE EVENTS ...................................................... 36 
 
7.4.1 
EXPEDITED REPORTING ..................................................................................... 36 
7.4.2 
ROUTINE REPORTING ........................................................................................ 37 
 
8.0 
DRUG INFORMATION.................................................................................................................. 37 
 
8.1 
STUDY DRUGS – COMMERCIALLY AVAILABLE................................................................ 37 
 
8.1.1 
CAPECITABINE (XELODA®)................................................................................ 37 
8.1.2 
CYCLOPHOSPHAMIDE (CYTOXAN®) .................................................................... 38 
8.1.3 
TRASTUZUMAB (HERCEPTIN®)........................................................................... 38 
 
8.2 
STUDY DRUG – SPONSOR PROVIDED.......................................................................................... 38 
 
8.2.1 LAPATINIB (TYKERB®) ...................................................................................... 38 
 
9.0 
STATISTICAL CONSIDERATIONS ................................................................................................. 38 
 
9.1 
Patient Accrual ......................................................................................................... 39 
9.2 
Statistical Analyses and Power Calculations for the Primary Objectives ............ 39 
 
9.2.1 STATISTICAL ANALYSIS FOR THE PRIMARY OBJECTIVE ........................................ 39 
9.2.2 POWER OF THE STATISTICAL ANALYSIS FOR THE PRIMARY OBJECTIVE................. 39 
 
9.3 
Futility Analysis ........................................................................................................ 39 
9.4 
Interim Monitoring of Toxicities .............................................................................. 40 
9.5 
Monitoring of Toxic Deaths ..................................................................................... 41 
 
10.0 STUDY MANAGEMENT ............................................................................................................... 41 
 
10.1 
Conflict of Interest.................................................................................................... 41 


UNIVERSITY OF SOUTHERN CALIFORNIA/KENNETH NORRIS, JR.
COMPREHENSIVE CANCER CENTER AND HOSPITAL 
 
Registration Procedures .......................................................................................... 42
10.3 
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the study sponsor. 
 
 
10.4 
Records and Data Submission ................................................................................ 42 
10.5 
Data Management and Monitoring / Auditing ......................................................... 43 
10.6 
Quality Assurance Monitoring Committee (QAMC) Oversight .............................. 44 
 
10.6.1 QAMC ANNUAL PATIENT AUDITS....................................................................... 44 
10.6.2 QAMC ANNUAL PROTOCOL REVIEW .................................................................. 45 
 
10.7 
Data and Safety Monitoring Committee (DSMC) Oversight ................................... 45 
10.8 
Adherence to the Protocol ....................................................................................... 45 
 
10.8.1 EMERGENCY MODIFICATIONS ............................................................................ 45 
10.8.2 NON-EMERGENCY DEPARTURES FROM PROTOCOL............................................. 45 
10.8.3 AMENDMENTS TO THE PROTOCOL...................................................................... 46 
 
10.9 
Record Retention...................................................................................................... 46 
10.10  Obligations of the Investigators .............................................................................. 47 
 
11.0 REFERENCES ........................................................................................................................... 47 
APPENDIX I: WORD LIST INHIBITORS INDUCERS ................................................................................... 51 


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the study sponsor. 
 
 
 
LIST OF ABBREVIATIONS 
 
AE 
ADVERSE EVENT 
ALT 
ALANINE AMINOTRANSFERASE 
ALC 
ABSOLUTE LYMPHOCYTE COUNT 
AST 
ASPARTATE AMINOTRANSFERASE 
BUN 
BLOOD UREA NITROGEN 
CBC 
COMPLETE BLOOD COUNT 
CMP 
COMPREHENSIVE METABOLIC PANEL 
CR 
COMPLETE RESPONSE 
CT 
COMPUTED TOMOGRAPHY 
CTCAE 
COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS 
DLT 
DOSE LIMITING TOXICITY 
DSMB 
DATA AND SAFETY MONITORING BOARD 
ECOG 
EASTERN COOPERATIVE ONCOLOGY GROUP 
IV (OR IV) 
INTRAVENOUSLY 
MTD 
MAXIMUM TOLERATED DOSE 
NCI 
NATIONAL CANCER INSTITUTE 
ORR 
OVERALL RESPONSE RATE 
OS 
OVERALL SURVIVAL 
PBMCS 
PERIPHERAL BLOOD MONONUCLEAR CELLS 
PD 
PROGRESSIVE DISEASE 
PFS 
PROGRESSION FREE SURVIVAL 
P.O. 
PER OS/BY MOUTH/ORALLY 
PR 
PARTIAL RESPONSE 
SAE 
SERIOUS ADVERSE EVENT 
SD 
STABLE DISEASE 
SGOT 
SERUM GLUTAMIC OXALOACETIC TRANSAMINASE 
SGPT 
SERUM GLUTAMIC PYRUVIC TRANSAMINASE 
WBC 
WHITE BLOOD CELLS 
IIT 
INVESTIGATOR INITIATED TRIAL 


UNIVERSITY OF SOUTHERN CALIFORNIA/KENNETH NORRIS, JR.
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the study sponsor. 
 
 
 
 
LIST OF TABLES 
 
 
TABLE 1: MAIN TOXICITIES RELATED TO DRUG COMBINATION.............................................................................................. 4 
 
TABLE 2: CLINICAL TRIALS USING METRONOMIC CHEMOTHERAPY ....................................................................................... 5 
 
TABLE 3: TREATMENT DOSAGE AND ADMINISTRATION ......................................................................................................... 9 
 
TABLE 4: NCI COMMON TERMINOLOGY CRITERIA FOR GRADING DIARRHEA........................................................................ 12 
 
TABLE 5: ALGORITHM FOR THE MANAGEMENT OF DIARRHEA ............................................................................................. 17 
 
TABLE 6: LIVER CHEMISTRY STOPPING RULES AND FOLLOW-UP CRITERIA ......................................................................... 20 
 
TABLE 7: DOSE REDUCTION GUIDELINES (HEMATOLOGIC TOXICITIES) ............................................................................... 23 
 
TABLE 8: DOSE REDUCTIONS (NON-HEMATOLOGIC TOXICITIES) ........................................................................................ 24 
 
TABLE 9: CAPECITABINE DOSE ADJUSTMENT LEVELS ....................................................................................................... 24 
 
TABLE 10: CYCLOPHOSPHAMIDE DOSE ADJUSTMENT LEVELS ........................................................................................... 25 
 
TABLE 11: LAPATINIB DOSE ADJUSTMENT LEVELS ............................................................................................................ 25 
 
TABLE 12: POTENTIAL DRUG INTERACTIONS WITH LAPATINIB............................................................................................. 26 
 
TABLE 13: STUDY VISIT SCHEDULE .................................................................................................................................. 28 
 
TABLE 14: TARGET LESION EVALUATION TABLE ................................................................................................................ 31 
 
TABLE 15: NON-TARGET LESION EVALUATION TABLE ....................................................................................................... 31 
 
TABLE 16: EVALUATION OF BEST OVERALL RESPONSE TABLE ........................................................................................... 31 
 
TABLE 17: GSK REPORTING REQUIREMENTS TABLE ........................................................................................................ 36 


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STUDY SUMMARY 
 
 
 
Title 
Phase II Trial of Metronomic Capecitabine and Cyclophosphamide 
with Lapatinib and Trastuzumab in Patients with HER2 Positive 
Metastatic Breast Cancer Who Have Progressed on a Previous 
Trastuzumab-Based Regimen 
 
Short Title 
Metronomic Capecitabine and Cyclophosphamide with Lapatinib 
and Trastuzumab in Patients with HER2 Positive Metastatic Breast 
Cancer 
Protocol Number (CIC) 
1B-12-10 
Protocol Number (HSIRB) 
TBA 
Phase 
Phase II 
Methodology 
Single Arm, Open Label 
Study Duration 
24 months 
Study Center(s) 
Single Center - USC 
 
Objectives 
To evaluate the combination of metronomic cycleophosphamide 
and capecitabine with lapatinib and trastuzumab in patients with 
HER-2 positive metastatic breast cancer. 
Number of Subjects 
40 
Diagnosis and Main 
Inclusion Criteria 
HER-2 positive metstatic breast cancer previously treated with 
trastuzumab 
 
Study Product(s), Dose, 
Route, Regimen 
Capecitabine (Xeloda®) 
1500mg 
PO 
QD 
Cyclophosphamide (Cytoxan®) 
 50mg 
 PO 
 QD 
Lapatinib (Tykerb®) 
 1000mg 
 PO 
 QD 
Trastuzumab (Herceptin®) 
6mg/kg 
IV 
Once 
 
 
 
 
 
 
Duration of administration 
In the absence of treatment delays due to adverse events, 
treatment may continue until: 
 
• 
Disease progression 
• 
Inter-current illness that prevents further administration of 
treatment 
• 
Unacceptable adverse event(s) 
• 
Patient decides to withdraw from the study, OR 
• 
General or specific changes in the patient’s condition render the 
patient unacceptable for further treatment in the judgment of the 
investigator” 


UNIVERSITY OF SOUTHERN CALIFORNIA/KENNETH NORRIS, JR.
COMPREHENSIVE CANCER CENTER AND HOSPITAL 
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the study sponsor. 
 
 
 
 
 
1.0 
BACKGROUND AND HYPOTHESES 
 
 
1.1 
METRONOMIC CHEMOTHERAPY 
 
Cytotoxic chemotherapy has traditionally been administered at the highest possible dose that 
does not cause life-threatening toxicity, and this is called the ‘maximum tolerated dose’ (MTD). 
MTD-based chemotherapy does not target tumor cells specifically, but interferes with cell 
division, thus damaging the normal dividing cells of rapidly regenerating tissues. This results in 
toxic side effects such as myelosuppression, alopecia, and mucosal damage. Prolonged 
therapy breaks of 2-3 weeks are required between cycles to allow recovery from these side 
effects. 
‘Metronomic chemotherapy’ is an emerging new paradigm in cancer therapy, in which frequent 
low doses of chemotherapeutic agents are administered at frequent intervals.  Metronomic 
chemotherapy targets the endothelial cells that are dividing in the growing blood vessels of 
tumors, rather than the tumor cells themselves, resulting in an anti-angiogenic effect.1, 2 In 
preclinical models, virtually every class of chemotherapeutic agent has been shown to inhibit 
angiogenesis, which contributes to their antitumor efficacy.3 However, the anti-angiogenic 
effects of chemotherapy are masked by the long breaks between drug administrations, which 
enable the tumor vasculature to be repaired.4 Frequent low-dose therapy has been shown to 
have impressive anti-angiogenic and antitumor effects in mice along with reduced toxicity.4 
 
The major advantage of metronomic chemotherapy is the low toxicity, which significantly 
improves patients’ quality of life, enables prolonged administration of chemotherapeutic agents 
without dose reductions or delays, and provides opportunities to combine different classes of 
agents that would otherwise be difficult with full dose regimens. Ideally metronomic 
chemotherapy would be administered on a daily basis. However, there are few chemotherapy 
agents that are available in an oral formulation. Nonetheless, the administration of a daily oral 
outpatient regimen has the additional practical benefit of decreasing clinic visits for patients. 
These benefits are most pronounced in the setting of metastatic cancer, where the goal is to 
prolong survival while maintaining quality of life for as long as possible. 
 
 
1.2 
METRONOMIC CHEMOTHERAPY IN METASTATIC BREAST CANCER 
 
Breast cancer is the most frequently diagnosed cancer and the second leading cause of cancer 
mortality in women.5 Approximately 20% of patients will be diagnosed with metastatic breast 
cancer initially, while of the patients with initial localized disease 20-80% will ultimately develop 
metastatic disease. Despite recent advances in therapy, metastatic breast cancer (MBC) 
remains an incurable disease, with 5-year survival of 23%,6 and further improvements in 
systemic therapy are necessary. 
 
Metronomic chemotherapy has been found to have moderate activity with low toxicity in several 
phase II clinical trials in patients with MBC. In an initial study by Colleoni et al, sixty-four women 
with MBC were given oral cyclophosphamide 50mg daily and oral methotrexate 2.5mg bid on 
two days per week.7 Fifty-two of the patients had previously received at least 1 line of 
chemotherapy. The overall clinical benefit was 32%, with 2 complete remissions (CR), 10 partial 
remissions (PR), and 12 patients with stable disease (SD) lasting 6 months or longer. Toxicity 
was minimal, with 12% grade ≥ 2 neutropenia, 2% grade ≥ 2 alopecia, and no grade ≥ 2 
mucositis, nausea or vomiting. Levels of serum vascular endothelial growth factor (VEGF) 
decreased significantly after treatment, supporting an anti-angiogenic mechanism of therapy. 


UNIVERSITY OF SOUTHERN CALIFORNIA/KENNETH NORRIS, JR.
COMPREHENSIVE CANCER CENTER AND HOSPITAL 
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the study sponsor. 
 
 
 
 
Another trial by Schott et al looked at the combination of metronomic cyclophosphamide and 
capecitabine.8 Cyclophosphamide was given 100mg daily on days 1-14 and capecitabine was 
given 1500mg bid on days 8-21 of a 21-day cycle. The overall response rate was 36%, with four 
CRs and 25 PRs among 80 patients with measurable disease. The median progression-free 
survival was 5.9 months, and median overall survival was 18.8 months. These outcomes 
compared favorably with those of full-dose capecitabine monotherapy, or combination therapy 
with bevacizumab, sorafenib or ixabepilone. Most common toxicities were lymphopenia (grade 
3-4 in 13 patients) and hand-foot syndrome (grade 3 in 7 patients). One case of grade 4 
thromboembolism was reported. 
 
Of note, capecitabine, an orally available tumor selective fluropyrimidine carbamate, has been 
approved by the United States Food and Drug Administration for treatment of MBC at a dose of 
2500 mg/m2/day for 2 weeks followed by a 1-week drug-free period. However, significant toxicity 
is encountered in clinical practice at this dose, in the form of diarrhea, mucositis and hand-foot 
syndrome. Therefore, capecitabine is routinely administered at a lower dose of 2000 mg/m2/day, 
and data from non-randomized clinical trials suggest that activity is maintained while toxicity is 
decreased at this dose.9 At USC we routinely treat patients with metastatic breast cancer using 
a low fixed dose of 1000 mg po bid, which is approximately 1130mg/m2/day, given continuously 
without a drug-free interval. The activity of this regimen appears to be comparable to that of 
published studies using more conventional doses but with reduced toxicity.10-12 
 
 
1.3 
HER2 TARGETED THERAPIES IN BREAST CANCER 
 
Human epidermal growth factor receptor 2 (HER2) plays a significant role in the pathogenesis of 
breast cancer. Around 20-30% of all breast cancers have overexpression of HER2, which is 
associated with earlier recurrence and shorter overall survival.13 Trastuzumab, a recombinant 
humanized monoclonal antibody against the extracellular domain of HER2, is an integral part of 
the treatment of HER2-positive breast cancer. Studies have shown that trastuzumab improves 
disease-free and overall survival in HER2 positive patients in both the adjuvant and metastatic 
disease settings.14-16 Trastuzumab monotherapy for HER2-positive MBC has a response rate of 
13-26%,16, 17 and in combination with chemotherapy, such as taxanes and vinorelbine, response 
rates are 60-70% in the first line setting.18-20 However, patients invariably progress after initial 
response, and the response rates decrease in subsequent lines of therapy.21 Also, in patients 
previously treated with trastuzumab in the adjuvant setting, response rates to HER2 targeted 
regimens are significantly lower when retreated in the metastatic setting. A recent report looking 
at the activity of HER2 targeted frontline chemotherapy for MBC found a response rate of 48% 
for patients who had not received adjuvant trastuzumab, while the response in the patients who 
had received it was only 13%.22 Therefore, further treatment options need to be explored for 
patients with HER2-positive MBC who have already received trastuzumab in the adjuvant 
setting. 
 
Trastuzumab is usually continued in patients with HER2-positive MBC even after they 
experience progression of disease while receiving trastuzumab. Preclinical data indicate that 
withdrawal of trastuzumab results in rapid tumor cell regrowth. The German Breast Group 
26/Breast International Group 03-05 trial compared capecitabine with continuation of 
trastuzumab versus capecitabine alone in patients who progressed on a prior trastuzumab- 
containing regimen. Overall response rates were 48% in the combined arm and 27% in the 
capecitabine alone arm (P=0.01). Median time to progression was 8.2 months in the combined 
arm and 5.6 months in the capecitabine alone arm (P=0.03). Continuation of trastuzumab 
beyond progression was not associated with increased toxicity. 


UNIVERSITY OF SOUTHERN CALIFORNIA/KENNETH NORRIS, JR.
COMPREHENSIVE CANCER CENTER AND HOSPITAL 
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the study sponsor. 
 
 
 
 
Lapatinib is an orally active small molecule that inhibits the tyrosine kinases of HER2 and 
epidermal growth factor receptor type 1 (EGFR). A phase III, randomized, open-label study 
showed that lapatinib in combination with capecitabine is also active in women with HER2- 
positive MBC who had previously received trastuzumab.23 The overall response rate for the 
combination therapy was 22%, compared to 14% for patients receiving capecitabine 
monotherapy (P=0.09). The median time to progression was 8.4 months with the combination 
therapy and 4.4 months with monotherapy (P<0.001). The treatment was well tolerated, with the 
most common grade ≥ 3 toxicities being diarrhea (13%) and hand and foot syndrome (7%). 
These toxicities were similar to those observed with capecitabine alone. Therefore, the 
combination of lapatinib and capecitabine now represents a standard approach for patients with 
HER2-positive MBC after treatment with trastuzumab. 
 
Trastuzumab and lapatinib have non-overlapping mechanisms of action, and synergistic 
interaction between these two agents has been well characterized in in-vitro breast cancer 
models.24-26 In a randomized phase III study of patients with trastuzumab-refractory HER2 
positive MBC, lapatinib 1000mg daily in combination with trastuzumab 2mg/kg weekly (after 
initial 4mg/kg loading dose) showed an improved median progression-free survival of 12 weeks 
compared to 8 weeks with lapatinib alone (P=0.008).27 Adverse events were similar in both 
groups, with a higher rate of grade 1-2 diarrhea with combination therapy. Another large phase 
III study looked at lapatinib plus trastuzumab in the neoadjuvant setting and found a significantly 
higher rate of pathologic complete response compared to either agent alone.28 These studies 
suggest that dual HER2 inhibition is better than single agent anti-HER2 therapy in the treatment 
of HER2-positive breast cancer. 
 
 
 
1.4 
HER2 TARGETED THERAPY WITH ANTI-ANGIOGENIC THERAPIES 
 
Tumor neovascularization, or angiogenesis, has been demonstrated to be a critical pathway in 
the development and progression of cancer. Inhibition of angiogenesis represents an important 
and promising therapy in the management of solid tumors.29 Agents that target angiogenesis 
such as bevacizumab, sunitinib, and pazopanib are now approved for the treatment of various 
tumors, including lung, colon and renal cancer. In breast cancer the addition of bevacizumab to 
cytotoxic chemotherapy led to statistically significant improvements in disease-free survival and 
overall response rates, although a benefit in overall survival was not observed.30 
 
Vascular endothelial growth factor (VEGF) is the most potent and specific regulator of both 
normal and pathologic angiogenesis.31 HER2 overexpression is associated with VEGF 
upregulation in breast cancer.32 In xenograft models, increased efficacy is observed when anti- 
HER2 antibody trastuzumab is given in combination with anti-VEGF antibody bevacizumab.33 
 
Rugo et al reported encouraging clinical activity for the combination of lapatinib and 
bevacizumab in heavily pretreated patients.34 A response rate of 13% and clinical benefit of 
34% was observed among 32 patients with metastatic breast cancer who had a median of 5 
prior chemotherapy regimens. Most of these patients had received 2 or 3 prior lines of 
trastuzumab containing regimens. 
Preliminary data from a phase I trial reported by Falchook et al suggests that the combination of 
trastuzumab, bevacizumab and lapatinib is active in heavily pretreated patients with metastatic 
breast cancer.35 Three out of 5 patients previously refractory to lapatinib and trastuzumab 
achieved a response. 


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The most compelling data evaluating the clinical activity of combining HER2 and anti-angiogenic 
therapies comes from a phase II trial of bevacizumab and trastuzumab as front line therapy for 
metastatic breast cancer conducted by Hurvitz et al.36 In this trial of 50 patients a response rate 
of 48% and a clinical benefit of 60% were obtained. Treatment was well tolerated with the 
expected toxicity profile of these agents. 
 
 
1.5 
METRONOMIC CHEMOTHERAPY COMBINED WITH TARGETED THERAPY 
 
A phase II trial by Dellapasqua et al evaluated bevacizumab, a recombinant humanized 
monoclonal antibody against VEGF, in combination with metronomic cyclophosphamide and 
capecitabine in MBC.37 Bevacizumab was given 10mg/kg intravenously every 2 weeks, with 
cyclophosphamide 50mg daily and capecitabine 500mg three times a day. An overall response 
rate of 48% was observed in 47 patients who had received 0-3 prior chemotherapy regimens. 
Median time to progression was 42 weeks. Treatment was well tolerated, and grade 3 or 4 
toxicities were uncommon. 
 
Another phase II trial by Montagna et al evaluated the activity of a 4-drug regimen of 
metronomic capecitabine and cyclophosphamide given with bevacizumab and erlotinib in 
patients with MBC.38 Erlotinib is a tyrosine kinase EGFR inhibitor with a mechanism of action 
and toxicity profile similar to that of lapatinib. Patients received bevacizumab 15mg/kg 
intravenously every 21 days in combination with cyclophosphamide 50mg daily, capecitabine 
500mg three times a day and erlotinib 100mg daily. In this trial an overall response rate of 62% 
was observed among 26 patients with HER2 negative disease who had not received prior 
chemotherapy for metastatic disease, although two thirds of the patients had received prior 
adjuvant chemotherapy. 
 
A particularly relevant finding from these 2 studies is that the 3 drug combination (metronomic 
capecitabine, cyclophosphamide and bevacizumab) and the 4 drug combination (metronomic 
capecitabine, cyclophosphamide, bevacizumab and erlotinib) were found to be well tolerated, 
with very few grade 3 or 4 toxicities. Diarrhea and myelosuppression, the main toxicities of 
concern, are summarized in the following table: 
 
 
TABLE 1: MAIN TOXICITIES RELATED TO DRUG COMBINATION 
 
 
Type of Comb 
Diarrhea 
Neutropenia 
All Grades 
Grade 3-4 
All Grades 
Grade 3-4 
3-Drug Comb 
34% 
0% 
32% 
4% 
4-Drug Comb 
76% 
1% 
20% 
0% 
 
In preclinical models the combination of metronomic cyclophosphamide plus trastuzumab was 
significantly more effective than either therapy used alone. The combination of metronomic 
chemotherapy and trastuzumab has comparable efficacy to that of trastuzumab in combination 
with the maximal tolerated dose of cyclophosphamide, while toxicity is significantly reduced.39 
 
The activity of metronomic chemotherapy and trastuzumab was reported in a small clinical trial 
by Orlando et al, looking at 22 patients with HER2 positive MBC previously treated with 
trastuzumab.40 Treatment consisted of methotrexate 2.5mg twice daily on day 1 and 4 every 
week, with cyclophosphamide 50mg daily and trastuzumab 6mg/kg every three weeks, after an 


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initial loading dose of 8mg/kg. A response rate of 18% and a clinical benefit of 46% were 
observed in patients who had received 2-8 prior chemotherapy regimens. 
 
The following table summarizes the clinical trials previously discussed using metronomic 
chemotherapy and/or targeted therapy in metastatic breast cancer. 
 
 
TABLE 2: CLINICAL TRIALS USING METRONOMIC CHEMOTHERAPY 
 
Trial 
N 
Prior 
therapy 
Treatment 
ORR 
CB 
Toxicity 
Metronomic chemotherapy 
Colleoni et al. 
63 
0-3 
Cyclophosphamide 
50mg daily 
Methotrexate 2.5mg 
bid D1, 2 
19% 
32% 
Grade 3/4: transaminitis 
(n=9); leukopenia, 
neutropenia, anemia (n=1) 
Schott et al. 
96 
0-2 
Cyclophosphamide 
100mg daily D1-14 
Capecitabine 1500 
bid D8-21 
q21 days 
36% 
68% 
Grade 3/4: leukopenia 
(n=15); neutropenia, hand- 
foot syndrome (n=7); 
fatigue, dehydration, 
diarrhea (n=2); dyspnea, 
febrile neutropenia, 
transaminitis, anemia, 
thrombocytopenia, 
hypokalemia, 
hyponatremia, depression, 
nausea, puritis, rash, 
thrombosis (n=1) 
Trial 
N 
Prior 
therapy 
Treatment 
ORR 
CB 
Toxicity 
HER2 targeted therapy + anti-angiogenic therapy
Rugo et al. 
52 
0-12 
Lapatinib 1500mg 
daily 
Bevacizumab 
10mg/kg q2weeks 
13% 
32% 
Grade 3: hypertension, 
rash (n=2); diarrhea, 
transaminitis (n=1) 
Falchook et 
al. 
24 
6 
Lapatinib 750mg 
daily 
Trastuzumab 
4mg/kg q3weeks 
Bevacizumab 
7.5mg/kg q3weeks 
60% 
N/A 
N/A 
Hurvitz et al. 
50 
0 
Trastuzumab 
2mg/kg weekly 
Bevacizumab 
10mg/kg q2weeks 
48% 
60% 
Grade 5: perforated ulcer 
(n=1) 
Grade 3/4: HTN (n=18); 
proteinuria (n=4); dyspnea, 
leukopenia, infusion 
reaction, headache (n=2); 
fatigue, diarrhea, 
inflammatory 
demyelination, 
hyperglycemia, 
hyponatremia, irregular 
menses, cardiac event 
(n=1) 


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TABLE 2: CONTINUED 
Trial 
N 
Prior 
therapy 
Treatment 
ORR 
CB 
Toxicity 
Metronomic chemotherapy + targeted therapy
Dellapasqua 
et al. 
46 
0-3 
Capecitabine 
500mg tid 
Cyclophosphamide 
50mg daily 
Bevaciumab 
10mg/kg q2weeks 
48% 
68% 
Grade 3: hypertension 
(n=8); transaminitis, 
nausea/vomitting, 
neutropenia, leukopenia 
(n=2) 
Montagna et 
al. 
26 
0 
Capecitabine 
500mg tid 
Cyclophosphamide 
50mg daily 
Bevacizumab 
15mg/kg q3weeks 
Erlotinib 100mg 
daily 
62% 
75% 
Grade 3: hypertension 
(n=2); diarrhea, thrombosis 
(n=1) 
Orlando et al. 
22 
2-8 
Cyclophosphamide 
50mg daily 
Methotrexate 2.5mg 
bid D1, 4 
Trastuzumab 
6mg/kg q3weeks 
18% 
46% 
Grade 3: transaminitis 
(n=2) 
 
 
1.6 
HYPOTHESIS 
 
Based on the above we propose a phase II clinical trial using metronomic chemotherapy 
(capecitabine and cyclophosphamide), in combination with dual HER2 inhibition (lapatinib and 
trastuzumab), in HER2 positive MBC patients previously treated with trastuzumab. Each of 
these agents has been shown to have activity in MBC, although they have never been 
combined in this 4-drug regimen. We postulate that this combination regimen will be highly 
active in patients with HER2 positive MBC while also having a favorable toxicity profile. 
 
 
 
2.0 
OBJECTIVES AND PURPOSE 
 
The primary and secondary objectives listed below apply to the combination of metronomic 
cyclophosphamide and capecitabine with lapatinib and trastuzumab in patients with HER2-positive 
metastatic breast cancer previously treated with trastuzumab. 


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2.1 
Primary Objective 
• 
To estimate the progression free survival (PFS) 
 
2.2 
Secondary Objectives 
• 
To evaluate the overall response rate (ORR) 
• 
To evaluate the clinical benefit rate (CBR; complete response, partial response, and stable 
disease for ≥24 weeks) 
• 
To estimate the overall survival (OS) 
• 
To assess the safety and tolerability 
 
 
 
 
3.0 
SELECTION AND WITHDRAWAL OF PARTICIPANTS 
 
Study participants (N=40) will be recruited from the Los Angeles County + University of Southern 
California (LAC+USC) Healthcare Network and the Keck Medical Center of USC, Norris 
Comprehensive Cancer Center in Los Angeles, California. Because of the multi-ethnic nature of this 
catchment area, the inclusion of minority groups into study enrollment will be supported. 
 
 
3.1 
INCLUSION CRITERIA 
 
Female patients 18 years of age and older who meet the following inclusion criteria for 
participation in the study will be considered for study enrollment: 
 
• 
Histologically confirmed HER2-positive metastatic breast cancer. 
 
• 
HER2 overexpression of tumor by either immunohistochemistry (IHC) or fluorescence in situ 
hybridization (FISH). Tumors tested by IHC must be 3+ positive. Tumors tested by FISH 
must have a ratio of HER2:CEP17>2.0. When both tests are performed, the FISH result 
must be positive. 
 
• 
Prior trastuzumab use in the adjuvant or metastatic setting. 
 
• 
No more than two prior cytotoxic chemotherapeutic regimens for metastatic breast cancer. In 
addition, prior Trastuzumab emtansine (TDM-1, Kadcyla) is allowed. 
 
• 
Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2. 
 
• 
Adequate organ and marrow function as follows: 
o ANC ≥ 1500/mm3 
o Platelets ≥ 100,000/mm3 
o Hemoglobin ≥ 9g/dL 
o Bilirubin ≤ 1.5 x the upper limit of normal 
o Serum creatinine ≤ 1.5 x the upper limit of normal or calculated creatinine clearance ≥ 
60ml/min 
o Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x the upper 
limit of normal. 
 
• 
Fully recovered from toxicity due to prior therapy. 


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• 
Capable of understanding the informed consent and complying with the protocol and signed 
the informed consent document prior to any study-specific screening procedures or 
evaluations being performed. 
 
• 
Patients must have the ability to swallow pills. 
 
• 
Patients may have either measurable or non-measurable disease by RECIST 1.1 criteria. 
 
• 
Sexually active participants must agree to the use of a medically accepted barrier method of 
contraception (i.e. male condom or female condom) during the course of the study and for 3 
months following discontinuation of study treatments. For participants of childbearing 
potential, a barrier method and a second method of contraception must be used. 
 
• 
Participants of childbearing potential must have a negative pregnancy test at screening and 
enrollment. Participants of childbearing potential are defined as premenopausal females 
capable of becoming pregnant, i.e. females who have had any evidence of menses in the 
past 12 months with the exception of those who had prior hysterectomy (oophorectomy or 
surgical sterilization). However, women who have been amenorrheic for ≥ 12 months are still 
considered to be of childbearing potential if the amenorrhea is possibly due to any other 
cause including prior chemotherapy, antiestrogens, or ovarian suppression. 
 
 
 
3.2 
EXCLUSION CRITERIA 
 
Women with any of the following exclusion criteria for this study will be ineligible to participate in 
the study: 
 
• 
The following restrictions on prior therapy apply: 
o Prior treatment with capecitabine or lapatinib. 
o Radiation therapy within 2 weeks before the first dose of study treatment 
o Hormonal therapy within 2 weeks before the first dose of study treatment 
o Cytotoxic chemotherapy (including investigational cytotoxic chemotherapy) within 3 
weeks before the first dose of study treatment 
o Biologic therapy (including antibodies [other than trastuzumab], immune modulators, 
cytokines) within 4 weeks before the first dose of study treatment. Note: There is no 
washout period required for trastuzumab. 
o Any other type of investigational agent within 4 weeks before the first dose of study 
treatment. 
o Major surgery, or not recovered from major surgery within 4 weeks before the first dose 
of study treatment 
 
• 
Untreated, symptomatic, or progressive brain metastases. Participants must have no 
radiographic or other signs of progression in the brain for ≥1 month after completion of local 
therapy. Any corticosteroid use for brain metastases must have been discontinued without 
the subsequent appearance of symptoms for ≥ 4 weeks prior to first study treatment. 
 
• 
Uncontrolled significant intercurrent illness that would preclude the patient from study 
participation per investigator assessment. 


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• 
Left ventricular ejection fraction (LVEF) ≤ 50% as documented by MUGA or echocardiogram 
performed within 28 days prior to the first study treatment. 
 
• 
Currently receiving anticoagulation with therapeutic doses of warfarin (low-molecular weight 
heparin is permited). 
 
• 
Pregnant or breastfeeding. 
 
• 
Known to be positive for the human immunodeficiency virus (HIV) (a test for HIV at 
screening is not required). 
 
• 
Have acute or currently active/requiring anti-viral therapy hepatic or biliary disease (with the 
exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or 
stable chronic liver disease per investigator assessment). 
 
• 
Previously identified allergy or hypersensitivity or intolerance to components of the study 
treatment formulation (cyclophosphamide, capecitabine, lapatinib, trastuzumab). 
 
• 
Any other diagnosis of malignancy or evidence of malignancy (except non-melanoma skin 
cancer, in-situ carcinoma of the cervix) within 2 years prior to screening for this study. 
 
• 
Unable or unwilling to abide by the study protocol or cooperate fully with the investigator or 
designee. 
 
 
 
 
4.0 
TREATMENT PLAN 
 
This is a single institution, phase II, single arm, open-label study. 
 
 
 
4.1 
TREATMENT DOSAGE AND ADMINISTRATION 
 
Each patient will be given the following treatment on a 21-day cycle, with an average of 8 cycles 
per patient: 
 
 
TABLE 3: TREATMENT DOSAGE AND ADMINISTRATION 
 
 
Drug 
 
Dose 
Route 
Frequency 
per Cycle 
 
Days 
Capecitabine 
1500mg 
PO 
Daily 
1-21 
Cyclophosphamide 
50mg 
PO 
Daily 
1-21 
Lapatinib 
1000mg 
PO 
Daily 
1-21 
Trastuzumab 
6mg/kg* 
IV 
Once 
1 
* A loading dose of 8mg/kg will be given for the first cycle of trastuzumab. 
 
Any patient who receives treatment on this protocol will be evaluable for toxicities (see Section 
4.2).  Each patient will be assessed for the development of toxicities according to the Study 


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Calendar (see Section 5.0).  Dose adjustments will be made according to the system showing 
the greatest degree of toxicity (see Section 4.4). 
 
 
4.2 
TOXICITIES AND SPECIFIC MANAGEMENT GUIDLINES 
 
Adverse events (AE) will be graded according to the National Cancer Institute (NCI) Common 
Toxicity Criteria for Adverse Events (CTCAE) version 4.0, which can be accessed at: 
http://ctep.cancer.gov/reporting/ctc.html. Information related to Reporting of Adverse Events 
can be found in Section 7.5 of this document. 
 
Participants experiencing one or more AEs due to the study treatment may require dose 
interruption and/or dose reduction for capecitabine, cyclophosphamide, lapatinib and/or 
trastuzumab. Guidelines for the management of AEs (ie, dose interruptions and dose 
reductions) are presented in the next sections. The study will be terminated if the incidence of 
unacceptable toxicities, as defined below, is greater than 15%. 
 
 
4.2.1 
UNACCEPTABLE TOXICITIES 
 
Unacceptable toxicities are defined as any of the following attributable to study drug 
(definitely, probably, or possibly) during treatment. 
• 
Any Grade 4 hematologic toxicity not resolving to Grade 1 or less by the time of the 
next scheduled blood draw a week later despite supportive care 
• 
Grade 3 thrombocytopenia with bleeding 
• 
Any Grade 3 or 4 non-hematologic toxicity not reversible to Grade 1 or less within 
96 hours despite supportive care, excluding: 
o Alopecia 
o Transient myalgia or fatigue 
o Inadequately treated nausea, vomiting, or diarrhea 
o Any uncomplicated hyperglycemia and hypertriglyceridemia defined as not 
being associated with any other grade 3 or greater toxicity 
 
 
4.2.2 
SPECIFIC SYMPTOM MANAGEMENT – CARDIAC AND RESPRIATORY EVENTS 
 
Asymptomatic cardiac events: 
Participants who have a ≥20% decrease in left ventricular cardiac ejection fraction 
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 lapatinib and trastuzumab. 
If the repeat ejection fraction evaluation confirms a ≥20% decrease in left ventricular 
cardiac ejection fraction, and the ejection fraction is below the institution's lower limit of 
normal, then lapatinib and trastuzumab should be temporarily discontinued. 
 
If the left ventricular ejection fraction recovers during the next 3 weeks, after 
consultation and approval of the medical monitor, the participant may be restarted on 
lapatinib and trastuzumab at a reduced dose. For such participants, monitoring of left 
ventricular ejection fraction 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 left ventricular 
ejection fraction relative to baseline, and the value is below the institution's lower limit 
of normal, then the participant should be withdrawn from study. 


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Symptomatic cardiac events: 
Participants with an NCI CTCAE grade 3 or 4, LVEF relative decrease must be 
withdrawn from study. 
 
Interstitial pneumonitis: 
Participants with an NCI CTCAE Grade 3 or 4, interstitial pneumonitis must be 
withdrawn from study and must be reported as a SAE to GlaxoSmithKline (Section 
7.5.1). 
 
 
4.2.3 
SPECIFIC SYMPTOM MANAGEMENT – DIARRHEA 
 
Experience thus far suggests that when lapatinib is used as monotherapy 51% of 
patients experience diarrhea; most diarrhea presents as uncomplicated NCI CTCAE 
Grade 1 or 2 (G1 30%, G2 15%, G3 6%, G4<1%). In rare cases, diarrhea can be 
debilitating, and potentially life threatening if accompanied by dehydration, renal 
insufficiency, and/or electrolyte imbalances. Standardized and universal guidelines 
have been developed by an American Society of Clinical Oncology (ASCO) panel for 
treating chemotherapy-induced diarrhea. Presented in the sections below are the 
recommended guidelines for the management of diarrhea in participants receiving 
lapatinib-based therapy; these guidelines were derived from the recommendations 
published by the ASCO panel. 
 
Early identification and intervention is critical for the optimal management of diarrhea. 
A participant’s baseline bowel patterns should be established so that changes in 
patterns can be identified while participant is on treatment. 
 
It is strongly recommended to give participants receiving lapatinib-based 
therapy a prescription of loperamide with instructions to start loperamide at the 
onset of diarrhea as per the recommendations outlined below. 
 
Participants should be instructed to first notify their physician/healthcare 
provider at onset of diarrhea of any severity. 
 
An assessment of frequency, consistency and duration as well as knowledge of other 
symptoms such as fever, cramping, pain, nausea, vomiting, dizziness and thirst should 
be taken at baseline. Consequently participants at high risk of diarrhea can be 
identified.  Participants should be educated on signs and symptoms of diarrhea with 
instructions to report any changes in bowel patterns to the physician. 
 
It is recommended that participants keep a diary and record the number of diarrhea 
episodes and its characteristics. They should also include information on any dietary 
changes or other observations that may be useful in the evaluation of their diarrhea 
history. 
 
If participants present with diarrhea of any Grade, check they are taking lapatinib 
correctly, i.e. single daily dose, rather than splitting it through the day.  Obtain 
information on food (solid and liquid) and over the counter (OTC) medication, including 
herbal supplements, taken during the lapatinib treatment period. 
 
 


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Definitions: 
 
 
National Cancer Institute (NCI) guidelines define diarrhea compared to baseline. 
 
 
TABLE 4: NCI COMMON TERMINOLOGY CRITERIA FOR GRADING DIARRHEA 
 
Adverse Event Grade 
Diarrhea 
Grade 1 
Increase of <4 stools/day over baseline; mild 
increase in ostomy output compared to 
baseline 
Grade 2 
Increase of 4-6 stools/day over baseline; 
moderate increase in ostomy output 
compared to baseline; 
Grade 3 
Increase of ≥7 stools/day over baseline; 
incontinence; hospitalization indicated; 
severe increase in ostomy output compared 
to baseline; limiting self care activities of daily 
living (ADL) 
Grade 4 
Life-threatening consequences; urgent 
intervention indicated 
Grade 5 
Death 
 
Uncomplicated diarrhea is considered mild-to-moderate and defined as CTCAE 
Grade 1 or 2 with no complicating signs or symptoms. 
 
Complicated diarrhea is severe and defined as any CTCAE Grade 3 or 4 diarrhea, or 
Grade 1 or 2 with one or more of the following signs or symptoms: 
• 
Moderate to severe abdominal cramping 
• 
Nausea/vomiting ≥Grade2 
• 
Decreased performance status 
• 
Fever 
• 
Sepsis 
• 
Neutropenia 
• 
Frank bleeding (red blood in stool) 
• 
Dehydration 
 
Management: 
 
A.  Uncomplicated Diarrhea 
 
I. 
CTCAE Grade 1 
 
NOTE:  Participant should be instructed to: start supportive care 
immediately at the first episode of diarrhea (i.e., unformed stool) and 
call their physician. 
 
1. 
Administer loperamide* 
 
a.  Initial dose 4mg followed by 2mg after every unformed stool. 
Re-evaluate after 24 hours, if: 


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i. 
Diarrhea is resolving: 
• 
Continue loperamide treatment at 2mg dose after 
every unformed stool until diarrhea free (i.e., 
<Grade 1/bowel patterns returned to baseline) for 
12 hours. 
o If diarrhea recurs, re-initiate loperamide 
treatment as needed to maintain normal 
bowel patterns 
 
ii. 
Diarrhea is not resolving: 
• 
Administer loperamide at 2mg every 4 hours for 
the next 24 hours.  Re-evaluate after 24 hours.  If 
diarrhea is resolving, administer loperamide at 
2mg after every unformed stool until diarrhea free 
(i.e., <Grade 1/bowel patterns returned to 
baseline) for 12 hours.  If diarrhea is not resolving 
continue loperamide treatment at 2mg every 4 
hours and re-evaluate every 24 hours. 
 
b.  If Grade 1 diarrhea persists for more than 1 week with 
loperamide treatment, consider treatment with second-line 
agents (i.e., octreotide, budesonide or tincture of opium). 
 
 
 
2. 
Dietary modifications which are essential in the management of 
diarrhea include the following recommendations (American 
Cancer Society; National Cancer Institute): 
a.  Stop all lactose containing products and eat small meals 
b.  Avoid spicy, fried and fatty foods, raw vegetables and 
other foods high in fiber 
• 
Eat foods low in fiber (i.e., lean meat, rice, skinless 
chicken or turkey, fish, eggs, canned or cooked 
skinless fruits, cooked/pureed vegetables) 
 
c.   Avoid caffeine and alcohol as they can irritate the bowel 
and increase motility 
 
d.  Hydration:  Drink 8-10 large glasses of clear liquids a day 
(e.g., water, electrolyte drink). 
• 
Avoid acidic drinks such as tomato juice and fizzy 
soft drinks 
 
e.  Supplement diet to include foods rich in potassium (e.g., 
bananas, potatoes, and apricots) , evaluate their impact 
on diarrhea due to the fiber content (e.g., apricots) 


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3. 
Continue with study treatment (i.e., lapatinib-based treatment) 
 
Continue with supportive care until diarrhea has resolved (diarrhea 
free for 12 hours/bowel pattern return to baseline).  Once diarrhea 
has resolved, the participant can begin to gradually re-introduce 
foods from their normal diet. 
 
If diarrhea recurs following stopping of loperamide treatment, 
resume loperamide treatment at the dose and schedule 
recommended above and re-introduce diet modifications.  Continue 
with study treatment. 
 
If Grade 1 diarrhea persists for ≥2 weeks, refer to the management 
guidelines for Persistent Grade 2 Diarrhea. 
 
II. 
CTCAE Grade 2 
 
NOTE:  Participant should be instructed to call physician at first 
episode of diarrhea and start supportive care immediately 
 
1. 
Administer loperamide* 
a.  Initial dose 4mg followed by 2mg every 4 hours or after every 
unformed stool.  Re-evaluate after 24 hours. If: 
 
i. 
Diarrhea is resolving, continue loperamide treatment at 
2mg dose after every unformed stool until diarrhea free 
(i.e., <Grade 1/bowel patterns returned to baseline) for 
12 hours 
o If diarrhea recurs, re-initiate loperamide treatment 
as needed to maintain normal bowel patterns 
 
ii. 
Diarrhea is not resolving, consider loperamide dose of 
2mg every 2 hours for 24 hours. If Grade 2 diarrhea 
persists after total of 48 hours of loperamide treatment, 
start second-line agents (i.e.,octreotide, budesonide or 
tincture of opium). 
o Consider performing stool work-up, CBC, 
electrolytes and other tests as appropriate 
 
 
 
2. 
Dietary modifications which are essential in the management of 
diarrhea include the following recommendations (American Cancer 
Society; National Cancer Institute): 
 
a.  Stop all lactose containing products and eat small meals 
 
b.  Avoid spicy, fried and fatty foods, bran, raw vegetables and other 
foods high in fiber 
• 
Eat foods low in fiber (i.e., lean meat, rice, skinless chicken 
or turkey, fish, eggs, canned or cooked skinless fruits, 
cooked/pureed vegetables) 


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c.   Avoid caffeine and alcohol as they can irritate the bowel and 
increase motility 
 
d.  Hydration:  Drink 8-10 large glasses of clear liquids a day (e.g., 
water, electrolyte drink). 
• 
Avoid acidic drinks such as tomato juice and fizzy soft drinks 
 
e.  Supplement diet to include foods rich in potassium (e.g., 
bananas, potatoes, and apricots), evaluate their impact on 
diarrhea due to the fiber content (e.g., apricots) 
 
3. 
Continue with study treatment (i.e., lapatinib-based treatment) 
Continue with supportive care until diarrhea has resolved (diarrhea 
free for 12 hours/bowel pattern return to baseline).  Once diarrhea 
has resolved, the participant can begin to gradually re-introduce 
foods from their normal diet.  Refer to Section IV “Recurrent 
Diarrhea” for study treatment guidelines. 
 
If diarrhea recurs following stopping of loperamide treatment, 
resume loperamide treatment at the dose and schedule 
recommended above and re-introduce diet modifications. 
 
 
 
III. 
Persistent (≥ 3days/72 hours) Grade 2 Diarrhea: hold lapatinib and 
chemotherapy until diarrhea resolves (<Grade 1/return to baseline bowel 
pattern). 
 
1.  If supportive care measures and the interruption of study treatment (i.e., 
lapatinib and chemotherapy) are ineffective in treating persistent Grade 
1 or Grade 2 diarrhea, perform stool work-up, CBC, electrolytes and 
other tests as appropriate, consider consulting with a gastrointestinal 
(GI) specialist. 
 
a. 
After diarrhea resolves (<Grade 1/return to baseline bowel 
pattern), resume treatment with lapatinib and chemotherapy. 
 
 
 
IV. 
Recurrent Diarrhea (more than 1 occurrence of Grade 2 diarrhea): 
once the 2nd occurrence of Grade 2 diarrhea resolves to ≤Grade 1, consider 
reducing the dose of lapatinib by one dose level. 
 
1.  Consider a dose reduction for chemotherapy. 
 
 
 
B 
Complicated Diarrhea 


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I. 
CTCAE Grade 3 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) 
 
1. 
Participant must call physician immediately for any complicated 
severe diarrhea event 
2. 
If loperamide has not been initiated, initiate loperamide immediately: 
Initial dose 4mg followed by 2mg every 2 hours or after every 
unformed stool* 
3. 
Refer to the dietary modification recommendations for Grade 1 and 
Grade 2 uncomplicated diarrhea 
4. 
For dehydration use intravenous fluids as appropriate, if participant 
presents with severe dehydration administer octreotide 
5. 
Perform stool work-up, CBC, electrolytes and other tests as 
appropriate 
6. 
Administer antibiotics as needed (example fluoroquinolones), 
especially if diarrhea is persistent beyond 24 hours or there is fever 
or Grade 3-4 neutropenia 
Hold lapatinib and chemotherapy until symptoms 
resolve to ≤Grade 1 (without complicating features) 
and reintroduce lapatinib at a reduced dose 
a.  Consider a dose reduction for chemotherapy 
7. 
Supportive care and other interventions should be continued until 
diarrhea free (i.e., <Grade 1/bowel patterns returned to baseline) for 
24 hours 
8. 
Intervention may require hospitalization for participants most at risk 
for life threatening complications 
 
 
II. 
CTCAE Grade 4 
 
1. 
Participant must call physician immediately for any Grade 4 diarrhea 
event 
2. 
Hold treatment with lapatinib and chemotherapy 
o Evaluate the patient case history when deciding on the re- 
initiation of study treatment, including dose modifications, 
following resolution of diarrhea (≤Grade 1) 
3. 
If loperamide has not been initiated, initiate loperamide immediately: 
Initial dose 4mg followed by 2mg every 2 hours or after every 
unformed stool* 
4. 
For dehydration use intravenous fluids as appropriate, if participant 
presents with severe dehydration administer octreotide 
5. 
Perform stool work-up, CBC, electrolyte and other tests as 
appropriate 
6. 
Administer antibiotics as needed (example fluoroquinolones), 
especially if diarrhea is persistent beyond 24 hours or there is fever 
or Grade 3/4 neutropenia 
7. 
Supportive care and other intervention should be continued until 
diarrhea free (i.e., <Grade 1/bowel patterns returned to baseline) for 
24 hours 


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8. 
Intervention may require hospitalization for participants most at risk 
for life threatening complications 
 
* Refer to and follow the recommended supportive care guidelines 
in the previous sections 
 
 
TABLE 5: ALGORITHM FOR THE MANAGEMENT OF DIARRHEA 
 
Algorithm for the management of diarrhea 
RECOMMENDATION 
   Loperamide prescription with instructions on administration for all participants 
   Patient diary to record baseline bowel patterns and changes; dietary changes 
EVALUATION 
   Obtain history of onset and duration of diarrhea 
   Describe number of stools and stool composition (Refer to baseline) 
    Assess participant for fever, dizziness, abdominal pain/cramping or weakness 
  
 
 
Medications (Prescription; OTC; herbal supplements) and dietary profile 
 
 
 
 
UNCOMPLICATED 
Grade 1 or Grade 2 with no complicating 
signs or symptoms 
 
 
 
MANAGEMENT 
 
ADDED RISK 
FACTORS 
COMPLICATED 
Grade 3 or 4 diarrhea or Grade 1 or 2 with 
≥ 1 of these signs or symptoms: 
•  Cramping (moderate/severe) 
•  Nausea/vomiting (≥ Grade 2) 
•  Decreased performance status 
•  Fever 
•  Participants should be instructed to administer loperamide and notify 
physician 
•  Discontinue lactose products 
•  Drink 8-10 large glasses of clear liquids per day 
•  Eat frequent small meals 
•  Eat foods low in fiber 
•  Sepsis 
•  Neutropenia 
•  Frank bleeding 
•  Dehydration 
b     d t    t 
t 
 
 
 
 
Reassess 24 hours later 
 
 
Diarrhea Unresolved 
•  Continue loperamide 
•  Continue dietary modifications 
•  Evaluate for possible infection 
(Grade 2) 
 
MANAGEMENT 
•  Participant must call physician immediately 
•  Grade 3: hold lapatinib and chemotherapy (if applicable) 
•  Grade 4:hold all study treatment (lapatinib + 
chemotherapy) 
•  Evaluate for possible infection 
•  Consider hospitalization 
SUGGESTED TREATMENT 
•  Administer loperamide 
•  Hydration (i.v. fluids as needed) 
•  Consider need for antibiotics and consider second line anti- 
diarrheals 
 
 
 
Diarrhea Resolving 
•  Continue instructions for dietary 
modification 
•  Gradually add solid food to diet 
•  Discontinue standard anti- 
diarrheal after 12-hour diarrhea- 
free interval 
•  If applicable resume treatment 
with lapatinib and chemotherapy 
Reassess 24 hours later 
 
 
 
Diarrhea unresolved 
   Continue loperamide (Grade 1) 
   Start second line anti-diarrheal agents 
(Grade 2) 
   Start second-line anti-diarrheal agents for 
Grade 1 diarrhea that does not improve after 
1 week of loperamide treatment 
 
 
 
 
Diarrhea Free for 24 hours 
   Discontinue diarrhea intervention 
For Grade 3 
   Reintroduce lapatinib at a reduced 
dose (if dose was >750mg) and 
chemotherapy (if applicable) 
   Consider dose reduction for 
chemotherapy 
For Grade 4 
Refer to Section B, subsection II 


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1. 
For Grade 1 diarrhea that persists for 2 weeks or longer, refer to Section III 
2. 
For Grade 2 diarrhea that persists longer than 3 days/72 hours, refer to Uncomplicated Diarrhea Section III 
3. 
For recurrent diarrhea, refer to Uncomplicated Diarrhea Section IV for further management guidelines 


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4.2.4 
SPECIFIC MANAGEMENT GUIDANCE – HEPATOTOXICITY 
 
If a participant experiences ALT >3 × ULN and total bilirubin >2.0 × ULN (>35% direct; 
bilirubin fractionation required*), or ALT>3 x ULN and INR>1.5 (if INR measured), then 
the following actions must be taken: 
 
• 
Immediately and permanently discontinue study treatment; 
• 
Complete the SAE data collection tool, the liver event CRF, and the liver 
imaging and/or liver biopsy CRFs, if these tests are performed; 
• 
Promptly report the event to Novartis within 24 hours of learning its occurrence 
(refer to Section 7.3.1.6 for guidance on prompt reporting to NOVARTIS); 
• 
Make every reasonable attempt to have participants return to clinic within 24 
hours for repeat liver chemistries, liver event follow up assessments, and close 
monitoring 
• 
Monitor every week until liver chemistries resolve, or return to within baseline 
values; 
• 
Do not re-challenge with study treatment. 
• 
A specialist or hepatology consultation is recommended 
 
 
*NOTE: Bilirubin fractionation should be performed if testing is available.  If testing is 
unavailable and a participant meets the criterion of total bilirubin >2.0 × ULN, then the 
actions detailed must still be performed.  If bilirubin fractionation testing is unavailable, 
record the presence of detectable urinary bilirubin on dipstick, indicating direct bilirubin 
elevations and suggesting liver injury. 
 
If a participant experiences: 
 
• 
ALT >8 × ULN or 
• 
ALT >5 × ULN persisting for ≥2 weeks: retest within 3 days from the first 
occurrence and then weekly to determine if ALT elevation persists or 
• 
ALT >3 × ULN with signs or symptoms of hepatitis or hypersensitivity (the 
appearance or worsening of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, or eosinophilia), 
• 
then hold study treatment for 2 weeks, make every reasonable attempt to have 
participants return to clinic within 24-72 hrs for repeat liver chemistries and liver 
event follow up assessments. Repeat liver chemistry testing in 2 weeks.  If ALT 
<3 x ULN discuss the possibility of re-challenging with study treatment with 
investigator. 
 
If the treatment is exhibiting efficacy and the participant wants to continue for potential 
benefit of lapatinib therapy after being informed of the results of liver chemistry testing, 
then the study treatment may be re-started at the reduced dose agreed upon by the 
investigator and the provider. The liver event CRF should be completed and liver 
chemistries and aforementioned signs and symptoms should be monitored at a 
minimum of every 2 weeks until resolution, stabilization, or a return to baseline values, 
at which point monitoring should be continued per protocol. 


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   If a participant experiences ALT >3 × ULN but <5 × ULN and total bilirubin ≤2 × ULN, 
without signs or symptoms of hepatitis or hypersensitivity, and who can be monitored 
weekly, then the following actions should be taken: 
 
• 
continue study treatment; 
• 
monitor weekly until liver chemistries resolve or return to within baseline, then 
monitor liver chemistries as per protocol assessment schedule; 
o if ALT >3 and < 5 × ULN for > 4 weeks, discontinue the treatment and 
complete liver safety testing and case report forms; 
• 
if at any time the participant meets any of the liver chemistry stopping criteria, 
then proceed as described above. 
 
 
Liver Chemistry Follow up 
For all participants who meet any of the liver chemistry criteria described, complete the 
following liver event assessments: 
 
• 
Viral hepatitis serology including: 
o Hepatitis A IgM antibody; 
o Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); 
o Hepatitis C RNA; 
o Cytomegalovirus IgM antibody; 
o Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing); 
o Hepatitis E IgM antibody; 
• 
Blood sample for pharmacokinetic (PK) analysis, obtained within one week of 
last dose.  Record the date/time of the PK blood sample draw and the date/time 
of the last dose of study treatment prior to blood sample draw on the CRF.  If 
the date or time of the last dose is unclear, provide the participant’s best 
approximation. If the date/time of the last dose cannot be approximated OR a 
PK sample cannot be collected in the time period indicated above, do not 
obtain a PK sample.  Instructions for sample handling and shipping are in the 
study procedures manual (SPM). 
• 
Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH); 
• 
Fractionate bilirubin if total bilirubin ≥2xULN. 
• 
Complete blood count with differential to assess eosinophilia; 
• 
Record the appearance or worsening of clinical symptoms of hepatitis, or 
hypersensitivity, fatigue, decreased appetite, nausea, vomiting, abdominal 
pain, jaundice, fever, or rash as relevant on the AE form; 
• 
Record use of concomitant medications, acetaminophen, herbal remedies, 
other over the counter medications, or putative hepatotoxins, on the 
concomitant medications form; 
• 
Record alcohol use on the liver event alcohol intake form. 
 
 
The following assessments are required for participants with ALT ≥3xULN and bilirubin 
≥2xULN (>35% direct) but are optional for other abnormal liver chemistries: 
 
• 
Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver 
kidney microsomal antibodies 


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COMPREHENSIVE CANCER CENTER AND HOSPITAL 
 
 
 
• 
Liver imaging (ultrasound, magnetic resonance, or computerized tomography), 
and/or liver biopsy to evaluate liver disease. 
 
 
TABLE 6: LIVER CHEMISTRY STOPPING RULES AND FOLLOW-UP CRITERIA 
 
Liver Chemistry Stopping Rules and Follow up Criteria 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a. 
bilirubin fractionation should be performed if testing is available.  If testing is unavailable and a participant meets the criterion of total 
bilirubin >2.0 × ULN, then the event should still be reported as an SAE and actions taken as described.  If bilirubin fractionation is 
unavailable, record presence of detectable urinary bilirubin on dipstick (indicating direct bilirubin elevations and suggesting liver injury). 
b. 
the appearance or worsening of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or eosinophilia 
c. 
once liver chemistries resolve, or return to baseline, then continue monitoring per the protocol assessment schedule 
d. 
retest within 3 days from the first occurrence and then weekly to determine if ALT elevation persists 


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4.2.5 
SPECIFIC MANAGEMENT GUIDANCE – SKIN DISORDERS 
 
Evaluation and Grading Guide 
The Most Commonly Reported Dermatological Reactions 
Papulopustular rash affecting especially the upper body, including face and scalp. 
Association with pruritus, burning or tenderness may occur; Maculopapular rash 
affecting the upper body. Pruritus may also occur; Nail or hair changes – any hair 
changes or loss, or paronychia; Dry skin, pruritus, and photosensitivity 
 
Severe Skin Events 
Lapatinib-related severe dermatological events are infrequent (1-3%). NCI-CTCAE 
(version 4.0) ≥ Grade 3 skin events are defined as: 
 
Macules/papules covering >30% BSA with or without associated symptoms; limiting 
self care ADL 
Surgical intervention or IV antibiotics indicated; limiting self care ADL Intense or 
widespread; constant; limiting self care ADL or sleep; oral corticosteroid or 
immunosuppressive therapy indicated Covering >30% BSA and associated with 
pruritus; limiting self care ADL Erythema covering >30% BSA and erythema with 
blistering; photosensitivity; oral corticosteroid therapy indicated; pain control indicated 
(e.g., narcotics or NSAIDs Despite the rarity of these events among participants 
treated with lapatinib, it is recommended that participants which present with these 
events be assessed for shortness of breath, angioedema, or generalized 
mucosal/cutaneous affectation with blisters or ulcers, suggestive of Type I 
hypersensitivity and/or NCI-CTCAE Grade 4 rash or dermatologic event, manifested 
as toxic epidermal necrolysis (i.e., Stevens-Johnson’s Syndrome etc).  If Grade 4 rash 
or dermatologic event occurs, lapatinib must be permanently discontinued. 
 
Stopping and holding rules 
If any Grade 4 dermatologic event occurs, lapatinib must be permanently discontinued. 
 
Holding rule 
For NCI-CTCAE Grade 3 dermatological reactions, or a Grade 2 dermatological 
reaction which is not improved after 2 weeks with recommended management 
strategies, a brief (up to 14 days) therapy interruption is recommended; the daily dose 
of lapatinib should then be reinstated. In some cases, the skin event may improve 
without the need for interrupting therapy with lapatinib.  In the lapatinib clinical program 
to date, many participants were able to resume lapatinib therapy at the same dose 
after resolution of skin event; these participants had less extensive and/or severe skin 
events. 
 
Re-challenge 
One re-challenge may be considered, if indicated in the opinion of the investigator, for 
participants who present with NCI-CTCAE Grade 3 skin events which recover briskly 
to NCI-CTCAE Grade 1 (within 14 days) after holding lapatinib. 
 
Stopping rules 
Lapatinib should be permanently discontinued if an NCI-CTCAE Grade 3 
dermatological reaction is intolerable to the patient despite recommended treatment 
interventions, or if a Grade 3 reaction recurs after one drug interruption/re-challenge 


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cycle.  For any occurrence of Stevens Johnson syndrome (toxic epidermal necrolysis), 
study therapy must be immediately and permanent discontinued. 
 
Treatment 
It is strongly recommended that participants who develop dermatological reactions 
receive evaluations for management on the specific side effect. 
 
Participants should be encouraged to avoid exposure to sunlight.  Broad spectrum 
sunscreens (containing titanium dioxide or zinc oxide) with an SPF of at least 30 
should be applied. 
A variety of agents can be used to manage skin reactions. These include mild-to- 
moderate strength steroid creams (fluticasone prioprionate 0.5%), topical or systemic 
antibiotics, topical or systemic antihistamines and immunomodulators, and 
hypoallergenic moisturizers and emolliens for dry skin (5-10% urea in cetomacrogel 
cream or soft paraffin). 
 
There is no standard treatment, known or established, that is proven effective for drug- 
related skin rashes or changes due to lapatinib. A papulopustular rash has been the 
most commonly observed skin adverse event, which frequently improves with an 
unchanged, uninterrupted dose of lapatinib therapy.  The need for oral or topical 
antibiotics (minocycline, doxycicline, flucolaciclline or metronidazole cream) and topical 
steroids is a clinical decision of the investigator and, if indicated, a dermatology 
consultation.  For pruritic lesions oral antihistamine agents were reported successful. 
For paronychia antiseptic bath and local potent corticosteroids in addition to 
tetracycline therapy is recommended. If no improvement, a dermatology or surgery 
consultation is recommended.  For infected lesions appropriate, culture driven, 
systemic or topical antibiotics are indicated. 
 
Oral retinoids are not recommended because of theoretical concerns about negatively 
affecting the lapatinib mechanism of action and topical steroids result in 
irritation/severe dryness. Oral steroids may be used for a short treatment course 
(maximum of 14 days) which may help participants to remain on study therapy. 
 
For participants with extensive or symptomatic NCI-CTCAE Grade 3 or 4 dermatologic 
event, or chronic, persistent or recurring lower grade skin events, dermatology 
consultation is encouraged.  Upon consultation with a dermatologist, other treatment 
options (including immunomodulators such as topical tacrolimis or pimecrolimus) may 
be recommended for difficult to treat/unresponsive skin toxicities. 
 
 
4.3 
TOXICITY RELATED DOSE REDUCTION GUIDELINES 
 
Guidelines for dose reduction of hematologic and non-hematologic toxicities are provided in the 
following tables. 


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4.3.1 
HEMATOLOGIC TOXICITIES 
 
 
TABLE 7: DOSE REDUCTION GUIDELINES (HEMATOLOGIC TOXICITIES) 
 
CTCAE v4 grade 
Intervention 
Grade 1-2 
No dose adjustments 
Grade 3 
Follow Guidance below based on occurance: 
1st occurance 
Interrupt capecitabine and cyclophosphamide 
treatment until resolution to Grade ≤2, and 
resume capecitabine treatment at one dose 
reduction and cyclophosphamide treatment at the 
same dose level 
2nd occurance 
Interrupt capecitabine and cyclophosphamide 
treatment until resolution to Grade ≤2, and 
resume capecitabine treatment at the same dose 
level cyclophosphamide treatment at one dose 
reduction 
3rd occurance 
Interrupt capecitabine and cyclophosphamide 
treatment until resolution to Grade ≤2, and 
resume capecitabine treatment at one dose 
reduction and cyclophosphamide treatment at 
one dose reduction 
4th occurance 
Discontinue treatment permanently 
Grade 4 
Follow Guidance below based on occurance: 
1st occurance 
Interrupt capecitabine and cyclophosphamide 
treatment until resolution to Grade ≤2, and 
resume capecitabine treatment at one dose 
reduction and cyclophosphamide treatment at 
one dose reduction 
2nd occurance 
Discontinue treatment permanently 


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COMPREHENSIVE CANCER CENTER AND HOSPITAL 
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4.3.2 
NON-HEMATOLOGIC TOXICITIES 
 
 
TABLE 8: DOSE REDUCTIONS (NON-HEMATOLOGIC TOXICITIES) 
 
CTCAE v4 grade 
Intervention 
Grade 1 
No dose adjustments 
Grade 2 
Follow Guidance below: 
(per investigator’s 
determination) 
No dose adjustments. 
Interrupt study treatment until resolution to Grade ≤1, 
and resume at same dose, or reduce dose of study 
drug most likely to have caused the AE by one dose 
level. If the dose of the likely causative drug is not 
reduced after the first occurrence, a dose reduction 
must be implemented after a second recurrence. 
Grade 3 
Interrupt study treatment until resolution to Grade ≤1, 
and reduce dose(s) of study drug(s) most likely to 
have caused the AE by one dose level. 
Grade 4 
Discontinue treatment permanently, unless determined 
by the investigator that the participant is deriving 
clinical benefit. In this case, interrupt study treatment 
until resolution to Grade ≤1, and resume treatment at 
a dose to be determined individually. 
 
 
4.4 
DOSE ADJUSTMENT 
 
The following tables show the dose adjustment levels for the study drugs in relation to the 
Hematologic Toxicities (Section 5.4.1) and Non-Hematologic Toxicities (Section 5.4.2) 
discussed above. 
 
 
4.5.1 
DOSE ADJUSTMENT LEVELS FOR CAPECITABINE 
 
 
TABLE 9: CAPECITABINE DOSE ADJUSTMENT LEVELS 
 
Dose Level 
Capecitabine 
0 
500mg tid
-1 
500mg tid alternating with 500mg bid 
-2 
500mg bid 


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4.4.2 
DOSE ADJUSTMENT LEVELS FOR CYCLOPHOSPHAMIDE 
 
 
TABLE 10: CYCLOPHOSPHAMIDE DOSE ADJUSTMENT LEVELS 
 
Dose Level 
Cyclophosphamide 
0 
50mg daily
-1 
50mg daily alternating with 25mg daily 
-2 
25mg daily 
 
 
4.4.3 
DOSE ADJUSTMENT LEVELS FOR LAPATINIB 
 
 
TABLE 11: LAPATINIB DOSE ADJUSTMENT LEVELS 
 
Dose Level 
Lapatinib 
0 
1000mg daily
-1 
750mg daily 
-2 
500mg daily 
 
 
4.4.4 
DOSE ADJUSTMENT GUIDELINES FOR TRASTUZUMAB 
 
Trastuzumab dose modifications are not permitted. Trastuzumab doses may be 
delayed as a result of adverse events. 
 
 
4.4.5 
OFF-TREATMENT 
 
In cases where the Hematologic Toxicities do not resolve to a Grade ≤2 Adverse 
Events or Non-Hematologic Toxicities do not resolve to a Grade ≤1 Adverse Event 
after two subsequent dose adjustments, and / or the investigator determines no clinical 
benefit is being derived; patients will have their treatment interrupted.  If after three 
weeks of no improvement, the patient will be permenantely taken off treatment. 
 
 
4.4.6 
MISSED DOSE OF ORAL MEDICATIONS 
 
Patients will be instructed on how and when to take the medications at home. They 
will be provided with a Daily Dose Diary1 and instructed on how to complete the form. 
They will also be informed to bring the completed diary and pill bottles with them to 
their next study visits, until discontinuation. 
 
In the event a patient misses one day of dose (all three oral medications) or a single 
medication with a daily dose, they will be instructed to: 
 
1. 
Record the missed medication(s) on the Daily Dose Diary 
2. 
Resume normal medication dose(s) on the following day 
 
If a patient misses >2 consecutive days of dose (all three oral medications) or a single 
medication within the daily dose >2 consecutive times, they will be instructed to: 
 
 
1 This study will utilize the CRIC / CISO standard Daily Dose Diary form. 


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1. 
Record the missed medication(s) on the Daily Dose Diary 
2. 
Contact the study team for instructions 
 
 
4.5 
CONCOMITANT MEDICATIONS 
 
The following table shows potential drug interactions with lapatinib: 
 
 
TABLE 12: POTENTIAL DRUG INTERACTIONS WITH LAPATINIB 
 
Lapatinib is a substrate for CYP3A4. Inducers and inhibitors of CYP3A4 may alter the 
metabolism of lapatinib. The following list of CYP3A4 inducers and inhibitors are prohibited 
from screening through discontinuation from study. 
Drug 
Class 
Specific Agents 
Wash-out1 
CYP3A4 Inducers 
rifamycin 
antibiotic 
s 
rifampicin, rifabutin, 
rifapentine 
 
 
 
 
 
2 weeks 
anticonv 
ulsants 
phenytoin, 
carbamezepine, 
barbiturates (e.g., 
phenobarbital) 
antiretrov 
irals 
efavirenz, nevirapine, 
tipranivir, etravirine 
 
glucocort 
ical 
steroids 
(oral 
only) 
cortisone (>50 mg), 
hydrocortisone (>40 mg), 
prednisone or 
prednisolone (>10 mg), 
methylprednisolone or 
triamcinolone (>8 mg), 
betamethasone or 
dexamethasone (>1.5 
mg)2 
other 
St. John’s Wort, modafinil 
CYP3A4 Inhibitors 
antibiotic 
s 
clarithromycin, 
erythromycin, 
troleandomycin 
 
 
 
 
 
1 week 
antifunga 
ls 
itraconazole, 
ketoconazole, fluconazole 
(>150 mg daily), 
voriconazole 
antiretrov 
irals 
delaviridine, nelfinavir, 
amprenavir, ritonavir, 
indinavir, saquinavir, 
lopinavir, atazanavir 
calcium 
channel 
blockers 
verapamil, diltiazem 


UNIVERSITY OF SOUTHERN CALIFORNIA/KENNETH NORRIS, JR.
COMPREHENSIVE CANCER CENTER AND HOSPITAL 
27 
CONFIDENTIAL 
This material is the property of the University Of southern California/ Norris Comprehensive Cancer Center. Do not disclose or use except as authorized in writing by 
the study sponsor. 
 
 
 
 
antidepre 
ssants 
nefazodone, fluvoxamine 
 
gastroint 
estinal 
agents3 
cimetidine 
fruit 
juices 
grapefruit, star fruit, and 
papaw 
other 
amiodarone 
6 months 
Miscellaneous 
antacids 
Mylanta, Maalox, Tums, 
Rennies 
1 hour before 
and after dosing
herbal 
supplem 
ents4 
ginkgo biloba, kava, grape 
seed, valerian, ginseng, 
echinacea, evening 
primrose oil 
2 weeks 
1.   Time period between last dose of listed drug and first dose of lapatinib, required to 
avoid drug-drug interaction potential for toxicity (inhibitors) or loss of efficacy 
(inducers) that could make the patient unevaluable.  Clinically appropriate 
substitution of drugs not on the list is recommended. 
2.   A standard 3-5 day course of dexamethasone at a dose following the institutions 
standard of care for the prevention and/or treatment of platinum-induced nausea 
and vomiting is allowed.  Glucocortical steroid oral dose equivalents (in 
parentheses) to dexamethasone 1.5 mg (or less) given daily are allowed. 
Intravenous dosing should be considered if clinically appropriate. 
3.   Emetogenic chemotherapy may require 3-4 daily doses of aprepitant.  CYP3A4 
inhibition by oral (not IV) aprepitant may require a concurrent dose reduction of 1-2 
lapatinib tablets. 
4.   This list is not all-inclusive; therefore, for herbal supplements not listed, please 
contact a NOVARTIS Medical Monitor or Clinical Scientist. 
NOTE: If future changes are made to the list of prohibited medications, 
formal documentation will be created and stored with the study file. 
Any changes will be communicated to the investigative sites in the form 
of a letter. 
 
An additional list of medications can be found in Appendix I. 
 
 
4.6 
DURATION OF THERAPY 
 
In the absence of treatment delays due to adverse events, treatment may continue until: 
 
•  Disease progression 
•  Inter-current illness that prevents further administration of treatment 
•  Unacceptable adverse event(s) 
•  Patient decides to withdraw from the study, OR 
•  General or specific changes in the patient’s condition render the patient unacceptable for 
further treatment in the judgment of the investigator”. 


UNIVERSITY OF SOUTHERN CALIFORNIA/KENNETH NORRIS, JR.
COMPREHENSIVE CANCER CENTER AND HOSPITAL 
28 
CONFIDENTIAL 
This material is the property of the University Of southern California/ Norris Comprehensive Cancer Center. Do not disclose or use except as authorized in writing by 
the study sponsor. 
 
 
 
 
4.7 
REMOVAL OF PATIENTS FROM PROTOCOL THERAPY 
 
Investigators, co-investigators, or clinical personnel associated with the study have the 
discression to withdraw participants from the whole study or portions of this study based on 
safety concerns that would add additional and untoward risks to the participant.  Study 
participants may withdraw from the study.  Participants who wish to withdraw consent must do 
so in writing. They may choose to continue follow-up and to have their data used for current 
and future projects. They may also choose to withdraw consent and to have any associated 
research data discarded.  However, in the event of participant withdrawal of consent, any prior 
work done with their data will remain in the data set and will be unable to be removed. 
Participant withdrawal of consent will not affect any clinical data that have already been utilized 
in analysis. 
 
 
 
4.8 
DURATION OF FOLLOW-UP 
 
Patients will be followed for one year after removal from treatment or until death, whichever 
occurs first. Patients removed from treatment for unacceptable adverse events will be followed 
until resolution or stabilization of the adverse event. The follow-up period will consist of either 
two telephone calls and / or two clinic visits occurring at three month intervals. 
 
 
 
5.0 
STUDY PROCEDURES 
 
A summary of required evaluations is presented on the following study calendar. 
 
 
TABLE 13: STUDY VISIT SCHEDULE 
 
 
Study Procedure 
Visit Schedule 
Screening 
1 
Each 
cycle2 
Every 2 
cycles 
Every 3 
cycles 
End of 
treatment 
Follow 
Up 
Eligibility Review 
X 
 
 
Informed 
Consent3 
 
X 
 
 
 
 
 
Demographic 
Information 
 
X 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
Toxicity 
Assessment 
 
X 
 
X 
 
 
X 
 
Performance 
Status 
 
X 
 
X 
 
 
X 
 
Physical 
Examination 
 
X 
 
X 
 
 
X 
 
CBC with 
differential 
 
X 
4 
X 
 
 
X 
 
Electrolytes, BUN, 
Creatinine, Mg 
 
X 
 
X 
 
 
X 
 
LFT (AST, ALT, 
alkaline 
phosphatase, 
bilirubin) 
 
 
X 
 
 
4 
X 
 
 
 
X 
 


UNIVERSITY OF SOUTHERN CALIFORNIA/KENNETH NORRIS, JR.
COMPREHENSIVE CANCER CENTER AND HOSPITAL 
29 
CONFIDENTIAL 
This material is the property of the University Of southern California/ Norris Comprehensive Cancer Center. Do not disclose or use except as authorized in writing by 
the study sponsor. 
 
 
 
 
 
Study Procedure 
Visit Schedule
Screening 
1 
Each 
cycle2 
Every 2 
cycles
Every 3 
cycles
End of 
treatment 
Follow 
Up
Pregnancy test5 
X 
X
X 
 
Ejection Fraction 
(MUGA/Echo)6 
 
X 
 
 
X 
X 
 
Imaging studies 
(CT/MRI)7 
 
X 
 
X 
 
X 
 
Treatment 
(detailed in Section 4.1) 
 
 
X 
X 
X 
 
 
Daily Dose Diary 
(Patient Completed) 
 
 
X 
X 
X 
 
 
Death 
 
 
X
1= Within 28 days before the first dose of study treatment. 
2= Within 1 day of treatment. 
3= Informed consent may be obtained >28 days before the first dose of study treatment but must have been signed before any study-specific 
screening procedures or evaluations are performed. 
4= During cycle 1 CBC and LFT will be evaluated weekly. 
5= For participants of childbearing potential. Test will be serum and / or blood (at the discression of the ordering physician). 
6= The same method of assessment and radiographic center should be used throughout the study. 
7= Imaging studies include a chest CT and contrast-enhanced CT or MRI of the abdomen and pelvis. 
 
 
 
 
6.0 
MEASUREMENT OF EFFECT 
 
The outcome status (in terms of toxicity, response, reason off study, progression, and survival) of all 
eligible patients will be reported. All eligible patients who begin treatment will be included in the analysis 
of response, survival and time-to-failure. 
 
Response will be evaluated according to the RECIST criteria v1.1: 
 
Measurable lesions - lesions that can be accurately measured in at least one dimension with 
longest diameter ≥10 mm and 2x slice thickness on CT scan.  Lymph nodes must be >15 mm in 
short axis.  Bone lesions may be measurable if there is a lytic/soft tissue component that meets 
minimum size criteria. CXR lesions must be >20 mm. 
 
Non-measurable lesions - all other lesions, including small lesions (i.e. longest diameter <10mm 
or pathologic lymph nodes with 10-15mm short axis) or lesions not conventionally measurable (i.e. 
leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast disease, 
lymphangitis cutis/pulmonis, cystic lesions, and also abdominal masses that are not confirmed). 
 
•   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 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. 
• 
Clinical lesions will only be considered measurable when they are superficial (e.g., skin 
nodules and palpable lymph nodes). For the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended. 


UNIVERSITY OF SOUTHERN CALIFORNIA/KENNETH NORRIS, JR.
COMPREHENSIVE CANCER CENTER AND HOSPITAL 
30 
CONFIDENTIAL 
This material is the property of the University Of southern California/ Norris Comprehensive Cancer Center. Do not disclose or use except as authorized in writing by 
the study sponsor. 
 
 
 
 
6.1 
METHODS OF MEASUREMENT 
 
CT and MRI are the best currently available and reproducible methods to measure target 
lesions selected for response assessment. Conventional CT and MRI should be performed with 
cuts of 10 mm or less in slice thickness contiguously. Spiral CT should be performed using a 5 
mm contiguous reconstruction algorithm. This applies to tumors of the chest, abdomen and 
pelvis. Head and neck tumors and those of extremities usually require specific protocols. 
 
Lesions on chest X-ray are acceptable as measurable lesions when they are clearly defined and 
surrounded by aerated lung. However, CT is preferable. 
 
When the primary endpoint of the study is objective response evaluation, ultrasound (US) 
should not be used to measure tumor lesions. It is, however, a possible alternative to clinical 
measurements of superficial palpable lymph nodes, subcutaneous lesions and thyroid nodules. 
US might also be useful to confirm the complete disappearance of superficial lesions usually 
assessed by clinical examination. 
 
Cytology and histology can be used to differentiate between PR and CR in rare cases (e.g., 
after treatment to differentiate between residual benign lesions and residual malignant lesions in 
tumor types such as germ cell tumors). 
 
 
6.1.1 
BASELINE DOCUMENTATION OF “TARGET” AND “NON-TARGET” LESIONS 
 
All measurable lesions up to a maximum of five lesions total (2 per organ), 
representative of all involved organs should be identified as target lesions and 
recorded and measured at baseline. 
 
Lymph node measurements should reflect the short diameter. 
 
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and their suitability for accurate repeated measurements (either by imaging 
techniques or clinically). 
 
A sum of the longest diameter (LD) for all target lesions will be calculated and reported 
as the baseline sum LD. The baseline sum LD will be used as reference by which to 
characterize the objective tumor. 
 
All other lesions (or sites of disease) should be identified as non-target lesions and 
should also be recorded at baseline. Measurements of these lesions are not required, 
but the presence or absence of each should be noted throughout follow-up. 
 
Non-measurable and non-target lesions are included in determination of progression if 
new sites of disease develop or if unequivocal progression occurs in the opinion of the 
treating physician. 
 
 
6.2 
RESPONSE CRITERIA 


31 
CONFIDENTIAL 
This material is the property of the University Of southern California/ Norris Comprehensive Cancer Center. Do not disclose or use except as authorized in writing by 
the study sponsor. 
UNIVERSITY OF SOUTHERN CALIFORNIA/KENNETH NORRIS, JR.
COMPREHENSIVE CANCER CENTER AND HOSPITAL 
 
 
 
 
 
 
 
6.2.1 
EVALUATION OF TARGET LESIONS 
 
 
TABLE 14: TARGET LESION EVALUATION TABLE 
 
* Complete Response (CR): 
Disappearance of all target lesions 
* Partial Response (PR): 
At least a 30% decrease in the sum of the LD of target 
lesions, taking as reference the baseline sum LD 
* Progressive Disease (PD): 
At least a 20% increase in the sum of the LD of target 
lesions, taking as reference the smallest sum LD recorded 
since the treatment started or the appearance of one or 
more new lesions 
* Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest 
sum LD since the treatment started 
 
 
6.2.2 
EVALUATION OF NON-TARGET LESIONS 
 
 
TABLE 15: NON-TARGET LESION EVALUATION TABLE 
 
* Complete Response (CR): 
Disappearance of all non-target lesions and normalization 
of tumor marker level 
* Incomplete Response / 
Stable Disease (SD): 
Persistence of one or more non-target lesion(s) or/and 
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 (1) 
(1) Although a clear progression of “non target” lesions only is exceptional, in such circumstances, the opinion of the treating 
physician should prevail and the progression status should be confirmed later on by the review panel (or study chair). 
 
 
6.2.3 
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 PD the smallest 
measurements recorded since the treatment started). In general, the patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria: 
 
 
TABLE 16: EVALUATION OF BEST OVERALL RESPONSE TABLE 
 
 
Target lesions 
 
Non-Target lesions 
New Lesions 
Overall response 
 
CR 
 
CR 
No 
CR 


32 
CONFIDENTIAL 
This material is the property of the University Of southern California/ Norris Comprehensive Cancer Center. Do not disclose or use except as authorized in writing by 
the study sponsor. 
UNIVERSITY OF SOUTHERN CALIFORNIA/KENNETH NORRIS, JR.
COMPREHENSIVE CANCER CENTER AND HOSPITAL 
 
 
 
 
 
 
 
Target lesions 
 
Non-Target lesions 
New Lesions 
Overall response 
 
CR 
Incomplete 
response/SD
No 
PR 
 
PR 
 
Non-PD 
No 
PR 
 
SD 
 
Non-PD 
No 
SD 
 
PD 
 
Any 
Yes or No 
PD 
 
Any 
 
PD 
Yes or No 
PD 
 
Any 
 
Any 
Yes 
PD 
 
• 
Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
classified as having “symptomatic deterioration”. Every effort should be made to 
document the objective progression even after discontinuation of treatment. 
• 
In some circumstances it may be difficult to distinguish residual disease from 
normal tissue. When the evaluation of complete response depends on this 
determination, it is recommended that the residual lesion be investigated (fine 
needle aspirate/biopsy) to confirm the complete response status. 
 
 
 
6.3 
CONFIRMATION 
 
• 
The main goal of confirmation of objective response is to avoid overestimating the response 
rate observed.  In cases where confirmation of response is not feasible, it should be made 
clear when reporting the outcome of such studies that the responses are not confirmed. 
• 
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed 
by repeat assessments that should be performed no less than 4 weeks after the criteria for 
response are first met. Longer intervals as determined by the study protocol may also be 
appropriate. 
• 
In the case of SD, follow-up measurements must have met the SD criteria at least once after 
study entry at a minimum interval (in general, not less than 6-8 weeks) that is defined in the 
study protocol 
 
 
6.3.1 
DURATION OF OVERALL RESPONSE 
 
• 
The duration of overall response is measured from the time measurement criteria 
are met for CR or PR (whichever status is recorded first) until the first date that 
recurrence  or  PD  is  objectively  documented,  taking  as  reference  for  PD  the 
smallest measurements recorded since the treatment started. 


33 
CONFIDENTIAL 
This material is the property of the University Of southern California/ Norris Comprehensive Cancer Center. Do not disclose or use except as authorized in writing by 
the study sponsor. 
UNIVERSITY OF SOUTHERN CALIFORNIA/KENNETH NORRIS, JR.
COMPREHENSIVE CANCER CENTER AND HOSPITAL 
 
 
 
 
 
 
6.3.2 
DURATION OF STABLE DISEASE 
 
• 
SD  is  measured  from  the  start  of  the  treatment  until  the  criteria  for  disease 
progression are met, taking as reference the smallest measurements recorded 
since the treatment started. 
• 
The clinical relevance of the duration of SD varies for different tumor types and 
grades. Therefore, it is highly recommended that the protocol specify the minimal 
time interval required between two measurements for determination of SD. This 
time interval should take into account the expected clinical benefit that such a 
status may bring to the population under study. 
 
 
6.3.3 
PROGRESSION-FREE SURVIVAL 
 
From the date of registration to date of first documentation of progression or symptomatic 
deterioration (as defined in above), or death due to any cause. Patients last known to 
be alive without report of progression are censored at date of last contact. 
 
 
6.3.4 
OVERALL SURVIVAL 
 
From the date of registration to date of death due to any cause. Patients last known to 
be alive are censored at date of last contact. 
 
 
 
7.0 
ADVERSE EVENTS 
 
7.1 
ADVERSE EVENT MONITORING 
 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of Participants enrolled in the studies as well as those who will enroll 
in future studies using similar agents. Adverse events are reported in a routine manner at 
scheduled times during a trial. Additionally, certain adverse events must be reported in an 
expedited manner to allow for optimal monitoring of patient safety and care. 
 
All patients experiencing an adverse event, regardless of its relationship to study drug, will be 
monitored until: 
• 
the adverse event resolves or the symptoms or signs that constitute the adverse event 
return to baseline; 
• 
any abnormal laboratory values have returned to baseline; 
• 
there is a satisfactory explanation other than the study drug for the changes observed; or 
death. 
 
7.2 
DEFINITIONS 
 
7.2.1 
DEFINITION OF ADVERSE EVENT 
An adverse event (AE) is any untoward medical occurrence in a patient receiving study 
treatment and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use 
of an experimental intervention, whether or not related to the intervention. 


34 
CONFIDENTIAL 
This material is the property of the University Of southern California/ Norris Comprehensive Cancer Center. Do not disclose or use except as authorized in writing by 
the study sponsor. 
UNIVERSITY OF SOUTHERN CALIFORNIA/KENNETH NORRIS, JR.
COMPREHENSIVE CANCER CENTER AND HOSPITAL 
 
 
 
 
 
 
7.2.2 
SEVERITY OF ADVERSE EVENTS 
All adverse events will be graded according to the NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0. The CTCAE v4 is available at 
http://ctep.cancer.gov/reporting/ctc.html 
 
If no CTCAE grading is available, the severity of an AE is graded as follows: 
Mild (grade 1): the event causes discomfort without disruption of normal daily activities. 
Moderate (grade 2): the event causes discomfort that affects normal daily activities. 
Severe (grade 3): the event makes the patient unable to perform normal daily activities 
or significantly affects his/her clinical status. 
Life-threatening (grade 4): the patient was at risk of death at the time of the event. 
Fatal (grade 5): the event caused death. 
 
7.2.3 
SERIOUS ADVERSE EVENTS 
 
A serious adverse event is an undesirable sign, symptom or medical condition 
which: 
• 
is fatal or life-threatening 
• 
results in persistent or significant disability/incapacity 
• 
constitutes a congenital anomaly/birth defect 
• 
requires inpatient hospitalization or prolongation of existing 
hospitalization, unless hospitalization is for: 
• 
routine treatment or monitoring of the studied indication, not 
associated with any deterioration in condition (specify what this 
includes) 
• 
elective or pre-planned treatment for a pre-existing condition that is 
unrelated to the indication under study and has not worsened since 
the start of study drug 
• 
treatment on an emergency outpatient basis for an event not fulfilling 
any of the definitions of a SAE given above and not resulting in 
hospital admission 
• 
social reasons and respite care in the absence of any deterioration in 
the patient’s general condition 
• 
is medically significant, i.e., defined as an event that jeopardizes the 
patient or may require medical or surgical intervention to prevent one of 
the outcomes listed above 
 
The principal investigator has the obligation to report all serious adverse 
events to the FDA, IRB, and Novartis Pharmaceuticals Drug Safety and 
Epidemiology Department (DS&E) (For patients taking Lapatinib / Novartis 
drugs). 
 
All events reported to the FDA by the investigator are to be filed utilizing the 
Form FDA 3500A (MedWatch Form).  
 
To ensure patient safety, every SAE, regardless of suspected causality, 
occurring 
• 
after the patient has provided informed consent and until atleast 30 days 
after the patient has stopped study treatment/participation 


35 
CONFIDENTIAL 
This material is the property of the University Of southern California/ Norris Comprehensive Cancer Center. Do not disclose or use except as authorized in writing by 
the study sponsor. 
UNIVERSITY OF SOUTHERN CALIFORNIA/KENNETH NORRIS, JR.
COMPREHENSIVE CANCER CENTER AND HOSPITAL 
 
 
 
 
 
• 
after protocol-specified procedures begin (e.g., placebo run-in, washout 
period, double-blind treatment, etc.) and 30 days after the patient has 
stopped study treatment 
• 
after the start of any period in which the study protocol interferes with the 
standard medical treatment given to a patient (e.g., treatment withdrawal 
during washout period, change in treatment to a fixed dose of 
concomitant medication) and until 30 days after the patient has stopped 
study treatment 
 
must be reported to Novartis within 24 hours of learning of its occurrence  
Information about all SAEs is collected and recorded on a Serious Adverse 
Event Report Form; all applicable sections of the form must be completed in 
order to provide a clinically thorough report. The investigator must assess and 
record the relationship of each SAE to each specific study treatment (if there is 
more than one study treatment), complete the SAE Report Form in English, 
and send the completed, signed form by fax to (fax: 877-778-9739) within 24 
hours to the oncology Novartis DS&E department with the provided FAX cover 
sheets. 
 
This includes serious, related, labeled (expected) and serious, related, 
unlabeled (unexpected) adverse experiences. All deaths during treatment or 
within 30 days following completion of active protocol therapy must be reported 
within 5 working days. 
 
Any SAEs experienced after this 30 days period should only be reported to 
Novartis if the investigator suspects a causal relationship to the study drug. 
Recurrent episodes, complications, or progression of the initial SAE must be 
reported as follow-up to the original episode within 24 hours of the investigator 
receiving the follow-up information. A SAE occurring at a different time interval 
or otherwise considered completely unrelated to a previously reported one 
should be reported separately as a new event.  The end date of the first event 
must be provided. 
 
The original copy of the SAE Report and the fax confirmation sheet must be 
kept within the Trial Master File at the study site. 
 
Follow-up information is sent to the same fax number as the original SAE 
Report Form was sent, using a new fax cover sheet, stating that this is a 
follow-up to the previously reported SAE, and giving the date of the original 
report. Each re-occurrence, complication, or progression of the original event 
should be reported as a follow-up to that event regardless of when it occurs. 
The follow-up information should describe whether the event has resolved or 
continues, if and how it was treated, whether the blind was broken or not (if 
applicable), and whether the patient continued or withdrew from study 
participation. 
 


36 
CONFIDENTIAL 
This material is the property of the University Of southern California/ Norris Comprehensive Cancer Center. Do not disclose or use except as authorized in writing by 
the study sponsor. 
UNIVERSITY OF SOUTHERN CALIFORNIA/KENNETH NORRIS, JR.
COMPREHENSIVE CANCER CENTER AND HOSPITAL 
 
 
 
 
 
If the SAE is not previously documented in the Lapatinib Investigator Brochure 
or Package Insert (new occurrence) and is thought to be related to the Novartis 
study drug, a DS&E associate may urgently require further information from the 
investigator for Health Authority reporting. Novartis may need to issue an 
Investigator Notification (IN), to inform all investigators involved in any study 
with the same drug that this SAE has been reported. Suspected Unexpected 
Serious Adverse Reactions (SUSARs) will be collected and reported to the 
competent authorities and relevant ethics committees in accordance with 
Directive 2001/20/EC or as per national regulatory requirements in participating 
countries. 
 
To ensure patient safety, each pregnancy occurring while the patient is on 
study treatment must be reported to Novartis within 24 hours of learning of its 
occurrence. 
 
Any event that does not meet the above criteria, but that in the judgment of the 
investigator jeopardizes the patient, may be considered for reporting as a serious 
adverse event. The event may require medical or surgical intervention to prevent one 
of the outcomes listed in the definition of “Serious Adverse Event“. 
 
Addition to SAE definition 
Cardiovascular events have been seen in participants taking other compounds that 
inhibit ErbB2 when used in combination with or following anthracyclines, and interstitial 
pneumonitis has been reported in participants taking compounds that inhibit ErbB1. As 
a precaution, the following will be reported as an SAE: 
 
• 
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 left ventricular cardiac ejection fraction relative to 
baseline which is below the institution's lower limit of normal.  Refer to NCI CTCAE 
grading of left ventricular cardiac function.   
• 
Any signs or symptoms of pneumonitis that are Grade 3 (NCI CTCAE) (defined as 
radiographic changes and requiring oxygen).  Refer to NCI CTCAE grading of 
pneumonitis/pulmonary infiltrates. 
 
Hepatobiliary events have been seen in participants taking lapatinib and other tyrosine 
kinase inhibitors.  As a precaution, the following will be reported as an SAE: 
 
• 
ALT >3 × ULN and total bilirubin >2.0 × ULN (>35% direct; bilirubin fractionation 
required) or ALT>3xULN and INR>1.5, if INR measured (INR measurement is not 
required and the threshold value stated will not apply to participants receiving 
anticoagulants). 
 
NOTE:  bilirubin fractionation should be performed if testing is available.  If testing is 
unavailable and a participant meets the criterion of total bilirubin >2.0 × ULN, then 
record presence of detectable urinary bilirubin on dipstick, indicating direct bilirubin 
elevations and suggesting liver injury. The event should still be reported as an SAE. 
 
Other hepatic events should be documented as an AE or an SAE as appropriate. 
 
 


37 
CONFIDENTIAL 
This material is the property of the University Of southern California/ Norris Comprehensive Cancer Center. Do not disclose or use except as authorized in writing by 
the study sponsor. 
UNIVERSITY OF SOUTHERN CALIFORNIA/KENNETH NORRIS, JR.
COMPREHENSIVE CANCER CENTER AND HOSPITAL 
 
 
 
 
 
7.3 
STEPS TO DETERMINE IF AN ADVERSE EVENT REQUIRES EXPEDITED REPORTING 
 
Step 1: 
Identify the type of adverse event using the NCI Common Terminology 
Criteria for Adverse Events (CTCAE v4). 
 
Step 2: 
Grade the adverse event using the NCI CTCAE v4. 
 
Step 3: 
Determine whether the adverse event is related to the protocol therapy 
 
Attribution categories are as follows: 
- 
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 unlikely related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
Note: This includes all events that occur within 30 days of the last dose of protocol 
treatment. Any event that occurs more than 30 days after the last dose of treatment 
and is attributed (possibly, probably, or definitely) to the agent(s) must also be 
reported accordingly. 
 
Step 4: 
Determine the prior experience of the adverse event. 
Expected events are those that have been previously identified as resulting from 
administration of the agent. An adverse event is considered unexpected, for 
expedited reporting purposes only, when either the type of event or the severity of 
the event is not listed in the current known adverse events listed in the Drug 
Information Section (section 4.0) of this protocol; 
• 
the drug package insert; 
• 
the current Investigator’s Brochure 
 
7.4 
REPORTING REQUIREMENTS FOR ADVERSE EVENTS 
 
7.4.1 
EXPEDITED REPORTING 
 
• 
The Principal Investigator must be notified within 24 hours of learning of any serious 
adverse events, regardless of attribution, occurring during the study or within 30 days 
of the last administration of the study drug. 
• 
SAEs will be reported to NOVARTIS and the FDA within 24 hours of learning of any 
serious adverse events, regardless of attribution, occurring during the study or within 
30 days of the last administration of the study drug. 
o To facilitate submission, the Prinicipal Investigator can submit to NOVARTIS 
and FDA via the MedWatch Form 3500A to the FDA, which can be accessed at: 
http://www.accessdata.fda.gov/scripts/MedWatch/ 
 
•  FDA Reporting 
MedWatch forms will be sent to the FDA online at the above internet address 
or to the following: 
MEDWATCH 
5600 Fishers Lane 
Rockville, MD  20852-9787 
(F) - 1-800-FDA-0178 (1-800-332-0178) 


38 
CONFIDENTIAL 
This material is the property of the University Of southern California/ Norris Comprehensive Cancer Center. Do not disclose or use except as authorized in writing by 
the study sponsor. 
UNIVERSITY OF SOUTHERN CALIFORNIA/KENNETH NORRIS, JR.
COMPREHENSIVE CANCER CENTER AND HOSPITAL 
 
 
 
 
 
 
•  NOVARTIS Reporting 
    Fax: 877-778-9739 
  
• 
The Institutional IRB must be notified of “any unanticipated problems involving risk to 
participants or others” in accordance with the Institutional policy. Such policies will be 
provided to the CISO QA prior to enrolling 1st patient. (for USC refer to HSPP Policies 
and Procedures chapter 14 available at 
http://www.usc.edu/admin/oprs/policies/hspp.html UPR/UPIRSO). 
 
The following events meet the definition of UPR: 
1. 
Any serious event (injuries, side effects, deaths or other problems), which in the 
opinion of the Principal Investigator was unanticipated, involved risk to 
participants or others, and was possibly related to the research procedures. 
2. 
Any serious accidental or unintentional change to the IRB-approved protocol that 
alters the level of risk. 
3. 
Any deviation from the protocol taken without prior IRB review to eliminate 
apparent immediate hazard to a research participant. 
4. 
Any new information (e.g., publication, safety monitoring report, updated sponsor 
safety report), interim result or other finding that indicates an unexpected change 
to the risk/benefit ratio for the research. 
5. 
Any breach in confidentiality that may involve risk to the participant or others. 
6. 
Any complaint of a participant that indicates an unanticipated risk or that cannot 
be resolved by the Principal Investigator. 
 
• 
The USC NCCC Data and Safety Monitoring Committee (DSMC) must be notified within 
24 hours of submission of such reportable event to the IRB. The patient ID and the study 
number as well as identifier of the SAE report should be submitted to the DSMC 
Coordinator via email or Fax to the attention of the DSMC Coordinator at 323-865-0089. 
 
7.4.2 
ROUTINE REPORTING 
All other adverse events- such as those that are expected, or are unlikely or definitely 
not related to the study participation- are to be reported annually as part of regular 
data submission.  For studies requiring USC DSMC review, this report should also be 
forwarded to the DSMC Coordinator. 
 
 
 
8.0 
DRUG INFORMATION 
Patients who enroll in this study will follow the treatment and dosage schedule (Section 4.1). There are 
four study drugs – 3 are commercially available, 1 will be provided by the Sponsor. 
 
8.1 
STUDY DRUGS – COMMERCIALLY AVAILABLE 
These drugs are commercially available and FDA approved for treatment of breast cancer. 
 
8.1.1 
CAPECITABINE (XELODA®) 


39 
CONFIDENTIAL 
This material is the property of the University Of southern California/ Norris Comprehensive Cancer Center. Do not disclose or use except as authorized in writing by 
the study sponsor. 
UNIVERSITY OF SOUTHERN CALIFORNIA/KENNETH NORRIS, JR.
COMPREHENSIVE CANCER CENTER AND HOSPITAL 
 
 
 
 
 
Capecitabine is an oral prodrug of 5’-deoxy-5-fluorouridine (5’DFUR) that is converted 
to 5’fluorouracil (5-FU). 5-FU is metabolized to 5-fluoro-2-deoxyuridine 
monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP) which cause cell 
injury in two ways. First, FdUMP and the folate cofactor, N5-10- 
methylenetetrahydrofolate, bine to thymidylate synthase to form a covalently bound 
ternary complex which inhibits the formation of thymidylate from uracil. Thymidylate is 
essential for the synthesis of DNA so a deficiency inhibits cell division. Secondly, 
nuclear transcriptional enzymes can mistakenly incorporate FUTP in place of uridine 
triphosphate during RNA synthesis; this interferes with RNA processing and protein 
synthesis. Capecitabine is commercially available (Xeloda®) and supplied in 150mg 
(light peach colored) and 500mg (film coated) tablets. Additional guidance and 
information regarding the marketed product capecitabine (Xeloda) can be found in the 
current capecitabine product labeling information. 
 
8.1.2 
CYCLOPHOSPHAMIDE (CYTOXAN®) 
Cyclophosphamide is an alkylating agent that is biotransformed principally in the liver 
to its primary active metabolite, phosphoramide mustard. Phosphoramide mustard 
forms inter-strand and intra-strand DNA crosslinks by covalently binding to N7 
guanines, and also causes single-strand DNA breaks. Cyclophosphamide is 
commercially available (Cytoxan®) and supplied in 25mg and 50mg tablets. Additional 
guidance and information regarding the marketed product cyclophosphamide 
(Cytoxan®) can be found in the current cyclophosphamide product labeling 
information. 
 
8.1.3 
TRASTUZUMAB (HERCEPTIN®) 
Trastuzumab is a HER2/neu receptor antagonist indicated for the treatment of HER2- 
overexpressing breast cancer. Trastuzumab is commercially available (Herceptin®) 
and provided as a sterile, white to pale yellow, preservative free lyophilized powder for 
intravenous (IV) administration. Each vial of trastuzumab contains 440mg of 
trastuzumab, 9.9mg of L-histidine HCl, 6.4mg of L-histidine, 400mg of α,α-trehalose 
dihidrate, and 1.8mg of polysorbate 20, USP. Reconstitution with 20ml of the supplied 
Bacteriostatic Water for Injection (BWFI) USP, containing 1.1% benzyl alcohol as a 
preservative, yields 21mL of a multidose solution containing 21mg/mL trastuzumab, at 
a pH of ~6. Additional guidance and information regarding the marketed product 
trastuzumab (Herceptin®) can be found in the current trastuzumab product labeling 
information. 
 
8.2 
STUDY DRUG – SPONSOR PROVIDED 
This drug is being provided by the Sponsor, GlaxoSmithKline. This drug is also approved by the FDA 
for treatment of breast cancer. 
 
8.2.1 
LAPATINIB (TYKERB®) 
Lapatinib is a 4-anilinoquinazoline kinase inhibitor of the intracellular tyrosine kinase 
domains of both epidermal growth factor receptor (EGFR) and human epidermal 
receptor type 2 (HER2). Lapatinib is commercially available (Tykerb®) and provided as 
a 250mg oval, biconvex, orange film-coated tablets with one side plain and the 
opposite side debossed with FG HLS. Each 250mg tablet of lapatinib contains 405mg 
of lapatinib ditosylate monohydrate, equivalent to 250mg lapatinib free base per tablet. 
Additional guidance and information regarding the marketed product lapatinib 
(Tykerb®) can be found in the current lapatinib product labeling information. 
 


40 
CONFIDENTIAL 
This material is the property of the University Of southern California/ Norris Comprehensive Cancer Center. Do not disclose or use except as authorized in writing by 
the study sponsor. 
UNIVERSITY OF SOUTHERN CALIFORNIA/KENNETH NORRIS, JR.
COMPREHENSIVE CANCER CENTER AND HOSPITAL 
 
 
 
 
 
 
 
9.0 
STATISTICAL CONSIDERATIONS 
 
9.1 
PATIENT ACCRUAL 
 
The study will enroll a total of 40 patients with HER-2 positive metastatic breast cancer.  We 
expect the study to be open to accrual for approximately 24 months. 
 
 
9.2 
STATISTICAL ANALYSES AND POWER CALCULATIONS FOR THE PRIMARY OBJECTIVES 
 
 
9.2.1 
STATISTICAL ANALYSIS FOR THE PRIMARY OBJECTIVE 
 
In the reported literature, when capecitabine and lapatinib were used to treat patients 
with HER-2 positive metastatic breast cancer, a median PFS of 8.4 months was 
reported 23. In our study, we propose a treatment regimen which adds well-tolerated 
metronomic cyclophosphamide and trastuzumab to capecitabine plus lapatinib, hence 
it is expected that this 4-drug regimen would result in a better PFS. One-sided one- 
sample logrank test will be used to evaluate the improvement in PFS compared to the 
reported historical PFS rate. 
 
 
9.2.2 
POWER OF THE STATISTICAL ANALYSIS FOR THE PRIMARY OBJECTIVE 
 
In the calculation of power, the PFS function of HER-2 positive metastatic breast 
cancer patients treated with capecitabine and lapatinib was approximated using the 
Kaplan-Meier PFS curves shown in Figure 2A of the published literature23. From 
Figure 2A of that paper, patients with HER-2 positive breast cancer treated with 
capecitabine and lapatinib had a 0.5-year PFS of approximately 54% and a 1-year 
PFS of approximately 18%. The median PFS for those patients was 8.4 months. 
 
As stated above, this study will be open to enrollment for approximately 2 years at a 
rate of 20 patients per year. A total of 40 patients will be enrolled. Given that most 
patients would progress within a year, the study will have one additional year for 
follow-up. The power for the comparison between PFS among this study cohort and 
that of the historical data was estimated for a detection of a difference in hazard ratio 
of 0.67, i.e., 1/3 decrease in hazard for disease progression. That corresponds to a 
PFS rate of approximately 66% at 0.5-year and 32% at 1-year in our patients, 
comparing to 54% and 18% at 0.5-year and 1-year in the historical data. With 10% 
type I error, a one-sided logrank test will have at least 80% power for detecting a 
hazard ratio of 0.67 with a sample size of 40 patients. This sample size and power are 
sufficient. 
 
 
9.3 
FUTILITY ANALYSIS 
 
One futility analysis will be performed during the trial, after first 20 patients are enrolled, by 
testing the following at the level of 0.005: 


4 1 
C O N FI D E N TI A L 
T his mat eri al is t h e pr o p ert y of t h e U ni versit y Of s o ut h er n Calif or ni a/ N orris C o m pre h e nsi ve Ca ncer C e nt er. D o n ot discl ose or use e xc e pt as a ut h ori ze d i n writi n g b y 
t h e st u d y s p o ns or. 
U NI V E R SI T Y O F S O U T H E R N C A LI F O R NI A/ K E N N E T H N O R RI S, J R.
C O M P R E H E N SI V E C A N C E R C E N T E R A N D H O S PI T A L 
 
 
 
 
 
l n
 
 
 1 
  l n 0. 6 7
 
 
1  
#
 
 
I n t h e f or m ul a, t h e n u m b er 0. 6 7 i s t h e H a z ar d R ati o f or pr o gr e s si o n ( c o m p ar e d t o t h e hi st ori c al 
d at a 2 3 ) u n d er t h e alt er n ati v e h y p ot h e si s f or t h e d e si g n of t hi s tri al.  B a s e d o n t h e a s s u m e d m o d el, 
at t h e e n d of t h e 1 st y e ar aft er t h e tri al st art s, a p pr o xi m at el y 6 e v e nt s ar e e x p e ct e d t o  h a v e 
o c c urr e d u n d er t h e alt er n ati v e h y p ot h e si s. Wit h 6 e v e nt s, it will b e v er y u nli k el y t o t er mi n at e t h e 
tri al d u e t o f utilit y at t h e e n d of t h e 1st y e ar. 
 
 
9. 4
 I N T E RI M M O NI T O RI N G O F T O XI CI TI E S  
 
T o xi citi e s m o nit ori n g will b e a d o pti n g a B a y e si a n a p pr o a c h. W e a s s u m e t h at t h e n u m b er of 
p ati e nt s e x p eri e n ci n g u n a c c e pt a bl e t o xi citi e s ( a s li st e d i n S e cti o n 4. 2. 1 ) a m o n g p ati e nt s w h o ar e 
e nr oll e d f oll o w s a bi n o mi al  di stri b uti o n, a n d t h at t h e pri or di strib uti o n of t h e pr o b a bilit y of t o xi cit y 
f oll o w s a u nif or m di stri b uti o n. A s af et y a n al y si s will b e u n d ert a k e n aft er a n i niti al 6 p ati e nt s ar e 
e nr oll e d a n d h a v e r e c ei v e d at l e a st 1 c y cl e of tr e a t m e nt. I n a d diti o n, i nt eri m m o nit ori n g a n al y si s 
of t o xi citi e s will b e p erf or m e d aft er e v er y 3 o c c urr e n c e s of u n a c c e pt a bl e t o xi citi e s t h at ar e li st e d 
i n  S e cti o n 4. 2. 1 .  At e a c h i nt eri m a n al y si s of t o xi citi e s, t h e p o st eri or di stri b uti o n of t h e pr o b a bilit y 
f or a p ati e nt t o e x p eri e n c e a n y u n a c c e pt a bl e t o xi cit y (p t o x) will b e c al c ul at e d. If it i s > 9 2. 7 % li k el y 
t h at p t o x≥0. 1 5, t h e st u d y will b e s u s p e n d e d p e n di n g D S M C a n d st u d y c o m mitt e e r e vi e w. 
Ot h er wi s e t h e tri al will c o nti n u e a s pl a n n e d. A si m u l ati o n st u d y s h o w e d t h at u si n g t hi s t o xi cit y 
m o nit ori n g r ul e, t h er e will b e 2 7 % pr o b a bilit y t o s u s p e n d/t er mi n at e t h e tri al if t h e tr u e t o xi cit y 
r at e i s 1 5 %. T h e pr o b a bilit y f or s u s p e n di n g/t er mi n ati n g t h e tri al i s 5 3 % if t h e tr u e t o xi cit y r at e i s 
2 0 %, a n d t h e pr o b a bilit y i s 8 0 % if t h e tr u e t o xi cit y r at e i s 2 6 %. S u s p e n si o n/ e arl y t er mi n ati o n 
pr o b a bilit y i s ar o u n d 5 % w h e n t h e tr u e t o xi cit y r at e i s 8 %. E x p e ct e d s a m pl e si z e i s 3 9, 3 4, 2 7, 
a n d 2 0, r e s p e cti v el y, f or t h e t o xi cit y r at e of 8 %, 1 5 %, 2 0 % or 2 6 %. Pl e a s e r ef er t o t h e fi g ur e 
b el o w f or t h e pr o b a bilit y of s u s p e n si o n/t er mi n ati o n a n d e x p e ct e d s a m pl e si z e f or diff er e nt 
t o xi cit y r at e s. 


42 
CONFIDENTIAL 
This material is the property of the University Of southern California/ Norris Comprehensive Cancer Center. Do not disclose or use except as authorized in writing by 
the study sponsor. 
UNIVERSITY OF SOUTHERN CALIFORNIA/KENNETH NORRIS, JR.
COMPREHENSIVE CANCER CENTER AND HOSPITAL 
 
 
 
 
 
Average N 
Prob. of Susp./Early Term. 
 
 
1.0 
0.9 
0.8 
0.7 
0.6 
0.5 
0.4 
0.3 
0.2 
0.1 
0.0 
40 
 
 
 
30 
 
 
 
20 
 
 
 
10 
 
 
 
0 
0.0 
0.1 
0.2 
0.3 
0.4 
0.5 
0.6 
Toxicity Probability 
 
Prob. of Suspension/Early Termination 
Average N 
 
 
 
 
 
 
9.5 
MONITORING OF TOXIC DEATHS 
 
There will not be a formal statistical rule for the monitoring of toxic deaths. However, for any 
occurrence of toxic deaths, we will immediately notify the Data Safety and Monitoring 
Committee (DSMC – see Section 10.7) of USC Norris Comprehensive Cancer Center and the 
study committee and it will be reviewed within 24 hours. 
 
 
 
10.0 
STUDY MANAGEMENT 
 
 
10.1 
CONFLICT OF INTEREST 
 
All investigators will follow the University conflict of interest policy. Any USC investigator who 
has a conflict of interest with this study (patent ownership, royalties, or financial gain greater 
than the minimum allowable by their institution, etc.) must complete a “Statement of Outside 
Interests Related to Research” Form. The application is reviewed and approved by the Conflict 
of Interest Review Committee (CIRC) USC conflict of interest policy is available at 
http://ooc.usc.edu/conflict-interest-research 
 
 
10.2 
INSTITUTIONAL REVIEW BOARD (IRB) APPROVAL AND CONSENT PROCESS 
 
It is expected that the IRB will have the proper representation and function in accordance with 
federally mandated regulations. The IRB should approve the consent form and protocol and all 
study related documents used in the study (e.g. pill diary, brochure, advertisement etc). 


UNIVERSITY OF SOUTHERN CALIFORNIA/KENNETH NORRIS, JR.
COMPREHENSIVE CANCER CENTER AND HOSPITAL 
43 
CONFIDENTIAL 
This material is the property of the University Of southern California/ Norris Comprehensive Cancer Center. Do not disclose or use except as authorized in writing by 
the study sponsor. 
 
 
 
 
 
 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) and to 
ethical principles that have their origin in the Declaration of Helsinki. 
 
Before recruitment and enrollment onto this study, the patient will be given a full explanation of 
the study and will be given the opportunity to review the consent form. Each consent form must 
include all the relevant elements currently required by the FDA Regulations and local or state 
regulations. Once this essential information has been provided to the patient and the 
investigator is assured that the patient understands the implications of participating in the study, 
the patient will be asked to give consent to participate in the study by signing a dated 
IRB-approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be signed 
and personally dated by the patient and by the person authorized to obtain the informed consent 
 
 
10.3 
REGISTRATION PROCEDURES 
 
For patients enrolled at USC, the Research Coordinator must complete the protocol eligibility 
form to ensure that the patient is eligible. The PI will review the patient eligibility (with assistance 
from the Research Coordinator- who will assemble the required source documents, and do an 
initial review) prior to registering the patient on study. 
 
The Research Coordinator or data manager will then register the patient into the Cancer Center 
database, CAFÉ, by accessing the Registration forms. Likewise, after the patient has completed 
the study, the Off Study forms in cafe will need to be completed, for Off Treatment and Off 
Study. 
 
 
10.4 
RECORDS AND DATA SUBMISSION 
 
 
A.  Confidentiality of Records 
The original data collection forms will be kept in secure file cabinets, for USC patients 
forms will be kept in the Clinical Investigations Support Office (CISO). 
 
B.  Patient Consent Form 
At the time of registration, signed and dated copies of the patient Informed Consent with 
the Human Rights and the HIPAA authorization must be given to the patient. Institutional 
policy regarding distribution and location of original consent documents should be 
followed. When a study is opened at two or more institutions, a copy of the signed 
consent and HIPAA should be sent to USC CISO QA team as soon as possible, and not 
later than within 5 business days of obtaining consent.  For patients consented at 
USC/LAC, institutional policy should be followed: a copy of ICF and HIPAA should be 
uploaded through  True to USC CRO and to CISO QA Team. The original will be kept in 
the patient research chart maintained by the study assigned Data Manager. 
 
C.  Registration Eligibility Worksheet 
At the time of registration, the completed Eligibility Worksheet will be submitted to the 
QA Monitor at CISO for review of eligibility compliance. 
 
D.  Data Collection Forms and Submission Schedule 


UNIVERSITY OF SOUTHERN CALIFORNIA/KENNETH NORRIS, JR.
COMPREHENSIVE CANCER CENTER AND HOSPITAL 
44 
CONFIDENTIAL 
This material is the property of the University Of southern California/ Norris Comprehensive Cancer Center. Do not disclose or use except as authorized in writing by 
the study sponsor. 
 
 
 
 
 
Protocol data will be entered into eCRFs in CAFÉ. 
 
Within two weeks of registration, the data manager will complete the initial set of On- 
Study forms and baseline Toxicities. 
 
Within two weeks of completion of each course of treatment, the data manager must 
complete the Course Assessment, Toxicities, and if appropriate Response data. 
 
•  After Off Treatment, within two weeks of each follow up, complete the Follow Up 
forms. 
 
 
10.5 
DATA MANAGEMENT AND MONITORING / AUDITING 
 
 
A. 
Adherence to Protocol/Per Patient: It is the responsibility of the USC Principal 
Investigator (PI) to ensure that patient recruitment and enrollment, treatment, follow-up 
for toxicities and response, and documentation and reporting at USC are all performed 
as specified in the protocol. When a study is opened at two or more institutions, the PI at 
each institution will assume the responsibilities for the day-to-day monitoring of the trial, 
as described below. 
 
B. 
Day-to-Day Monitoring – Eligibility:  At USC, the Study Coordinator will assist the 
Investigator in reviewing eligibility and will assemble the required source documents, and 
do a final review by completing an Eligibility Registration Worksheet. When a study is 
opened at two or more institutions, the PI at each institution will review the patient 
eligibility in accordance with that institution’s policy..  For all institutions, the Eligibility 
Registration Worksheet with a copy of Informed Consent and supporting source 
documents will be submitted to CISO QA via email or Fax for verification prior to 
registering the patient on study. 
 
C. 
Day-to-Day Monitoring – Informed Consent: Prior to registering the patient on study, 
the Study Coordinator will review the informed consent, to ensure that the patient has 
signed and dated the most current IRB-approved form, and that the form has been 
signed and dated by the person obtaining the consent as well as appropriate witnesses. 
A copy of the ICF will also be provided to CISO QA for review. CISO SOP 3.3 will be 
followed. 
 
D. 
Day-to-Day Monitoring – Treatment: The PI and co-investigators are responsible for 
ensuring that treatment is given per protocol. The Study Coordinator will review the 
treatment orders with the treating investigator. Regardless of who the treating physician 
is, there will be only one responsible Study Coordinator for each study at each of the 
hospitals affiliated with the USC Norris Cancer Center. The treating investigator will 
review the status of each patient on-study, with the Study Coordinator and treating 
physicians, on an on-going basis. When a study is opened at two or more institutions, 
CISO QA will periodically audit medical records for the participants on study at other 
institutions to ensure compliance and adherence to the protocol. 
 


UNIVERSITY OF SOUTHERN CALIFORNIA/KENNETH NORRIS, JR.
COMPREHENSIVE CANCER CENTER AND HOSPITAL 
45 
CONFIDENTIAL 
This material is the property of the University Of southern California/ Norris Comprehensive Cancer Center. Do not disclose or use except as authorized in writing by 
the study sponsor. 
 
 
 
 
E. 
Data Management – Patient Charts: When a study is opened at two or more 
institutions, the policy in place at each institution will be followed for maintaining medical 
and research related records. Such policies will be provided to the CISO QA prior to 
enrolling 1st patient.  At USC, All written source documents not associated with the study 
research are maintained in the patient chart, which is stored in the Department of 
Medical Records at the appropriate hospital. At the Norris Hospital, the official medical 
record is the Electronic Patient File (EPF). Radiographical images are stored in the 
Department of Radiology and in an electronic system called Synapse. At Los Angeles 
County General Hospital the official medical record is called Affinity. These are the 
permanent, official documents for each patient on-study. A copy of the signed informed 
consent, physician’s notes, orders, test results and pathology notes are maintained in 
the patients’ hospital charts. It is the responsibility of the research staff to ensure that the 
patient chart contains the required documents and work closely with treating 
investigators to ensure all protocol-related assessments are carefully documented. 
 
F. 
Data Management – Research Charts: When a study is opened at two or more 
institutions, the policy in place at each institution will be followed for maintaining medical 
and research related records. Such policies will be provided to the CISO QA prior to 
enrolling 1st patient.  At USC, to facilitate adherence to the protocol schedule and data 
management, research charts are created to collect copies of the relevant notes, orders 
and results, that are in the Patient Chart. In Addition, all source documents related to the 
research, such as original informed consent forms, HIPAA Forms, AE assessment 
worksheets, disease response worksheets and NTFs are maintained in the Research 
Charts. Protocol calendars, worksheets, and checklists, are also kept in the research 
chart. These are maintained in the Clinical Investigation Support Office until the study is 
completed and the results are published and no further need is anticipated. These are 
then stored off-site. It is the responsibility of the Data Manager to ensure that the 
research chart contains all the required documents. 
 
G. 
Data Management – Case Report Forms: It is the responsibility of the Data Manager 
to complete the required case report forms. For in-house trials, case report forms are 
developed for each trial; these are used to finalize the data entry screens in the Cancer 
Center clinical trials database. It is the responsibility of the PI to review the Off-Study 
Summary form which summarizes pertinent toxicity, response and adherence 
information, once the patient has completed treatment. 
 
 
10.6 
QUALITY ASSURANCE MONITORING COMMITTEE (QAMC) OVERSIGHT 
 
The Quality Assurance and Monitoring Committee (QAMC) of the NCCC has the responsibility 
for study auditing and monitoring for protocol compliance, data accuracy, performance of audits 
and monitoring of accrual. QAMC procedures are detailed in the NCCC Data Safety and 
Monitoring Plan available on CISO Website. 
 
 
10.6.1 
QAMC ANNUAL PATIENT AUDITS 
 
The QAMC is responsible for conducting audits and providing the initial review of the 
audits, for all open institutional (i.e. USC initiated), CCCP-sponsored trials, and any 
trials identified by the CIC.  These trials are audited by the QAMC once a year. Faculty 
and staff at the Cancer Center involved in clinical research – but not directly involved 
in the research under evaluation – are asked to serve as auditors. Twenty percent of 
patients accrued during the past 12 months – and a minimum of 2 patients – are 


UNIVERSITY OF SOUTHERN CALIFORNIA/KENNETH NORRIS, JR.
COMPREHENSIVE CANCER CENTER AND HOSPITAL 
46 
CONFIDENTIAL 
This material is the property of the University Of southern California/ Norris Comprehensive Cancer Center. Do not disclose or use except as authorized in writing by 
the study sponsor. 
 
 
 
 
selected at random; however, additional patients may be selected for audit if there is 
some indication that there might have been a problem or unusual circumstance 
(possibly related to compliance, toxicity, response or some indication of an 
irregularity). The audit involves a review of the research chart, hospital medical record 
(i.e., source documentation) and evaluates the following: documentation of eligibility 
(including failure to obtain appropriate informed consent) and baseline status of the 
patient; documentation of adherence to protocol-specified treatment and follow-up; 
evaluation of toxicity; and evaluation of response or other outcome. In addition, for 
investigative agents, a drug audit is also performed for these patients by the Research 
Pharmacist. In addition, for Institutional, Investigator Initiated Trials, Data in the CAFÉ 
database are compared to the information in the medical record. 
 
 
10.6.2 
QAMC ANNUAL PROTOCOL REVIEW 
 
All open trials are reviewed at least once a year by the QAMC (or more often if 
stipulated by the CIC). This annual review includes the following: evaluation of the 
current accrual relative to the planned total accrual; examination of gender and 
minority accrual; examination of all reported violations; review of past audits and 
correspondence with the PI; review of results of current audit (by an outside agency or 
by the NCCC QAMC); review of previous correspondence between the PI and the 
QAMC/DSMC. The QAMC review process is detailed in USC NCCC DSM Plan 
available on the CISO website. 
 
 
10.7 
DATA AND SAFETY MONITORING COMMITTEE (DSMC) OVERSIGHT 
 
The Data and Safety Monitoring Committee (DSMC) is an independent body responsible for the 
safety of study participants through the review of new protocols to ensure an adequate adverse 
event assessment/reporting plan, study stopping rules and through the real-time and periodic 
monitoring of severe adverse events (SAEs) or those AEs that require expedited reporting. The 
DSMC performs quarterly and annual safety reviews as well as interim efficacy/futility analyses 
on institutional trials. DSMC procedures are detailed in USC NCCC DSM Plan available on the 
CISO website. 
 
 
10.8 
ADHERENCE TO THE PROTOCOL 
 
Except for an emergency situation in which proper care for the protection, safety, and well-being 
of the study patient requires alternative treatment, the study shall be conducted exactly as 
described in the approved protocol. 
 
 
10.8.1 
EMERGENCY MODIFICATIONS 
 
Investigators may implement a deviation from, or a change of, the protocol to eliminate 
an immediate hazard(s) to trial participants without prior IRB approval. 
 
For any such emergency modification implemented, an IRB modification form must be 
completed within five (5) business days of making the change. 
 
 
10.8.2 
NON-EMERGENCY DEPARTURES FROM PROTOCOL 
 
A protocol deviation is any variance from an IRB approved protocol. 


UNIVERSITY OF SOUTHERN CALIFORNIA/KENNETH NORRIS, JR.
COMPREHENSIVE CANCER CENTER AND HOSPITAL 
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This material is the property of the University Of southern California/ Norris Comprehensive Cancer Center. Do not disclose or use except as authorized in writing by 
the study sponsor. 
 
 
 
 
If the deviation meets all of the following criteria, it is considered a minor protocol 
deviation that: 
• 
Is generally noted or recognized only after it occurs 
• 
Has no substantive effect on the risks to research participants 
• 
Has no substantive effect on the scientific integrity of the research plan or the 
value of the data collected 
• 
Did not result from willful or knowing misconduct on the part of the 
investigator(s). 
 
If the deviation meets any of the following criteria, it is considered a protocol violation: 
• 
Has harmed or increased the risk of harm to one or more research 
participants. 
• 
Has damaged the scientific integrity of the data collected for the study. 
• 
Results from willful or knowing misconduct on the part of the investigator(s). 
• 
Demonstrates serious  noncompliance with federal regulations, State laws, or 
University policies. 
 
Protocol Deviations: personnel will report to any sponsor or data and safety 
monitoring committee in accordance with their policies. 
 
Protocol Violations: All protocol violations will be entered in the clinical trial database 
by the Research Coordinator. In addition, Research Coordinator and Investigator 
should report all protocol violations within one (1) week of the knowledge of the event 
using iStar. 
 
 
10.8.3 
AMENDMENTS TO THE PROTOCOL 
 
Should amendments to the protocol be required, the amendments will be originated 
and documented by the Principal Investigator. It should also be noted that when an 
amendment to the protocol substantially alters the study design or the potential risk to 
the patient, a revised consent form might be required. 
 
The written amendment, and if required the amended consent form, must be sent to the 
IRB as well as to Novartis for review and for approval prior to implementation. It is the 
responsibility of the study PI to ensure that the appropriate agencies have been 
informed of the proposed amendments and that these have been reviewed and 
approved. 
 
 
 
10.9 
RECORD RETENTION 
 
Study documentation includes all Case Report Forms, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory 
documents (e.g., protocol and amendments, IRB correspondence and approval, signed patient 
consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research 
study. 
 


UNIVERSITY OF SOUTHERN CALIFORNIA/KENNETH NORRIS, JR.
COMPREHENSIVE CANCER CENTER AND HOSPITAL 
48 
CONFIDENTIAL 
This material is the property of the University Of southern California/ Norris Comprehensive Cancer Center. Do not disclose or use except as authorized in writing by 
the study sponsor. 
 
 
 
 
Government agency regulations and directives require that the study investigator must retain all 
study documentation pertaining to the conduct of a clinical trial. In the case of a study with a drug 
seeking regulatory approval and marketing, these documents shall be retained for at least two 
years after the last approval of marketing application in an International Conference on 
Harmonization (ICH) region. In all other cases, study documents should be kept on file until 
three years after the completion and final study report of this investigational study. 
 
 
 
10.10  OBLIGATIONS OF THE INVESTIGATORS 
 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki. 
The Principal Investigator is responsible for personally overseeing the treatment of all study 
patients. The Principal Investigator must assure that all study site personnel, including sub- 
investigators and other study staff members, adhere to the study protocol and all FDA/GCP/NCI 
regulations and guidelines regarding clinical trials both during and after study completion. 
 
The Principal Investigator at each institution or site will be responsible for assuring that all the 
required data will be collected and entered onto the Case Report Forms. Periodically, 
monitoring visits will be conducted and the Principal Investigator will provide access to his/her 
original records to permit verification of proper entry of data. At the completion of the study, all 
case report forms will be reviewed by the Principal Investigator and will require his/her final 
signature to verify the accuracy of the data. 
 
 
 
11.0 
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UNIVERSITY OF SOUTHERN CALIFORNIA/KENNETH NORRIS, JR.
COMPREHENSIVE CANCER CENTER AND HOSPITAL 
49 
CONFIDENTIAL 
This material is the property of the University Of southern California/ Norris Comprehensive Cancer Center. Do not disclose or use except as authorized in writing by 
the study sponsor. 
 
 
 
 
 
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15. Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE, Davidson NE, et al. Trastuzumab plus 
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16. Vogel CL, Cobleigh MA, Tripathy D, Gutheil JC, Harris LN, Fehrenbacher L, et al. Efficacy and Safety 
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18. Esteva FJ, Valero V, Booser D, Guerra LT, Murray JL, Pusztai L, et al. Phase II Study of Weekly 
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19. Seidman AD, Fornier MN, Esteva FJ, Tan L, Kaptain S, Bach A, et al. Weekly Trastuzumab and 
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21. Garcia-Saenz JA, Martin M, Puente J, Lopez-Tarruella S, Casado A, Moreno F, et al. Trastuzumab 
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22. Murthy RK, Varma A, Mishra P, Hess KR, Young EJ, Murray JL, et al. Impact of adjuvant trastuzumab 
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23. Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, et al. Lapatinib plus 
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355(26): 2733-43. 
 


UNIVERSITY OF SOUTHERN CALIFORNIA/KENNETH NORRIS, JR.
COMPREHENSIVE CANCER CENTER AND HOSPITAL 
50 
CONFIDENTIAL 
This material is the property of the University Of southern California/ Norris Comprehensive Cancer Center. Do not disclose or use except as authorized in writing by 
the study sponsor. 
 
 
 
 
24. Konecny GE, Pegram MD, Venkatesan N, Finn R, Yang G, Rahmeh M, et al. Activity of the dual kinase 
inhibitor lapatinib (GW572016) against HER-2-overexpressing and trastuzumab-treated breast cancer 
cells. Cancer research. 2006; 66(3): 1630-9. 
 
25. Xia W, Gerard CM, Liu L, Baudson NM, Ory TL, Spector NL. Combining lapatinib (GW572016), a small 
molecule inhibitor of ErbB1 and ErbB2 tyrosine kinases, with therapeutic anti-ErbB2 antibodies 
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26. Scaltriti M, Verma C, Guzman M, Jimenez J, Parra JL, Pedersen K, et al. Lapatinib, a HER2 tyrosine 
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27. Blackwell KL, Burstein HJ, Storniolo AM, Rugo H, Sledge G, Koehler M, et al. Randomized study of 
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33. du Manoir JM, Francia G, Man S, Mossoba M, Medin JA, Viloria-Petit A, et al. Strategies for delaying or 
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34. Rugo HS, Jo Chien A, Franco SX, Stopeck AT, Glencer A, Lahiri S, et al. A phase II study of lapatinib 
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35. Falchook G, Moulder S, Wheler J. Combination of trastuzumab, lapatinib, and bevacizumab in HER2+ 
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36. Hurvitz S, Pegram M, Lin L, Chan D, Allen H, Dichmann R, et al. Final results of a phase II trial 
evaluating trastuzumab and bevacizumab as first line treatment of HER2-amplified advanced breast 
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905. 


UNIVERSITY OF SOUTHERN CALIFORNIA/KENNETH NORRIS, JR.
COMPREHENSIVE CANCER CENTER AND HOSPITAL 
51 
CONFIDENTIAL 
This material is the property of the University Of southern California/ Norris Comprehensive Cancer Center. Do not disclose or use except as authorized in writing by 
the study sponsor. 
 
 
 
 
 
38. Montagna E, Cancello G, Bagnardi V, Pastrello D, Dellapasqua S, Perri G, et al. Metronomic 
Chemotherapy Combined With Bevacizumab and Erlotinib in Patients With Metastatic HER2-Negative 
Breast Cancer: Clinical and Biological Activity. Clinical Breast Cancer. 2012; 12(3): 207-14. 
 
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cancer. BMC cancer. 2006; 6: 225. 


UNIVERSITY OF SOUTHERN CALIFORNIA/KENNETH NORRIS, JR.
COMPREHENSIVE CANCER CENTER AND HOSPITAL 
52 
CONFIDENTIAL 
This material is the property of the University Of southern California/ Norris Comprehensive Cancer Center. Do not disclose or use except as authorized in writing by 
the study sponsor. 
 
 
 
 
 
APPENDIX I: WORD LIST INHIBITORS INDUCERS 
 
INHIBITOR 
Therapeutic class
Substrate 
CYP2C8 
 
 
POTENT INHIBITORS 
 
 
gemfibrozil 
Fibric acid derivatives
Repaglinide 
MODERATE INHIBITORS   
 
deferasirox 
Miscellaneous
Repaglinide 
WEAK INHIBITORS 
 
 
trimethoprim 
Antibiotics
repaglinide 
ketoconazole 
Antifungals
rosiglitazone 
fluvoxamine 
Selective Serotonin Reuptake Inhibitors
rosiglitazone 
 
 
 
CYP3A4 
 
 
POTENT INHIBITORS 
 
 
indinavir /RIT 
Protease Inhibitors
alfentanil 
tipranavir/RIT 
Protease Inhibitors 
midazolam 
ritonavir 
Protease Inhibitors
midazolam 
cobicistat (GS‐9350) 
None
midazolam 
indinavir 
Protease Inhibitors 
vardenafil 
ketoconazole 
Antifungals
midazolam 
troleandomycin 
Antibiotics
midazolam 
Saquinavir/RIT 
Protease Inhibitors 
midazolam 
Itraconazole 
Antifungals
midazolam 
voriconazole 
Antifungals
midazolam 
telaprevir 
Antivirals
midazolam 
mibefradil 
Calcium Channel Blockers
midazolam 
clarithromycin 
Antibiotics
midazolam 
lopinavir / RIT 
Protease Inhibitors
aplaviroc 
elvitegravir / RIT 
Treatments of AIDS
midazolam IV 
posaconazole 
Antifungals 
midazolam 
nelfinavir 
Protease Inhibitors
simvastatin 
telithromycin 
Antibiotics
midazolam 
grapefruit juice DS2 
Food Products 
midazolam 
conivaptan 
Diuretics
midazolam 
nefazodone 
Antidepressants
midazolam 
saquinavir 
Protease Inhibitors 
midazolam 
boceprevir 
Antivirals
midazolam 
MODERATE INHIBITORS   
 
fluconazole 
Antifungals 
midazolam 
atazanavir / RIT 
Protease Inhibitors
maraviroc 
darunavir 
Protease Inhibitors
saquinavir 
erythromycin 
Antibiotics
midazolam 
diltiazem 
Calcium Channel Blockers 
midazolam 
darunavir / RIT 
Protease Inhibitors
sildenafil 
dronedarone 
Antiarrhythmics
simvastatin 


53 
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the study sponsor. 
UNIVERSITY OF SOUTHERN CALIFORNIA/KENNETH NORRIS, JR.
COMPREHENSIVE CANCER CENTER AND HOSPITAL 
 
 
 
atazanavir 
Protease Inhibitors
maraviroc 
aprepitant 
Antiemetics
midazolam 
casopitant 
Antiemetics
midazolam 
amprenavir 
Protease Inhibitors
rifabutin 
imatinib 
Antineoplastic Agents 
simvastatin 
verapamil 
Calcium Channel Blockers
midazolam 
grapefruit juice 
Food Products
midazolam 
tofisopam 
Benzodiazepines 
midazolam 
cyclosporine 
Immunosuppressants
Imidazolam 
ciprofloxacin 
Antibiotics
sildenafil 
schisandra 
sphenanthera 
Herbal Medications 
midazolam 
cimetidine 
H‐2 Receptor Antagonists 
midazolam 
FK1706 
Central Nervous System Agents
midazolam 
WEAK INHIBITORS 
 
 
tabimorelin 
Hormone Replacement 
midazolam 
ranolazine 
Cardiovascular Drugs
simvastatin 
fosaprepitant (IV) 
Antiemetics
midazolam 
Seville orange juice 
Food Products
felodipine 
chlorzoxazone 
Muscle Relaxants 
midazolam 
M100240 
Antihypertensive Agents
midazolam 
fluvoxamine 
Antidepressants
midazolam 
ranitidine 
H‐2 Receptor Antagonists 
midazolam 
goldenseal 
Herbal Medications
midazolam 
clotrimazole 
Antifungals 
midazolam 
tacrolimus 
Immunosuppressants 
midazolam 
cilostazol 
Antiplatelets
lovastatin
peppermint oil 
Food Products
felodipine
roxithromycin 
Antibiotics 
midazolam 
propiverine 
Anticholinergics
midazolam 
isoniazid 
Antibiotics 
triazolam
oral contraceptives 
Oral contraceptives 
triazolam 
delavirdine 
NNRTIs 
indinavir
atorvastatin 
HMG CoA Reductase Inhibitors (Statins)
midazolam IV 
tolvaptan 
Vasopressin Antagonists
lovastatin
linagliptin 
Dipeptidyl Peptidase 4 Inhibitors
simvastatin 
resveratrol 
Food Products 
buspirone 
lacidipine 
Calcium Channel Blockers
simvastatin 
cranberry juice 
Food Products
midazolam 
pazopanib 
Kinase Inhibitors 
midazolam 
nilotinib 
Kinase Inhibitors
midazolam 
AMD070 
Fusion Inhibitors
midazolam 
alprazolam 
Benzodiazepines 
buspirone 
amlodipine 
Calcium Channel Blockers
simvastatin 
bicalutamide 
Antiandrogens
midazolam 
sitaxentan 
Endothelin Receptor Antagonists 
sildenafil 


54 
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the study sponsor. 
UNIVERSITY OF SOUTHERN CALIFORNIA/KENNETH NORRIS, JR.
COMPREHENSIVE CANCER CENTER AND HOSPITAL 
 
 
 
azithromycin 
Antibiotics 
midazolam 
ginkgo 
Herbal Medications
midazolam 
 
 
 
INDUCER 
 
Object 
3A4 
 
 
POTENT INDUCERS 
 
 
rifampin 
 
budesonide 
mitotane 
 
midazolam 
avasimibe 
 
midazolam 
phenytoin 
 
nisoldipine 
carbamazepine 
 
quetiapine 
St John's Wort 
 
midazolam 
rifabutin 
 
delavirdine 
phenobarbital 
 
verapamil 
MODERATE INDUCERS 
 
 
ritonavir and St. Johns 
wort 
 
midazolam 
tipranavir and ritonavir 
 
saquinavir 
bosentan 
 
sildenafil 
nafcillin 
 
nifedipine 
[talviraline] 
 
indinavir 
efavirenz 
 
simvastatin acid
modafinil 
 
triazolam 
etravirine 
 
sildenafil 
WEAK INDUCERS 
 
 
garlic 
 
saquinavir 
amprenavir 
 
lopinavir 
[troglitazone] 
 
simvastatin 
sorafenib 
 
sirolimus 
rufinamide 
 
triazolam 
[pleconaril] 
 
midazolam 
gingko 
 
midazolam 
vinblastine 
 
midazolam IV 
nevirapine 
 
indinavir 
armodafinil (R‐ 
modafinil) 
 
midazolam 
prednisone 
 
tacrolimus 
oxcarbazepine 
 
felodipine 
danshen 
 
midazolam 
echinacea 
 
midazolam 
pioglitazone 
 
midazolam 
dexamethasone 
 
aprepitant 
terbinafine 
 
midazolam 
glycyrrhizin 
 
midazolam 
aprepitant 
 
midazolam IV 
methylprednisolone 
 
cyclosporine 


55 
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the study sponsor. 
UNIVERSITY OF SOUTHERN CALIFORNIA/KENNETH NORRIS, JR.
COMPREHENSIVE CANCER CENTER AND HOSPITAL 
topiramate 
ethinyl estradiol