Conditions: Breast Cancer Brain Tumor - Metastatic
Keywords: Metastatic breast cancer and brain metastases HER-2 Positive Breast Cancer ER-Positive PR-Positive HER-2 Negative Breast Cancer ER-Negative PR-Negative HER2-Negative Breast Cancer
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 36
Healthy volunteers: no

Brief summary:
This research study is evaluating the effectiveness of the drug called cabozantinib (alone or in combination with trastuzumab) as a possible treatment for advanced breast cancer in which the cancer has spread to the brain.

Detailed description:
This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease. "Investigational" means that the intervention is being studied.

The FDA (the U.S. Food and Drug Administration) has not approved cabozantinib for your specific disease but it has been approved for other uses.

Few treatments exist for brain metastases from breast cancer. Radiation and surgery are generally included as a possible standard of care treatments for this diagnosis.

In this research study, the investigator are looking at how well cabozantinib works in treating breast cancer that has spread to the brain. Cabozantinib has been used in some phase I studies and information from those other research studies suggests that cabozantinib may help to shrink or stabilize the participant's breast cancer. In addition, information from these studies has shown that cabozantinib may pass through the blood brain barrier (a protective layer that prevents most large molecules and cells found in the blood from entering the brain tissue) and may be an effective treatment for brain metastases.

If the participant has HER2-positive breast cancer, they will receive trastuzumab in addition to cabozantinib. Trastuzumab is an FDA approved drug for the treatment of HER2-positive metastatic breast cancer. However, the combination of cabozantinib and trastuzumab has not yet been tested. Trastuzumab may help to shrink or stabilize breast cancer in combination with cabozantinib. If the participant's breast cancer is HER2-negative, they will not receive trastuzumab as part of this clinical trial.

The names of the study interventions involved in this study are:

* Cabozantinib (XL184)
* Trastuzumab (herceptin) (participants with HER2-positive disease only)

Arms:
arm 1: HER2-positive

* Cabozantinib- orally administered daily per treatment cycle, 60 mg per day
* Trastuzumab- IV administered once per cycle, 8 mg/kg IV loading dose followed by 6 mg/kg IV Cycle duration equals 3 weeks. Patients are treated indefinitely based on unacceptable toxicity, disease progression, or withdrawal for other reasons. arm 2: Hormone receptor-positive (ER+ and/or PR+)

\- Cabozantinib- orally administered daily per treatment cycle, 60 mg per day Cycle duration equals 3 weeks. Patients are treated indefinitely based on unacceptable toxicity, disease progression, or withdrawal for other reasons. arm 3: Triple negative (ER-, PR-, HER2-)

\- Cabozantinib- orally administered daily per treatment cycle, 60 mg per day Cycle duration equals 3 weeks. Patients are treated indefinitely based on unacceptable toxicity, disease progression, or withdrawal for other reasons.

Interventions: intervention 1: Cabozantinib intervention 2: Trastuzumab
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_SAP_000.pdf: 
Status Page 
 
 
 
PROTOCOL 14-359 
 
 
 
 
 
Permanent  
Closed to New Accrual  
 
 
 
 
 
 
 
 
 
 
 
Closure Effective Date: 06/11/2018 
No new subjects may be enrolled in the study as described above.  
Any questions regarding this closure should be directed to the 
study’s Principal Investigator 
 
 
 
 


Page 1 of 1 
Date Submitted: 10/23/2017 
Alert Page 
DF/HCC Protocol #:  14-359 
 
Revised: 07.01.13 
 
Safety / Drug (includes preparation, administration, dose modifications, 
equations) 
 
 
 
Protocol Section 2.7.6, Section 9.7, Section 10, and Appendix F:  The 
research blood draw for cfDNA will occur at baseline and at end of treatment. 
[Amendment forthcoming] 
 
Protocol Section 10: The research blood draw for Plasma biomarkers should 
occur at baseline, C1D8, C2D1, C3D1, C4D1, C5D1, C6D1 and then every 2 
cycles, and at end of treatment. [Amendment forthcoming]  
 
Protocol Section 10: If the research blood draws are not performed at screening 
then it can be collected on C1D1 prior to the start of treatment.  [Amendment 
forthcoming]  
 
Protocol Section 5.2: Urine protein / creatinine ratio (UCPR) is collected at the 
start every odd cycle beginning C3D1. The UCPR from odd cycles may be used 
as the criteria to treat on even cycles.  
 
 
 


Phase II study of cabozantinib in breast cancer with brain metastases 
 
 
Version 9/ July 17, 2017 
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Protocol Version/Date:  Version 9/ July 17, 2017 
 
NCI Protocol #: N/A 
 
Local Protocol #:  14-359 
 
 
Title:  A Phase II study of cabozantinib alone or in combination with trastuzumab in breast 
cancer patients with brain metastases 
 
 
Principal Investigator:  
Sara Tolaney, MD, MPH 
 
 
 
 
 
 
 
 
   
 
 Dana-Farber Cancer Institute 
 
 
 
 
 
 
 
 
   
 
 450 Brookline Avenue, Y1257 
 
 
 
 
 
 
 
 
   
 
 Boston, MA 02215 
 
Coordinating Center: Dana-Farber Cancer Institute 
 
Co-Investigators:  
Dan G. Duda, DMD, PhD 
 
Steele Laboratory 
 
149 Thirteenth Street, MGH East, CNY 3.407 
  
Charlestown, MA 02129 
 
Email: dan@steele.mgh.harvard.edu 
 
Nancy Lin, MD 
 
450 Brookline Avenue, Yawkey 1237 
 
Dana-Farber Cancer Institute 
 
Boston, MA 02215 
 
Phone: 617-632-2335 
 
Fax: 617-632-1930 
 
Email: nlin@partners.org  
 
 
Eric Winer, MD 
 
450 Brookline Avenue, Yawkey 1244 
 
Dana-Farber Cancer Institute 
 
Boston, MA 02215 
 
Phone: 617-632-6876 
 
Fax: 617-632-1930 
 
Email: ewiner@partners.org  
 
 
Sally Tan 
 
25 Shattuck Street 
 
Boston, MA 02115  
 
Harvard Medical School 
 
Phone: 917-232-5818 
 
Email: sally_tan@hms.harvard.edu  
 


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Study Coordinator:  
Madeline Tenenbaum 
 
 
450 Brookline Ave, Dana 157 
 
 
Boston, MA 02215 
 
 
Phone: 617-632-2342  
 
 
Fax: 617-632-3550 
 
 
Email: Madeline_Tenenbaum@DFCI.HARVARD.EDU  
 
 
Responsible Research Nurse:  Elizabeth Kasparian 
 
 
450 Brookline Ave., Yawkey 1220  
 
 
Boston, MA 02215 
 
 
 
Phone: 617-632-5046 
 
 
Fax: 617-632-3380 
 
 
 
Email: ekasparian@partners.org  
 
 
Agent(s):  Cabozantinib (NSC #; IND# 116866) 
 
 
 


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SCHEMA 
 
 
Eligibility: 
Metastatic breast cancer 
New or progressive CNS lesions, one of which must be measurable 
 
Cohort 2:  
Hormone receptor-
positive  
(ER+ and/or PR+) 
Cohort 3:  
Triple negative 
(ER-, PR-, HER2-) 
REGISTER 
Treatment 
 
cabozantinib  
(21 day cycle) 
Imaging every 
6 weeks 
REGISTER 
Treatment 
 
cabozantinib  
(21 day cycle) 
+ trastuzumab  
(every 3 weeks) 
Imaging every 
6 weeks 
Cohort 1:  
HER2-positive* 
REGISTER 
Treatment 
 
cabozantinib  
(21 day cycle) 
Imaging every 
6 weeks 
* Accrual will be paused when 6 patients have received first doses of cabozantinib and trastuzumab in 
this cohort (see section 5.3 for safety evaluation) 


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TABLE OF CONTENTS 
SCHEMA ....................................................................................................................................... 3 
1. 
OBJECTIVES ................................................................................................................... 8 
1.1 
Study Design ........................................................................................................... 8 
1.2 
Primary Objectives ................................................................................................. 8 
1.3 
Secondary Objectives .............................................................................................. 8 
2. 
BACKGROUND ............................................................................................................... 9 
2.1 
Cabozantinib ........................................................................................................... 9 
2.2 
Cabozantinib Nonclinical Toxicology................................................................... 10 
2.3 
Clinical Experience of cabozantinib ..................................................................... 11 
2.4 
Trastuzumab .......................................................................................................... 16 
2.5 
Brain Metastases in Breast Cancer ...................................................................... 18 
2.6 
Rationale ............................................................................................................... 18 
2.7 
Correlative Studies Background ........................................................................... 22 
3 
PARTICIPANT SELECTION ...................................................................................... 24 
3.1 
Inclusion Criteria .................................................................................................. 24 
3.2 
Exclusion Criteria ................................................................................................. 28 
3.3 
Inclusion of Women, Minorities and Other Underrepresented Populations ........ 31 
4 
REGISTRATION PROCEDURES ............................................................................... 31 
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions ................................. 31 
4.2 
Registration for DF/HCC Institutions .................................................................. 32 
5 
TREATMENT PLAN ..................................................................................................... 33 
5.1 
Treatment Overview ............................................................................................. 33 
5.2 
Pre-treatment Criteria ......................................................................................... 35 
5.3 
Initial Safety Evaluation of cabozantinib + trastuzumab ................................. 36 
5.4 
Agent Administration ........................................................................................... 38 
5.5 
General Concomitant Medication and Supportive Care Guidelines .................... 39 
5.6 
Potential Drug Interactions .................................................................................. 40 
5.7 
Compliance ........................................................................................................... 42 
5.8 
Study Drug Accountability .................................................................................... 43 
5.9 
Duration of Therapy .............................................................................................. 43 


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5.10 
Duration of Follow Up.......................................................................................... 44 
5.11 
Criteria for Removal from Study........................................................................... 44 
6 
EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS 
DUE TO CABOZANTINIB ........................................................................................... 45 
6.1 
Anticipated Toxicities............................................................................................ 45 
6.2 
Dose Modifications/Delays and Toxicity Management ........................................ 45 
6.3 
Management of Adverse Events ............................................................................ 46 
7 
EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS 
DUE TO TRASTUZUMAB ........................................................................................... 65 
7.1 
Recommendations for Dose Modification of Trastuzumab Based on Cardiac 
Monitoring ............................................................................................................. 65 
7.2 
Management of Acute Infusion Syndrome ............................................................ 66 
8 
DRUG FORMULATION AND STORAGE ................................................................. 67 
8.1 
Cabozantinib ......................................................................................................... 67 
8.2 
Trastuzumab .......................................................................................................... 69 
9 
CORRELATIVE / SPECIAL STUDIES METHODS ................................................. 70 
9.1 
Evaluate c-Met and phosphor-c-Met expression in FFPE tumor tissue (and 
optional baseline tumor biopsies, if available) ..................................................... 70 
9.2 
Evaluate the incidence of c-Met positive circulating tumor cells at baseline ...... 70 
9.3 
Evaluate potential plasma biomarkers of cabozantinib ........................................ 71 
9.4 
Cerebral blood volume, blood flow, vessel size, tumor infiltration ...................... 72 
9.5 
Pain Assessments .................................................................................................. 73 
9.6 
Tumor biopsies ...................................................................................................... 74 
9.7 
Blood sample collection ........................................................................................ 74 
10 
STUDY CALENDAR ..................................................................................................... 76 
11 
MEASUREMENT OF EFFECT ................................................................................... 80 
11.1 
Definitions ............................................................................................................. 80 
11.2 
Disease Parameters .............................................................................................. 80 
11.3 
Methods for Evaluation of Measurable Disease ................................................... 82 
11.4 
Response Criteria.................................................................................................. 84 
11.5 
Neurological Signs and Symptoms (NSS) ............................................................. 89 
12 
ADVERSE EVENT REPORTING REQUIREMENTS.............................................. 90 


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12.1 
Definitions ............................................................................................................. 90 
12.2 
Procedures for AE and SAE Recording and Reporting ........................................ 92 
12.3 
Expedited SAE Reporting Guidelines ................................................................... 93 
12.4 
Reporting to the Institutional Review Board (IRB)............................................... 94 
12.5 
Reporting to the Food and Drug Administration (FDA) ...................................... 94 
12.6 
Reporting to the Hospital Risk Management ........................................................ 95 
12.7 
Monitoring of Adverse Events and Period of Observation ................................... 95 
13 
DATA AND SAFETY MONITORING ........................................................................ 95 
13.1 
Data Reporting...................................................................................................... 95 
13.2 
Safety Meetings ..................................................................................................... 96 
13.3 
Monitoring ............................................................................................................ 97 
14 
REGULATORY CONSIDERATIONS ........................................................................ 97 
14.1 
Protocol Review and Amendments........................................................................ 97 
14.2 
Informed Consent .................................................................................................. 97 
14.3 
Ethics..................................................................................................................... 98 
14.4 
Study Documentation ............................................................................................ 98 
14.5 
Records Retention ................................................................................................. 99 
15 
STATISTICAL CONSIDERATIONS .......................................................................... 99 
15.1 
Study Design / Endpoints ...................................................................................... 99 
15.2 
Sample Size / Accrual Rate ................................................................................... 99 
16 
PUBLICATION PLAN ................................................................................................ 102 
REFERENCES .......................................................................................................................... 103 
APPENDIX A:  PERFORMANCE STATUS CRITERIA.................................................... 107 
APPENDIX B:  PAIN QUESTIONNAIRE ............................................................................ 109 
APPENDIX D:  PARTICIPANT’S MEDICATION DIARY ............................................... 112 
APPENDIX E:  NEUROLOGICAL SIGNS AND SYMPTOMS ......................................... 113 
APPENDIX F:  RESEARCH SPECIMEN COLLECTION/SHIPPING GUIDELINES .. 115 
APPENDIX G:  STUDY DRUG ORDER FORM ................................................................. 119 


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APPENDIX H:  STRECK COLLECTION AND PROCESSING INSTRUCTIONS – FOR 
OUTSIDE OF DFCI LAB USE ONLY ....................................................................... 120 


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1. 
OBJECTIVES 
1.1 
Study Design 
This is a two-stage Phase 2 study assessing the efficacy of cabozantinib (alone or in 
combination with trastuzumab) in patients with metastatic breast cancer and brain 
metastases. Cabozantinib is a small molecule inhibitor of multiple receptor tyrosine 
kinases (RTKs) including MET, VEGF receptor-2 (VEGFR2), RET, and KIT, when 
given as monotherapy.  The population to be studied will consist of patients with 
metastatic breast cancer with measurable central nervous system (CNS) lesions.  
Treatment will consist of once daily oral dosing of cabozantinib (60 mg po day), during 
a 21 day cycle.  Patients will also receive trastuzumab (8 mg/kg IV loading dose 
followed by 6 mg/kg IV every 3 weeks) if they have a HER2-positive breast cancer.  
Patients will undergo restaging scans at 6 weeks.  Patients with stable or responsive 
disease after completion of 6 cycles may have the frequency of restaging scans reduced 
to once every 3 cycles. Patients with complete or partial responses, or stable disease, 
will continue to receive cabozantinib.  Patients with progressive disease will be taken off 
study.  Archival tissue from patients will be obtained if possible (please refer to 
Appendix F for archival tissue guidelines); however, if archival tissue is not 
available the patient may still participate in the study.  The patient will have an 
opportunity to participate in an optional tumor biopsy study; however, the biopsy is not 
mandatory to participate in the study.  Goal accrual is 37 patients (up to 40 patients will 
be enrolled), including 21 HER2-positive patients, 8 ER-positive patients, and 8 triple-
negative patients. 
 
1.2 
Primary Objectives 
1) 
To evaluate the CNS objective response rate (ORR), defined by RECIST 1.1, in 
patients with HER2-positive metastatic breast cancer and brain metastases  
1.3 
Secondary Objectives 
1) To evaluate the CNS ORR in patients with hormone receptor positive metastatic 
breast cancer and brain metastases by RECIST 1.1 
2) To evaluate the CNS ORR in patients with triple-negative metastatic breast cancer 
and brain metastases by RECIST 1.1 


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3) To evaluate the CNS ORR in patients with HER2-positive, hormone receptor 
positive, and triple-negative metastatic breast cancer and brain metastases by 
volumetric criteria and composite criteria 
4) To evaluate ORR in non-CNS sites (by RECIST 1.1) 
5) To evaluate Progression-Free Survival (PFS) 
6) To evaluate the clinical benefit rate 
7) To evaluate site of first progression (CNS versus non-CNS) 
8) To evaluate overall survival (OS) in total study population.  
9) To evaluate c-Met and phospho c-Met expression in archival tumor tissue 
10) To evaluate the incidence of c-Met amplified circulating tumor cells at baseline 
11) To evaluate potential plasma biomarkers of cabozantinib when given in combination 
with trastuzumab 
12) To assess vascularity of CNS tumors, through descriptive analysis of tumor vessel 
size, cerebral blood volume, cerebral blood flow, perfusion, and diffusion before and 
after exposure to cabozantinib 
13) To assess the safety and tolerability of cabozantinib when given in combination with 
trastuzumab 
14) To collect blood to study cell-free DNA for comparison to tumor specimens 
 
2. 
BACKGROUND 
2.1 
Cabozantinib 
A summary of cabozantinib clinical and nonclinical experience is contained in the 
Investigator’s Brochure supplied by Exelixis. The Investigator’s Brochure should be 
reviewed in conjunction with this study protocol. 


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Cabozantinib is a new chemical entity that inhibits multiple RTKs with 
growth-promoting and angiogenic properties. The primary targets of cabozantinib are 
RET, MET, VEGFR2/KDR, and KIT (see below).   
Table 1.  Cabozantinib IC50 Values in Biochemical, Enzymatic Assays 
 
Kinase 
IC50 (biochemical) [nM] 
RET 
3.8 
MET 
1.8 
VEGFR2/KDR 
0.035 
KIT 
4.6 
IC50, concentration required for 50 % target inhibition. 
In vivo data from pharmacodynamic experiments show that cabozantinib inhibits key 
RTKs that promote tumor cell proliferation and/or angiogenesis (RET, MET, and 
VEGFR2). In xenograft tumor models, cabozantinib inhibited VEGFR2 phosphorylation 
in lung tissue, with an ED50 of 26 mg/kg. The duration of action for cabozantinib was 
sustained with > 50 % inhibition observed 10-24 hours post-dose at a dose level of 
100 mg/kg for all targets studied.  
Treatment with cabozantinib shows rapid effects on the tumor endothelium, resulting in 
breakdown of the vasculature beginning 24 hours after administration of cabozantinib, 
thus suggesting potent anti-angiogenic effects of cabozantinib. These effects translate 
into significant tumor growth inhibition after cabozantinib treatment in multiple tumor 
models including human MTC, human breast cancer, human lung carcinoma, and rat 
glioblastoma. Overall, the data generated in vivo demonstrate that the target profile of 
cabozantinib translates to potent anti-angiogenic activity and potent anti-tumor efficacy. 
 
2.2 
Cabozantinib Nonclinical Toxicology 
In nonclinical toxicity studies in rodents and non-rodents, histopathological changes 
associated with cabozantinib administration were observed in gastrointestinal (GI) tract, 
bone marrow, lymphoid tissues, kidney, adrenal, and reproductive tract tissues. 
Histopathological changes present in bone and pancreas were considered secondary to 
cabozantinib administration. Cabozantinib was negative in in vitro bacterial, in vitro 
mammalian cell, and in vivo mammalian genotoxicity bioassays. In reproductive toxicity 


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studies, cabozantinib was embryotoxic in rats, produced fetal soft tissue changes in 
rabbits, and decreased fertility in male and female rats. 
Safety pharmacology studies of cabozantinib administration did not demonstrate adverse 
effects on neurobehavioral or respiratory-system function in rats; furthermore, no 
significant changes in electrocardiographic parameters (including corrected QT [QTc] 
interval) were observed by telemetry in dogs. 
Cabozantinib was not an inhibitor of cytochrome P450 (CYP) 3A4 in vitro and is not 
predicted to have significant effects on CYP3A4 induction. Cabozantinib was shown to 
be an inhibitor of CYP2C8, CYP2C9*3, and CYP2C19 isozymes, in vitro and was also a 
substrate of CYP3A4-mediated metabolism. The mean plasma protein binding by 
cabozantinib in vitro was greater than 98%. 
Additional toxicology information may be found in the Investigator’s Brochure. 
2.3 
Clinical Experience of cabozantinib 
2.3.1 Clinical Summary 
The single agent maximum tolerated dose (MTD) on the once daily (qday) oral dosing 
schedule has been determined to be 60 mg po qday. Details of all studies may be found 
in the Investigator’s Brochure. 
2.3.2 Clinical Safety Profile 
The adverse event (AE) and serious adverse event (SAE) data summarized in the 
following section includes those reported and entered in the clinical database and safety 
database published as of July 2013 (IBv9). The clinical studies with cabozantinib are 
ongoing, thus the AE data from the clinical database does not yet include all SAEs. Data 
from double-blinded studies are not presented. The severity of AEs was assessed using 
the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.  
2.3.3 Adverse Events 
As of February 28, 2013, 1311 subjects have been studied in open-label clinical trials 
with cabozantinib, including treatment with cabozantinib as a single agent. The available 
pooled data in this database include studies XL184-001, XL184-008, XL184-201, 
XL184-203, XL184-205, and XL184-301 cabozantinib arm. The most frequently (≥ 


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12 
20%) observed AEs, regardless of causality, were fatigue (66.7%), diarrhea (63.1%), 
decreased appetite (51.9%), nausea (51.9%), weight decreased (36.0%), PPES (35.9%), 
vomiting (34.1%), constipation (33.2%), dysgeusia (28.0%), hypertension (27.8%), 
dysphonia (26.3%), abdominal pain (23.3%), aspartate aminotransferase (AST) 
increased (23.0%), dyspnea (21.3%), headache (20.9%), rash (20.4%), and ALT 
increased (20.2%). The safety profile of single-agent cabozantinib is consistent across 
tumor types. 
The most frequently (≥ 20%) observed AEs reported as related to cabozantinib, were 
fatigue (60.0%), diarrhea (56.1%), decreased appetite (44.1%), nausea (42.4%), PPES 
(35.6%), weight decreased (29.1%), dysgeusia (27.1%), hypertension (24.0%), vomiting 
(23.5%), dysphonia (22.0%), and AST increased (20.1%). 
The most common AEs (≥ 5%) reported at severity of Grade 3 and above include fatigue 
(15.9%), diarrhea (11.1%), hypertension (9.7%), PPES (8.9%), lipase increased (6.8%), 
PE (5.9%), abdominal pain (5.5%), decreased appetite (5.3%), and asthenia (5.0%).  
Serious Adverse Events 
Out of all 1311 subjects enrolled in open-label, single-agent clinical trials with 
cabozantinib, 688 subjects (52.5%) experienced one or more SAEs recorded in the 
Argus Safety Database, and 300 (22.4%) subjects experienced one or more SAEs that 
were assessed to be related to treatment with cabozantinib. The most commonly reported 
SAEs (≥ 2%) were pulmonary embolism (5.1%), vomiting (3.4%), dehydration (3.2%), 
pneumonia (3.0%), nausea (3.0%), abdominal pain (2.4%), diarrhea (2.4%), deep vein 
thrombosis (DVT; 2.1%), and convulsion (2.0%). subjects), abdominal pain (in three 
subjects), and perirectal abscess (in three subjects). In addition, one late-breaking case of 
reversible posterior leukoencephalopathy syndrome (RPLS) was reported after the data 
cut-off in the double-blinded placebo-controlled Study XL184-301. 
As of 28 February 2013, 192 fatal SAEs were reported (182 on single-agent 
cabozantinib or cabozantinib in combination with other therapies, 10 on placebo) across 
all open-label or unblinded company-sponsored studies (Studies evaluated include 
XL184-001, XL184- 002, XL184-008, XL184-014, XL184-201, XL184-202, XL184-
203, XL184-205, XL184-209, XL184-900, and all clinical pharmacology studies, for a 
total N = 1754). The majority of these SAEs were attributed to disease progression 
(70.3%). Fifty-seven subjects had fatal SAEs that were not attributed to disease 


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progression, and of these 27 subjects had events related to cabozantinib (24 as single 
agent, 3 in combination with erlotinib). 
Detailed information regarding the safety profile of Cabozantinib from all studies may 
be found in the Investigator’s Brochure (version 9).  
2.3.4 Clinical Pharmacokinetics 
Pharmacokinetic (PK) analysis showed dose proportional increases in maximum plasma 
concentration (Cmax) and area under the plasma concentration-vs-time curve (AUC) both 
for the powder-in-bottle (PIB) formulation (dose range: 0.08 to 11.52 mg/kg) and the 
capsule formulation (dose range: 125 mg to 175 mg). Terminal-phase half-life (t1/2, z) 
values were 59.1 to 136 hours. More detailed information regarding cabozantinib PK 
from all studies and product metabolism in humans may be found in the Investigator’s 
Brochure. 
2.3.5 Blood Brain Barrier 
No studies of cabozantinib exposure in cerebrospinal fluid in humans have been 
performed. Two preclinical studies evaluating tissue distribution of cabozantinib in brain 
or CNS tissue have been conducted. In a study employing nude mice dosed orally with 
10 mg/kg cabozantinib, exposure in brain tissue was 1.32 ± 0.083 µM four hours post-
dose, compared to 8.19 ± 0.709 µM in plasma at the same time point. A cabozantinib 
tissue distribution study in pigmented and albino rats has also been performed using 
radiolabeled cabozantinib. The exposure of CNS tissue to cabozantinib-associated 
radioactivity was relatively low (tissue to blood ratio of 0.09-0.10 µg equiv/g) compared 
to most other tissues (e.g. tissue to blood ratios of 2.65 µg equiv/g for liver, 1.28 µg 
equiv/g for lung, and 0.43 µg equiv/g for prostate gland).  
2.3.6 Clinical Activity 
In addition to MTC, cabozantinib has demonstrated findings consistent with broad 
clinical anti-tumor activity in early Phase 1 and Phase 2 studies in several other tumor 
types. In a randomized discontinuation trial (RDT) XL184-203, the following disease 
control rates (DCR = complete response [CR] + partial response [PR] + stable disease 
[SD]) at Week 12 were observed in tumor types including non-small cell lung cancer 
(NSCLC), 38%; breast cancer, 48%; melanoma, 46%; ovarian cancer, 53%; 
hepatocellular carcinoma (HCC), 66%; and CRPC, 66%. In Study XL184-008, clinical 


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activity was also observed in differentiated thyroid cancer (DTC; DCR = 73% at 24 
weeks) and renal cell carcinoma (RCC; median progression-free survival [PFS] = 12.9 
months). Observations of clinical activity have included decrease of soft tissue tumor 
lesions including visceral metastases, effects on metastatic lesions on bone scan (partial 
or complete bone scan resolution), reduction in serum markers of bone resorption and 
formation, reduction in circulating tumor cells (CTCs; subjects with prostate cancer), 
increases in hemoglobin, and improvements in bone pain and reductions in narcotic use 
in subjects with bone metastases. Activity in MTC and CRPC subjects is described in 
more detail below. 
In the placebo-controlled Phase 3 study XL184-301 in 330 MTC subjects, a significant 
increase in median PFS was seen in the cabozantinib arm compared with placebo (11.2 
vs 4.0 months; hazard ratio [HR] =0.28; 95 CIs: 0.19, 0.40). Confirmed PRs occurred in 
28% of cabozantinib-treated subjects and none in the placebo arm; responses were 
durable (median duration 14.6 months). An unplanned administrative analysis of overall 
survival (OS) performed at the request of the FDA with a data cut-off of 15 June 2012 
(75% of required deaths) showed a trend for improved duration of OS in the 
cabozantinib arm compared with placebo (26.0 months vs 20.3 months; HR = 0.83; 95% 
CI: 0.60, 1.14). In the Phase 1 Study XL184-001, with an enriched MTC population, 
PRs were reported in 29% of 35 MTC subjects with measurable disease across all dose 
levels and in 28% of 25 MTC subjects treated at the MTD. The median duration of 
treatment for the subjects in Study XL184-001 with PRs was 17.7 months with one 
subject receiving treatment for 68.4 months on XL184-001 before rolling over onto 
maintenance trial XL184-900 to continue to receive cabozantinib. 
In the Phase 2 study XL184-203, cabozantinib demonstrated broad clinical activity in 
men with CRPC (Smith et al. 2013). During the RDT phase, the majority of CRPC 
subjects with bone metastases and elevated total alkaline phosphatase (t-ALP) levels at 
baseline showed reductions in t-ALP (Smith et al. 2013). Similarly, during the non-
randomized expansion (NRE) phase, the majority of CRPC subjects at the 100 mg 
assigned dose showed reductions in circulating bone specific alkaline phosphatase 
(BSAP) (Smith et al. 2012). These effects were independent of prior or concomitant 
bisphosphonate treatment. Reductions in bone biomarkers were also evident in the 40 
mg CRPC NRE cohort (de Bono et al, 2012). Effects on bone scan were assessed by an 
independent reader, and pain and narcotic use were prospectively assessed using an 
interactive voice recording system (IVRS) and a diary. Subjects achieved a bone scan 


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15 
response (BSR) in both the 100 mg and 40 mg assigned NRE dose cohorts (67% and 
49%, respectively). Among subjects with baseline pain of at least 4 (0-10 scale by Brief 
Pain Inventory [BPI]), a majority had at least a decrease of 30% in the average daily 
worst pain compared with baseline in both cohorts (100 mg: 64% of subjects; 40 mg: 
69% of subjects). In addition, more than half of subjects decreased narcotic use. 
Table 2.  Summary of Clinical Studies of Cabozantinib in Cancer Patients 
Protocol 
Number 
Study 
Population 
Study Title 
Study 
Status 
Phase 1 
XL184-001 
Advanced 
tumors, MTC 
A Phase 1 Dose-Escalation Study of the Safety and 
Pharmacokinetics of XL184 Administered Orally to 
Subjects with Advanced Malignancies 
Complete 
XL184-002 
GB 
A Phase 1 Dose Finding Study of the Safety and 
Pharmacokinetics of XL184 Administered Orally in 
Combination with Temozolomide and Radiation 
Therapy in the First Line Treatment of Subjects with 
Glioblastoma 
Complete – 
analysis 
pending 
XL184-008 
Solid tumors, 
RCC, DTC 
A Phase 1 Drug-Drug Interaction Study of the Effects 
of XL184 on the Pharmacokinetics of a Single Oral 
Dose of Rosiglitazone in Subjects with Solid Tumors 
Complete – 
analysis 
pending 
XL184-014 
Solid tumors 
Phase 1 Multiple Ascending Dose Study of XL184 
Monotherapy in Japanese Subjects with Advanced or 
Metastatic Solid Tumors 
Active, 
enrollment 
ongoing 
Phase 1/2 
XL184-202 
NSCLC 
A Phase 1b/2 Study of XL184 with or without Erlotinib 
in Subjects with Non-Small Cell Lung Cancer 
Complete 
Phase 2 
XL184-201 
GB 
A Phase 2 Study of XL184 in Subjects with Progressive 
or Recurrent Glioblastoma Multiforme in First or 
Second Relapse 
Complete – 
analysis 
pending 
XL184-203 
CRPC, ovarian, 
NSCLC, HCC, 
melanoma, 
breast, 
gastric/GEJ, 
SCLC, 
pancreatic 
A Randomized Discontinuation Study of XL184 in 
Subjects with Advanced Solid Tumors 
Active, 
enrollment 
completed 
XL184-205 
GB 
A Phase 2 Non-Comparative Randomized Open-Label 
Study of Multiple Regimens of Single-Agent XL184 in 
Subjects with Grade IV Astrocytic Tumors in First or 
Second Relapse 
Complete – 
analysis 
pending 
XL184-301 
MTC 
An International, Randomized, Double-Blinded, Phase 
3 Efficacy Study of XL184 Versus Placebo in Subjects 
with Unresectable, Locally Advanced or Metastatic 
Medullary Thyroid Cancer (EXAM) 
Active, 
enrollment 
completed 


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XL184-307 
CRPC 
A Phase 3, Randomized, Double-Blind, Controlled 
Study of Cabozantinib (XL184) vs. Prednisone in 
Metastatic Castration-Resistant Prostate Cancer 
Patients who have Received Prior Docetaxel and Prior 
Abiraterone or Enzalutamide [COMET-1] 
Active, 
enrollment 
ongoing 
XL184-306 
CRPC 
A Phase 3, Randomized, Double-Blind, Controlled 
Trial of Cabozantinib (XL184) vs. Mitoxantrone Plus 
Prednisone in Men with Previously Treated 
Symptomatic Castration-Resistant Prostate Cancer 
[COMET-2] 
Active, 
enrollment 
ongoing 
Maintenance “Roll Over” Study 
XL184-900 
Advanced 
malignancies 
A Maintenance Study Evaluating the Long Term Safety 
of XL184 in Subjects with Advanced Malignancies 
Previously Enrolled in Other XL184 Studies 
Active, 
enrollment 
ongoing 
 
Expanded Access Study 
XL184-209 
MTC 
An Open-Label, Expanded Access Study of 
Cabozantinib (XL184) in Subjects with Unresectable, 
Locally Advanced, or Metastatic Medullary Thyroid 
Cancer 
Active, 
enrollment 
completed 
 
2.4 
Trastuzumab 
2.4.1 Overview 
Trastuzumab is a humanized anti-HER2 antibody that binds to the subdomain IV of the 
HER2 extracellular domain and exerts its antitumor effects by blocking HER2 cleavage, 
stimulating antibody-dependent, cell-mediated cytotoxicity and inhibiting ligand-
independent, HER2-mediated mitogenic signaling. 
2.4.2 Safety profile 
Trastuzumab is a humanized murine antibody. It was engineered so that conserved units 
of the antibody molecule were transcribed from human DNA sequences, while the 
specific anti-HER2 domain remained of mouse DNA origin. As a result of these 
modifications, the antibody is not immunogenic in the vast majority of people. The 
resulting antibody (Herceptin®, Trastuzumab; Genentech) has been studied both as a 
single agent and in combination therapy for metastatic breast cancer. 
Trastuzumab is associated with the potential for left ventricular cardiac dysfunction and 
congestive heart failure (CHF).  In the pivotal trial of trastuzumab for metastatic breast 
cancer, the rate of cardiac dysfunction was highest when given concurrently with 
doxorubicin, with a rate of NYHA class III/IV CHF of 4% in patients receiving 


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trastuzumab with paclitaxel (D. Slamon & Leyland-Jones, 2001). In an adjuvant study of 
carboplatin, docetaxel, and trastuzumab (BCIRG 006), the rate of grade 3 or 4 left 
ventricular cardiac dysfunction was 0.3% and no cardiac deaths were observed (D. 
Slamon, Eiermann, Robert, & Al., 2006). 
Other reported adverse events include infusion reactions, characterized by fever, chills, 
nausea, vomiting, headache, dyspnea, hypotension, and rash. Trastuzumab may also 
exacerbate chemotherapy-induced neutropenia. Very rarely, trastuzumab can result in 
serious and fatal pulmonary toxicity. 
2.4.3 Rationale for Trastuzumab in HER2-positive Breast Cancer 
The HER2/neu oncogene lies on chromosome 17q, and encodes a transmembrane 
glycoprotein (p185) with homology to the epidermal growth factor receptor. 
Overexpression of HER2 at the genetic or protein level is observed in 20 to 25% of all 
breast cancers, and is primarily a consequence of gene amplification (D. J. Slamon et al., 
1987, 1989). 
Trastuzumab has been studied as first-line therapy for metastatic breast cancer. In a study 
of 114 women with HER2-positive tumors who had not previously received chemotherapy 
for advanced breast cancer, a response rate of 26% was observed with single agent 
trastuzumab (Vogel, 2002). Trastuzumab has also been used in combination with other 
chemotherapy to treat women with metastatic breast cancer. In a phase III clinical trial, 
patients with HER2-positive metastatic breast cancer were randomized to receive 
treatment with either chemotherapy, or chemotherapy and trastuzumab given concurrently 
(Slamon et al., 2001). A subsequent analysis of this phase III study has demonstrated that 
initial therapy with trastuzumab and chemotherapy, as opposed to chemotherapy alone, is 
associated with both higher response rates, as well as improved time-to-progression and, 
most significantly, improved overall survival. 
In patients who have progressed on trastuzumab, data from one study supports the concept 
that continuation of trastuzumab beyond progression improves the efficacy of 
chemotherapy on systemic (i.e. extra-CNS) metastases. In a study of 156 patients who had 
previously progressed on trastuzumab-based therapy, the continuation of trastuzumab with 
capecitabine was associated with a doubling of the response rate and improvement in PFS 
compared to capecitabine alone (Von Minckwitz, Vogel, Schmidt, & Al., 2007).  


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Trastuzumab does not cross the blood-brain barrier (Pestalozzi & Brignoli, 2000) and no 
CNS responses to trastuzumab, given intravenously, have been documented in the 
literature. The rationale for including trastuzumab is to maintain maximum disease 
control systematically (i.e. outside of the CNS). It is anticipated that the addition of 
trastuzumab to patients with HER2-positive breast cancer will not alter the primary 
endpoint of CNS objective response. 
 
2.5 
Brain Metastases in Breast Cancer 
It is estimated that approximately 10-15% of women with metastatic breast cancer will 
eventually develop brain metastases (Tsukada, Fouad, Pickren, & Lane, 1983; Tsukada, 
Hurwitz, Kashi, & Al., 1983). It has been noted that several features predict an increased 
risk of CNS recurrence, including young age, African American ethnicity, HER2 
positive or ER-negative primary breast cancer, and the presence of visceral metastases 
(Barnholtz-Sloan et al., 2004). Our group and Dana-Farber was the first to describe an 
increased incidence in women with HER2-positive metastatic breast cancer, of whom up 
to one-third will be diagnosed with brain metastases (Lin, Bellon, & Winer, 2004). More 
recently, a high rate of brain metastases has also been described in patients with triple-
negative (ER, PR, and HER2-negative) tumors with an incidence of 46% (Lin et al., 
2008). Brain metastases are associated with considerable morbidity and mortality. 
   
2.6 
Rationale 
Few treatments exist for such brain metastases from breast cancer. Treatment is mainly 
aimed at palliation, and generally includes whole brain radiation (WBRT), stereotactic 
radiosurgery (SRS), and/or surgical resection.  As systemic therapies have improved, 
CNS progression after WBRT and/or SRS is becoming a significant problem.  Currently 
there is no optimal therapy once this occurs.  Unfortunately, very few prospective 
studies have examined the role of chemotherapy in the treatment of brain metastases 
from breast cancer, and most studies of novel agents have excluded patients with brain 
metastases.  Developing effective agents for the treatment of brain metastases from 
breast cancer is critical. 
Recently, data suggests that anti-angiogenic therapy can be given safely to patients with 
brain metastases, and that clinical activity has been demonstrated.  Norden and 
colleagues reported a retrospective case series of 55 patients treated with bevacizumab 
and chemotherapy in patients with glioma (Norden et al., 2008). Of these patients, 2.3% 


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achieved a complete response, 31.8% partial response, 29.5% minimal response, and 
29.5% stable disease.  Vredenburgh and colleagues treated a total of 35 patients with 
recurrent glioma with irinotecan and bevacizumab and demonstrated a 57% ORR.    
Given the postulated importance of the VEGF pathway in the pathogenesis of brain 
metastases from breast cancer, exploration of anti-angiogenesis approaches for CNS 
metastases from breast cancer is warranted.  Nancy Lin and colleagues have conducted a 
trial of carboplatin + bevacizumab +/- trastuzumab for patient with metastatic breast 
cancer and brain metastases and demonstrated a composite CNS ORR of 63% (Lin et al, 
2013).  
A pre-clinical study in mice by Kodack and colleagues found that treating HER2-
amplified breast cancer patients with a combination of trastuzumab and anti-VEGF 
receptor-2 (VEGFR2) antibody slowed tumor growth in the brain and conferred a 
significant survival benefit. This benefit was postulated to be due to enhanced 
antiangiogenic effects of these two drugs reducing total and functional microvascular 
density in the brain, resulting in more necrosis of brain lesions (Kodack et al., 2012). 
Taken together, these evidence suggest some clinical efficacy of anti-angiogenic therapy 
in treating brain tumors and metastases that warrant further clinical study. 
Evidence shows that inhibiting VEGF alone may only produce a temporary clinical 
response, but that simultaneously inhibiting both VEGF and MET with cabozantinib can 
achieve a more durable clinical benefit. Though VEGF inhibitors alone are 
therapeutically effective for many types of cancer, their clinical benefit often only last 
for several weeks or months before tumor progression recurs. Preclinical studies have 
found that VEGF pathway inhibition initially slows tumor growth and reduces tumor 
vasculature, this is followed by a refractory period of rapid revascularization and 
increased tumor invasiveness (Casanovas, Hicklin, Bergers, & Hanahan, 2005; Ebos et 
al., 2009). Resistance to VEGF pathway inhibition may develop in response to hypoxia. 
Under hypoxic conditions, hypoxia-inducible factor 1α is upregulated, which in turn 
increases expression of both VEGF and MET (Kitajima, Ide, Ohtsuka, & Miyazaki, 
2008; Pennacchietti et al., 2003). These responses are a compensatory mechanism 
during periods of hypoxia, and result in more angiogenesis or migration away from the 
hypoxic zone. Because VEGF pathway inhibition can result in hypoxia, it may also 
subsequently trigger MET expression. Several studies have shown that the MET 
pathway plays an important role in development of resistance to VEGF pathway 
inhibition by sunitinib treatment (Pàez-Ribes et al., 2009; Shojaei et al., 2010). 


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Moreover, additional evidence demonstrates that VEGF inhibitors such as cediranib can 
lead to increased tumor invasiveness and metastasis and higher MET expression levels 
(di Tomaso et al., 2011). Taken together, this suggests that simultaneously targeting both 
MET and VEGF can critically disrupt angiogenesis, tumorigenesis and cancer 
progression. 
Evidence from studies suggests that cabozantinib has anti-angiogenic (anti-VEGFR2) 
activity, CNS penetration, and activity in breast cancer, and could be efficacious in 
treatment of brain metastases from breast cancer.  Cabozantinib inhibits c-met, RET, 
VEGFR2/KDR, and KIT.  The safety and tolerability of cabozantinib have been 
established in a Phase I, single-arm, dose-escalation studies in adult patients with 
advanced solid tumors, and in another Phase Ib trial evaluating the combination of 
cabozantinib and erlotinib.  The most commonly reported drug-related adverse events 
were diarrhea (40%), fatigue (37%), anorexia (31%), nausea (29%), PPE syndrome 
(20%), increased AST (19%), and rash (18%).  Data from a randomized discontinuation 
study in heavily pretreated patients with metastatic breast cancer demonstrated an ORR 
of 14% and a clinical benefit rate at 12 weeks of 48%.  Additionally, there are two 
ongoing studies of cabozantinib in metastatic breast cancer, one in ER+ disease, and one 
in triple-negative breast cancer.  We have noted two patients who likely had brain 
metastases at time of enrollment onto study, though it was unknown at the time, and 
noted that there was treatment effect in the brain with cabozantinib.  One of these 
patients had TNBC, and another had ER+, HER2- breast cancer.  
The c-Met receptor is the only high-affinity receptor for hepatocyte growth factor 
(HGF), also known as scatter factor.  Binding of HGF to the c-Met extracellular ligand-
binding domain results in receptor multimerization and phosphorylation of multiple 
tyrosine kinase residues in the intracellular portion of c-Met.  Activation of c-Met results 
in the binding and phosphorylation of adaptor proteins, such as Gab-1, Grb-2, Shc, and 
c-Cbl, and subsequent activation of signal transducers such as PI3K, STATs, ERK1 and 
2, and FAK (Christensen et al., 2003; Trusolino, Bertotti, & Comoglio, 2001). c-Met and 
HGF are expressed in numerous tissues, and their expression is predominantly confined 
to cells of epithelial and mesenchymal origin, respectively (Trusolino et al., 2001). HGF 
and Met promote cell proliferation, motility, invasion, and stimulate tissue repair and 
tumor growth (Bottaro et al., 1991; Gherardi & Stoker, 1990; Ma, Maulik, Christensen, 
& Salgia, 2003; Nakamura et al., 1989; Stoker, Gherardi, Marion, & Gray, 1987). c-Met 
overexpression, with or without gene amplification, has been reported in a variety of 


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malignancies, including breast, colorectal, lung, gastric, and hepatocellular carcinoma 
(Boix et al., 1994; Kuniyasu, Yasui, Yokozaki, Kitadai, & Tahara, 1993). Elevated 
expression of c-Met has been associated with poor prognosis in breast cancer (Kang et 
al., 2003; Lengyel et al., 2005). Interestingly, data suggests the HGF and c-Met are 
expressed to a greater degree in triple-negative and HER2-positive breast cancer (Camp, 
Rimm, & Rimm, 1999; Sheen-Chen, Liu, Eng, & Al, 2005; Toi et al., 1998; Yamashita 
et al., 1994).  
Mouse models also suggest a critical role of the c-Met pathway during the development 
of triple-negative breast cancer.  Mice harboring mutant c-Met knock-in or mutant c-Met 
transgene under mouse mammary tumor virus promoter, developed breast cancers with a 
triple-negative phenotype (Graveel, DeGroot, Su, & Al, 2009; Ponzo, Lesurf, 
Petkiewicz, & Al, 2009). Additionally, a c-Met-driven pathway signature clustered with 
basal and triple-negative breast cancer from human tissue samples and correlated with 
worse patient outcome (Graveel et al., 2009; Ponzo et al., 2009). These studies suggest 
that c-Met expression and activation is important for initiation and progression of triple-
negative breast cancer. 
C-Met has been found to frequently be coexpressed in HER2+ breast cancer and appears 
to contribute to resistance through sustained AKT activation. Resistance to trastuzumab 
presents a significant barrier to effective treatment of HER2+ breast cancer.  Loss of Met 
function, either through RNA interference-mediate depletion or small molecular 
mediated inhibition, significantly improves the response to trastuzumab (Shattuck, 
Miller, & Carraway, 2008). Conversely, Met activation protects the cells against 
trastuzumab.  The mechanism of resistance likely lies in the ability of Met to drive 
EGFR-independent/ERbB3-dependent PI3K/AKT activation.   
In ER-positive breast cancer cells, activation of the receptor tyrosine kinase by its ligand 
results in increased ER phosphorylation on Ser118 and Ser167 and estrogen-independent 
activation of ER transcriptional activity (Plaza-Menacho, Morandi, Robertson, & Al, 
2010). Expression of RET protein is significantly associated with ER positive tumors 
and with the development of recurrent disease after adjuvant tamoxifen treatment, thus 
along with MET, cotargeting RET may be a potentially important therapeutic target in 
ER-positive and hormone-resistant breast cancers.  
Given the data suggesting the c-Met expression is increased in the triple-negative breast 
cancer, may be important in trastuzumab-resistant HER2+ breast cancer, and RET 


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inhibition may be important in hormone refractory ER+ breast cancer, cabozantinib may 
have benefit in all subtypes of breast cancer.  Moreover, data suggests that cabozantinib 
penetrates the blood brain barrier, and with its anti-angiogenic activity, may be critical 
for treatment of brain metastases.  We will assess the efficacy of cabozantinib in patients 
with metastatic breast cancer with known brain metastases.  Patients with HER2+ breast 
cancer will receive trastuzumab in combination with cabozantinib. 
2.7 
Correlative Studies Background 
2.7.1 Evaluate c-Met and phospho-c-Met expression in FFPE tumor tissue 
Since cabozantinib inhibits MET expression, it is hypothesized that tumors in patients who 
express higher levels of c-Met will respond more robustly to cabozantinib therapy. Testing 
c-Met and phospho-c-Met expression in previously collected FFPE tumor tissue is one 
method to genotype patient tumors. Caveats to this technique are that patients’ malignant 
cells may have acquired additional mutations since these tissues were collected, and this 
sampling may not detect the heterogeneity of gene expression within a tumor. However, 
this technique is an accessible option to profile genetic expression, especially when paired 
with additional profiling approaches. In this study, patients will be dichotomized as to 
whether or not their tumor expresses c-Met and the association between expression and 
response to cabozantinib will be explored. 
2.7.2 Evaluate the incidence of c-Met amplification in circulating tumor cells at 
baseline  
Simultaneously, we will also use another approach to determine c-Met amplification levels 
based on circulating tumor cells. These results may corroborate the c-Met and phospho-c-
Met expression studies with FFPE tumor tissue samples. The primary advantage of this 
technique is that malignant cells are collected via purification of circulating tumor cells 
(CTCs) from whole blood, which is a far less invasive technique for malignant cell 
sampling than traditional biopsies. Interestingly, these CTCs are indicative of tumor 
metastases and predictive of clinical outcomes in breast cancer patients (Cristofanilli et al., 
2004). Patients will be grouped as to whether or not their tumor has amplified c-Met and 
the association between amplification and response to cabozantinib will be evaluated. 
2.7.3 Evaluate potential plasma biomarkers of cabozantinib 


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Exploratory analyses of potential biomarkers of cabozantinib activity will be performed 
by measuring proteins in the plasma and circulating cells at baseline, on days 1 and 8 of 
each cycle of therapy, and, if available, at the end of treatment. Plasma analysis will be 
carried out for a panel of circulating angiogenic and inflammatory molecules previously 
identified as potential biomarkers of response to anti-VEGF therapy in breast cancer 
patients (Boucher et al., ASCO 2013). They include vascular endothelial growth factor 
(VEGF), placental-derived growth factor (PlGF), soluble (s)VEGFR1, basic fibroblast 
growth factor (bFGF), and stromal-derived factor 1 (SDF1). In addition, we will 
measure the plasma concentration of biomarkers that are related to cabozantinib activity: 
HGF, s-MET, s-c-KIT and sVEGFR2. Finally, we will evaluate biomarkers of tumor 
hypoxia, by measuring plasma carbonic anhydrase IX (CAIX) levels as well as 
biomarkers of osteoclast and osteoblast activity (plasma C-telopeptide and total alkaline 
phosphatase). Baseline and on treatment biomarker values will be correlated with 
patient’s response to cabozantinib therapy. 
2.7.4 Vessel density and tortuosity 
Visualization of vessel density and tortuosity enables longitudinal assessment of 
cabozantinib’s impact on tumor angiogenesis within brain tumors. 
The feasibility of this technique has been previously demonstrated in a prospective trial of 
lapatinib for patients with brain metastases from HER2-positive breast cancer (Bullitt et 
al., 2007). This study demonstrated widespread abnormalities in vessel shape in the brain 
at baseline, in some cases extending far beyond the visible tumors. Vessel tortuosity 
measurements enabled correct prediction of treatment failure earlier than other methods. 
In that small study, of the three patients who had quantitative improvements in vessel 
tortuosity at 2-month follow-up, each of the two patients for whom further follow up data 
were available remained on protocol-based therapy for 6 months or longer. Particularly 
given the postulated mechanism of action of cabozantinib, visualization of changes in 
vessel tortuosity is of great interest. 
2.7.5 Cerebral blood volume, blood flow, and vessel size 
Vascularity of tumors indicates active angiogenesis, a process that cabozantinib targets 
through its inhibitory effects on VEGFR and c-MET. Patients on this study will receive 
routine brain MRIs to assess the vascularity of their brain tumors – blood flow, blood 
volume, permeability and surface area of capillary bed. In a previous study of AZD2171, 


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a small molecule inhibitor of VEGFRs, these techniques successfully demonstrated 
normalization of tumor vessels and reduction of vasogenic edema in patients with 
gliomas. Furthermore, early changes in vascular parameters were predictive of improved 
overall outcomes in these patients (Batchelor TT et al., 2007). 
2.7.6 Blood sample collection 
Blood will be collected at baseline and at the end of treatment for cell-free DNA 
(cfDNA).  The cfDNA will be processed by the Clinical Trial Core Laboratory at DFCI 
and then banked in the DF/HCC Clinical Trials Core laboratory for future research 
purposes.  The banked samples will be used to analyze DNA, RNA and protein in future 
studies.   
3 
PARTICIPANT SELECTION 
3.1 
Inclusion Criteria 
Participants must meet the following criteria on screening examination to be eligible to 
participate in the study: 
3.1.1 Patients must have histologically or cytologically confirmed invasive breast 
cancer, with stage IV disease.  Patients without pathologic or cytologic 
confirmation of metastatic disease should have unequivocal evidence of metastasis 
from physical examination or radiologic evaluation. 
(i) 
Measurable disease: patients must have measurable CNS disease, defined as 
at least one parenchymal brain lesion that can be accurately measured in at 
least one dimension with the longest diameter ≥10 mm by local radiology 
review (measurable non-CNS disease is not required for study participation) 
(ii) 
Patients will be defined as HER2+ if either the primary tumor and/or the 
metastasis are HER2-positive, defined as 3+ by IHC or FISH≥2.0 
3.1.2 New or progressive CNS lesions, as assessed by the patient’s treating physician.  
(i) 
It is anticipated that some patients may have multiple progressive CNS 
lesions, one or several of which are treated with SRS or surgery with 
residual untreated lesions remaining.  Such patients are eligible for 
enrollment on this study providing that at least one lesion is measurable 


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(≥10 mm) per RECIST 1.1.  The location of the measurable lesion should 
be documented in the patient chart and case report form. 
(ii) 
Patients who have had prior cranial surgery are eligible provided that there 
is evidence of measurable residual or progressive lesions, and at least 3 
months have passed since surgery.  If a patient has surgical resection 
followed by WBRT, then there must be evidence of progressive CNS 
disease after the completion of WBRT 
(iii) 
Patients who had had prior WBRT and/or SRS and then whose lesions have 
progressed thereafter are also eligible.  In this case, lesions that have been 
treated with SRS may be considered as target lesions if there is unequivocal 
evidence, in the opinion of the treating physician, of progression. 
(iv) 
Patient who have not previously been treated with cranial radiation (e.g. 
WBRT or SRS) are eligible to enter the study, but such patients must be 
asymptomatic or minimally symptomatic from their CNS metastases and 
not requiring corticosteroids. 
3.1.3 For patients who have received prior cranial radiation, no increase in 
corticosteroid dose in the week prior to the baseline brain MRI 
3.1.4 Prior therapy: Patients must have discontinued all chemotherapy, investigational 
therapy or biologic therapy at least 14 days prior to initiating study treatment 
(with the exception of trastuzumab for patients with HER2+ breast cancer) 
3.1.5 Recovery to baseline or ≤ Grade 1 CTCAE v.4.0 from toxicities related to any 
prior treatments, unless AE(s) are clinically nonsignificant and/or stable on 
supportive therapy; 
3.1.6 Cohort 1: HER2-positive, defined by ASCO CAP 2013 guidelines:  
 IHC 3+ based on circumferential membrane staining that is complete, 
intense  
-OR- 
 FISH positive based on one of the three following criteria: 


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o Single-probe average HER2 copy number ≥ 6.0 signals/cell; OR 
o Dual-probe HER2/CEP17 ratio < 2.0 with an average HER2 copy 
number ≥ 6.0 signals/cell; OR 
o Dual-probe HER2/CEP17 ratio ≥ 2.0 
Cohort 2: Hormone receptor positive (ER-positive and/or PR-positive, defined as 
≥ 1% staining by immunohistochemistry) and HER2-negative 
Cohort 3: Triple negative (ER-negative, PR-negative, HER2-negative) 
3.1.7 The subject is 18 years old on the day of consent 
3.1.8 The subject has an Eastern Cooperative Oncology Group (ECOG) performance 
status of 0 or 1 
3.1.9 Patients must have normal organ and marrow function and laboratory values as 
follows within 14 days before the first dose of cabozantinib: 
(i) 
Absolute neutrophil count  1000/mm3 without colony stimulating factor 
support 
(ii) 
Platelets  100,000/mm3 
(iii) 
Hemoglobin  9 g/dL 
(iv) 
Total Bilirubin  1.5 mg/dL × the ULN 
(v) 
Serum albumin  2.8 g/dl 
(vi) 
Serum creatinine ≤ 1.5  ULN or creatinine clearance (CrCl) ≥ 50 mL/min. 
For creatinine clearance estimation, the Cockcroft and Gault equation 
should be used: 
 Male: CrCl (mL/min) = (140 - age) × wt (kg) / (serum creatinine 
× 72); 
 Female: Multiply above result by 0.85; 
(vii) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)  3 
× the ULN.  For patients with documented liver metastases, AST/ALT ≤ 5.0 
times the upper limit of normal.  


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(viii) Lipase < 2.0 x the upper limit of normal and no radiologic or clinical 
evidence of pancreatitis 
(ix) 
Urine protein:creatinine ratio ≤ 1 
(x) 
Serum phosphorus, calcium, magnesium and potassium ≥ LLN 
3.1.10 The subject is capable of understanding and complying with the protocol and has 
signed the informed consent document 
3.1.11 Sexually active subjects (men and women) must agree to use medically accepted 
barrier methods of contraception (e.g., male or female condom) during the course 
of the study and for 4 months after the last dose of study drug(s), even if oral 
contraceptives are also used. All subjects of reproductive potential must agree to 
use both a barrier method and a second method of birth control during the course 
of the study and for 4 months after the last dose of study drug(s); 
3.1.12 Female subjects of childbearing potential must not be pregnant at screening. 
Females of childbearing potential are defined as premenopausal females capable 
of becoming pregnant (ie, females who have had any evidence of menses in the 
past 12 months, with the exception of those who had prior hysterectomy). 
However, women who have been amenorrheic for 12 or more months are still 
considered to be of childbearing potential if the amenorrhea is possibly due to 
prior chemotherapy, antiestrogens, low body weight, ovarian suppression or 
other reasons. 
3.1.13 Patients on bisphosphonates may continue receiving bisphosphonate therapy 
during study.  Patients wanting to initiate bisphosphonate therapy may do so. 
3.1.14 The subject has had an assessment of all known non-CNS disease sites eg, by 
computerized tomography (CT) scan, magnetic resonance imaging (MRI), bone 
scan as appropriate, within 28 days before the first dose of cabozantinib 
3.1.15 Research MRI sequences performed at Massachusetts General Hospital 
Charlestown Navy Yard must be completed ≤ 7 days of Cycle 1 Day 1 
3.1.16 Clinical MRIs performed at baseline must be completed within 28 days of the 
first dose of cabozantinib 


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3.2 
Exclusion Criteria 
Participants who exhibit any of the following conditions at screening will not be eligible 
for admission into the study: 
3.2.1 The subject has received cabozantinib or another c-Met inhibitor (please note 
ARQ 197 is not considered a MET inhibitor for purposes of this study given data 
to suggest it inhibits tubulin) 
3.2.2 The subject has uncontrolled, significant intercurrent or recent illness including, 
but not limited to, the following conditions: 
a. Cardiovascular disorders including: 
i. Congestive heart failure (CHF): New York Heart Association (NYHA) 
Class III (moderate) or Class IV (severe) at the time of screening; 
ii. Concurrent uncontrolled hypertension defined as sustained blood 
pressure (BP) > 150 mm Hg systolic or > 90 mm Hg diastolic despite 
optimal antihypertensive treatment within 7 days of the first dose of 
cabozantinib; 
iii. Any history of congenital long QT syndrome; 
iv. Any of the following within 6 months before the first dose of 
cabozantinib: unstable angina pectoris; clinically-significant cardiac 
arrhythmias; stroke (including transient ischemic attack (TIA), or other 
ischemic event); myocardial infarction; thromboembolic event requiring 
therapeutic anticoagulation (Note: subjects with a venous filter (eg, vena 
cava filter) are not eligible for this study). 
b. GI disorders particularly those associated with a high risk of perforation or 
fistula formation including: 
i. Any of the following within 28 days before the first dose of 
cabozantinib: intra-abdominal tumor/metastases invading GI mucosa; 
patients must be completely recovered from any evidence of active peptic 
ulcer disease; patients must be completely recovered from these conditions - 
any evidence or inflammatory bowel disease (including ulcerative colitis 


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and Crohn’s disease), diverticulitis, cholecystitis, symptomatic cholangitis 
or appendicitis; malabsorption syndrome. 
ii. Any of the following within 6 months before the first dose of 
cabozantinib: abdominal fistula; gastrointestinal perforation; bowel 
obstruction or gastric outlet obstruction; intra-abdominal abscess. Note: 
Complete resolution of an intra-abdominal abscess must be confirmed prior 
to initiating treatment with cabozantinib even if the abscess occurred more 
than 6 months before the first dose of cabozantinib. 
c. Other disorders associated with a high risk of fistula formation including PEG 
tube placement within 3 months before the first dose of study therapy 
d. Other clinically significant disorders such as: 
i. active infection requiring systemic treatment within 28 days before the 
first dose of cabozantinib; 
ii. serious non-healing wound/ulcer/bone fracture within 28 days before the 
first dose of cabozantinib; 
iii. history of organ transplant; 
iv. concurrent uncompensated hypothyroidism or thyroid dysfunction within 
7 days before the first dose of cabozantinib. 
 
3.2.3 Leptomeningeal disease as the only site of CNS involvement 
3.2.4 Known contraindication to MRI with gadolinium contrast, such as cardiac 
pacemaker, shrapnel, or ocular foreign body 
3.2.5 More than 2 seizures over the last 4 weeks prior to study entry 
3.2.6 Grade 1 or higher CNS hemorrhage on baseline brain MRI, or history of grade 2 
or higher CNS hemorrhage within 12 months 
3.2.7 The subject has experienced any of the following: 
a. clinically-significant GI bleeding within 6 months before the first dose of 
cabozantinib; 


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b. hemoptysis of ≥ 0.5 teaspoon (2.5ml) of red blood within 3 months before the 
first dose of cabozantinib; 
c. any other signs indicative of pulmonary hemorrhage within 3 months before 
the first dose of cabozantinib. 
3.2.8 The subject has tumor in contact with, invading or encasing any major blood 
vessels 
3.2.9 The subject has evidence of tumor invading the GI tract (esophagus, stomach, 
small or large bowel, rectum or anus), or any evidence of endotracheal or 
endobronchial tumor within 28 days before the first dose of cabozantinib 
3.2.10 The subject requires concomitant treatment, in therapeutic doses, with 
anticoagulants such as warfarin or warfarin-related agents, heparin, thrombin or 
Factor Xa inhibitors, or antiplatelet agents (eg, clopidogrel). Low dose aspirin (≤ 
81 mg/day), low-dose warfarin (≤ 1 mg/day), and prophylactic LMWH are 
permitted; 
3.2.11 The subject has prothrombin time (PT)/INR or partial thromboplastin time (PTT) 
test ≥ 1.3 × the laboratory ULN within 7 days before the first dose of 
cabozantinib. 
3.2.12  Inability to swallow intact tablets  
3.2.13 Pregnant or lactating females  
3.2.14 Diagnosis of another malignancy within 2 years before the first dose of 
cabozantinib, except for superficial skin cancers, or localized, low grade tumors 
deemed cured and not treated with systemic therapy 
3.2.15 Radiation therapy within 7 days before the first dose of cabozantinib. Subjects 
with clinically relevant ongoing complications from prior radiation therapy are 
not eligible 
3.2.16 The subject is known to be positive for the human immunodeficiency virus 
(HIV) 


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3.2.17 Major surgery within 12 weeks before the first dose of cabozantinib. Complete 
wound healing from major surgery must have occurred 1 month before the first 
dose of cabozantinib. Minor surgery (including uncomplicated tooth extractions) 
is allowed if it occurred 28 days before the first dose of cabozantinib with 
complete wound healing at least 10 days before the first dose of cabozantinib. 
Subjects with clinically relevant ongoing complications from prior surgery are 
not eligible 
3.2.18 QTcF > 500 msec on average of screening EKGs performed within 28 days of 
first dose of cabozantinib. Three EKGs must be performed at screening. If the 
average of these three consecutive results for QTcF is > 500 msec, the subject is 
ineligible. 
3.2.19 Active infection requiring IV antibiotics at Day 1 of cycle 1 
3.2.20 No prior lapatinib within 7 days prior to initiation of protocol treatment 
3.2.21 Patients may not receive any concurrent investigational agents while on study 
3.2.22 Patients may not receive any cancer-directed concurrent therapy, such as 
concurrent chemotherapy, radiotherapy, or hormonal therapy while on study.  
3.2.23 Previously identified allergy or hypersensitivity to components of the 
cabozantinib formulations 
3.2.24 The subject requires chronic concomitant treatment with strong CYP3A4 
inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, 
phenobarbital, and St. John’s Wort). 
3.3 
Inclusion of Women, Minorities and Other Underrepresented Populations 
 
Both men and women of all races and ethnic groups are eligible for this trial.   
4 
REGISTRATION PROCEDURES 
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions 
Institutions will register eligible participants with the DF/HCC Quality Assurance 
Office for Clinical Trials (QACT) central registration system. Registration must occur 


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prior to the initiation of therapy. Any participant not registered to the protocol before 
treatment begins will be considered ineligible and registration will be denied. 
  
An investigator will confirm eligibility criteria and a member of the study team will 
complete the QACT the protocol-specific eligibility checklist. 
 
Following registration, participants may begin protocol treatment. Issues that would 
cause treatment delays should be discussed with the Overall Principal Investigator (PI). 
If a participant does not receive protocol therapy following registration, the participant’s 
registration on the study must be canceled. Notify the QACT Registrar of registration 
cancellations as soon as possible. 
 
4.2 
Registration for DF/HCC Institutions 
The QACT registration staff is accessible on Monday through Friday, from 8:00 AM to 5:00 
PM Eastern Standard Time. In emergency situations when a participant must begin 
treatment during off-hours or holidays, call the QACT registration line at 617-632-3761 and 
follow the instructions for registering participants after hours. 
The registration procedures are as follows: 
 Obtain written informed consent from the participant prior to the performance of 
any protocol specific procedures or assessments.  
 Complete the QACT protocol-specific eligibility checklist using the eligibility 
assessment documented in the participant’s medical record and/or research chart. 
To be eligible for registration to the protocol, the participant must meet all 
inclusion and exclusion criterion as described in the protocol and reflected 
on the eligibility checklist. 
 
Reminder: Confirm eligibility for ancillary studies at the same time as eligibility for a 
treatment protocol. Registration to both treatment and ancillary protocols will not be 
completed if eligibility requirements are not met for all studies.  
 
 Fax the eligibility checklist(s) and all pages of the consent form(s) to the QACT 
at 617-632-2295. For Phase I protocols, attach participant dose level assignment 
confirmation from the sponsor. 
 


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 The QACT Registrar will (a) review the eligibility checklist, (b) register the 
participant on the protocol, and (c) randomize the participant when applicable. 
 
 An email confirmation of the registration and/or randomization will be sent to 
the Overall PI, study coordinator(s) from the Lead Site, treating investigator and 
registering person immediately following the registration and/or randomization. 
5 
TREATMENT PLAN  
5.1 
Treatment Overview 
Treatment will be administered on an outpatient basis. Expected toxicities and potential 
risks as well as dose modifications for cabozantinib are described in Section 6 (Expected 
Toxicities and Dosing Delays/Dose Modification). No investigational or commercial 
agents or therapies other than those described below may be administered with the intent 
to treat the participant’s malignancy. 
The target accrual is up to a maximum of 40 patients who receive at least one dose of 
protocol-based therapy in order to enter 37 patients who have “assessable” CNS disease. 
Assessable disease is defined as at least one parenchymal brain lesion that can be 
accurately measured in at least one dimension with the longest dimension ≥ 10 mm by 
local radiology review (measureable non-CNS disease is not required for study 
participation). The estimated rate of accrual is 1-2 patients per month. Patients will be 
followed for up to two years after removal from study or until death, whichever comes 
first. 
Exelixis will provide each investigator with adequate supplies of cabozantinib, which 
will be supplied as 60-mg, and 20-mg yellow film-coated tablets. The 60-mg tablets are 
oval, and the 20-mg tablets are round.  
Subjects will receive cabozantinib orally administered daily and continuously. Dosing 
will begin at 60 mg cabozantinib per day taken orally for all patients with dosing 
delays/dose modifications as outlined in Section 6.  
A full cycle length will be defined as 21 days (3 weeks). Cabozantinib will be given on 
day 1 and taken daily for 21 day cycle. Patients with HER2 positive disease will 
concurrently receive 6 mg/kg intravenous trastuzumab on Day 1 of each cycle. HER2 
positive patients naïve to trastuzumab receive an 8 mg/kg loading dose during cycle 1, 
and resume the 6 mg/kg dosing for every subsequent cycle.  Correlative imaging studies 


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will be done 21 days post dose of cabozantinib at the Cycle 2 Day 1 timepoint (day 22), 
prior to patient receiving Cycle 2 Day 1 dose. 
Cycle 2 of treatment will begin 21 days following the first dose of cabozantinib. Starting 
with cycle 2, minor deviations to the treatment schedule are allowed for patient 
scheduling requests with a + 4 days window (i.e. infusion chair availability, weather-
related issues, vacation, etc.). Additionally, minor deviations to the scan schedule will be 
allowed (i.e. Day 22 brain MRI, CT, MUGA) for patient scheduling requests with a + 7 
days window. 
Subjects will be provided with a sufficient supply of cabozantinib and instructions for 
taking the cabozantinib on days without scheduled clinic visits. After fasting (with 
exception of water) for 2 hours, participants will take cabozantinib daily each morning 
with a full glass of water (minimum of 8 oz/ 240 mL) and continue to fast for 1 hour 
after each dose of cabozantinib. Participants should be instructed to swallow the tablets 
whole and not crush, chew or dissolve in water prior to swallowing. Participants should 
record dosing time and doses taken in a study drug dosing diary while on cabozantinib. 
If doses are withheld, the original schedule of assessments should be maintained when 
cabozantinib is restarted. The participant should be instructed to not make up the missed 
doses and to maintain the planned dosing schedule. As described in Appendix D, 
Participant’s Medication Diary, if it has been more than 12 hours since missing their 
scheduled dose, then the participants should not take the missed dose. However, if it has 
been less than 12 hours since the missed dose, then the dose should be taken 
immediately and the participant should continue taking their dose at the regular time the 
next day.  Participants must be instructed to not make up missed doses that are vomited. 
Participants should be instructed to wait until the next day to take the next scheduled 
dose and should be reminded to tell their doctor or nurse at their next visit which dose(s) 
were missed. 
At study sites, all study medication will be stored as described in the local institution’s 
pharmacy policies (or SOPs) and inventoried in accordance with applicable state and 
federal regulations.  
 
 
 


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Table 3. Cycle 1 and beyond 
REGIMEN DESCRIPTION 
Agent 
Dose 
Route 
Schedule 
Cycle 
Length 
Cabozantinib 
60 po qday 
Oral 
Daily 
3 weeks (21 
days) 
Trastuzumab* 
6 mg/kg 
(8mg/kg 
loading dose) 
  
IV 
Day 1 
*Trastuzumab will only be administered to patients with HER2-positive disease. 
Loading dose of trastuzumab not required if patients have received a weekly 
trastuzumab dose (2 mg/kg) within 3 weeks of anticipated trastuzumab start date on this 
protocol, or if patients have received a Q3 weekly dose (6 mg/kg) of trastuzumab within 
6 weeks of anticipated trastuzumab start date on this protocol. In such cases, patients 
should receive 6 mg/kg IV starting on Cycle 1 Day 1. 
5.2 
Pre-treatment Criteria 
The following pre-treatment criteria must be met in order to begin cabozantinib on 
Cycle 1, Day 1:   
 Absolute neutrophil count (ANC) ≥ 1000/mm3 
 Platelets ≥ 100,000/mm3 
 Total bilirubin ≤ 1.5  the upper limit of normal 
 Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 the 
upper limit of normal for patients with no liver involvement; or ≤ 5  the upper 
limit of normal for patients with liver involvement 


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 Urine protein/creatinine ratio (UPCR) ≤ 1. 
The following pre-treatment criteria must be met in order to begin cabozantinib on Day 
1 of each subsequent cycle:   
 Absolute neutrophil count (ANC) ≥ 1000/mm3 
 Platelets ≥ 100,000/mm3 
 Total bilirubin ≤ 1.5  the upper limit of normal 
 Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3  the 
upper limit of normal if no liver involvement; or ≤ 5  the upper limit of normal 
for patients with ≤ 3  the upper limit of normal  (i.e. Grade 1) LFTs at baseline 
or liver involvement 
 Urine protein/creatinine ratio (UPCR) ≤ 1. 
5.3 
Initial Safety Evaluation of cabozantinib + trastuzumab 
As an extra safety precaution, accrual will be paused when 6 patients have received first 
doses of cabozantinib and trastuzumab in this cohort. These 6 patients will be observed 
for 3 weeks and assessed for DLTs (dose-limiting toxicities), defined below. A 
teleconference call with all investigators will be held at the end of this period to discuss 
any unexpected SAEs that may have been observed. Accrual will be suspended either 
temporarily or permanently to the combination of cabozantinib and trastuzumab, if, in 
the opinion of the principal investigator, any such SAE warrants further evaluation or 
discontinuation of the cohort. If DLTs are observed in 1 or fewer patients, accrual will 
continue at a starting cabozantinib dosage of 60 mg po qday. If 2 or more patients 
experience a DLT, cabozantinib dosage will be reduced to 40 mg po qday, and an 
additional DLT safety assessment will be done after enrollment of another 6 patients. If 
DLTs are observed in 1 or fewer patients, accrual will continue at a starting cabozantinib 
dosage of 40 mg po qday. If 2 or more patients experience a DLT, accrual to the HER2-
positive cohort will be stopped permanently. Management for these patients is illustrated 
below. 
 


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Definition of Dose-Limiting Toxicity 
All adverse events will be reported, with severity assessed according to the NCI CTCAE 
v4.0.  Dose limiting toxicity (DLT) refers to both non-hematologic and hematologic 
toxicities experience during the first cycle (i.e., first 3 weeks) of treatment. 
A DLT will be defined as any of the following assessed by the investigator to be 
possibly related to cabozantinib occurring during cycle 1 (for the first 6 patients in the 
trastuzumab/cabozantinib pilot cohort: 
1. Any AE that results in a dose reduction during the DLT evaluation period 
2. Non-Hematologic Toxicity 
Any Grade 3 or 4 event, excluding: 
a. Grade 3 nausea and/or vomiting controlled with supportive measures within 24 
hours 
b. Grade 3 diarrhea controlled with supportive measures within 24 hours 
c. Grade 3 fatigue that resolves within 24 hours 
d. Grade 3 constipation controlled with supportive measures within 24 hours 
 
Cabozantinib dose 
Trastuzumab dose 
Dose Level 1 (D1) 
60 mg po qday 
6 mg/kg IV (every 3 weeks)
Dose Level -1 (D-1) 
40 mg po qday 
6 mg/kg IV (every 3 weeks)


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e. Grade 3 hypophosphatemia 
f. Grade 3 hyponatremia 
g. Grade 3 hypomagnesemia 
h. Grade 3 hypokalemia 
i.  Grade 3 hypertension controlled with medical management 
j.  Grade 3 hepatic transaminase (ALT or AST) lasting less than 72 hours 
Note: For patients with Grade 1 hepatic transaminase at baseline as a result of 
liver or bone metastases, a ≥ 1.5 fold increase in AST or ALT, or hepatic 
transaminase ≥ 5 x the upper limit of normal (ULN) lasting more than 72 hours 
will be considered a DLT.  For patients with grade 2 hepatic tranasminases at 
baseline as a result of liver or bone metastases, hepatic transaminase >7.5x ULN 
lasting more than 72 hours will be considered a DLT. 
3. Hematologic Toxicity 
a. Grade 3 neutropenia with infection requiring intervention or lasting > 7 days, or 
Grade 4 neutropenia 
b. Grade 3 or 4 febrile neutropenia  
c. Grade 4 thrombocytopenia or grade 3 thrombocytopenia with clinically 
significant bleeding 
d. Other Grade 4 hematologic toxicities (e.g., anemia) 
4. Failure to take more than 7 days of treatment within Cycle 1 due to treatment-related 
adverse effects 
5. Any cabozantinib-related death 
 
5.4 
Agent Administration  
5.4.1 Cabozantinib 
Subjects will receive cabozantinib orally administered daily and continuously. Dosing 
will begin at 60 mg cabozantinib per day taken orally for all patients with dosing 
delays/dose modifications as outlined in Section 6.  
Participants will be provided with a sufficient supply of cabozantinib and instructions 
for taking the cabozantinib on days without scheduled visits. After fasting (with 
exception of water) for 2 hours, participants will take cabozantinib daily each morning 
with a full glass of water (minimum of 8 oz / 240 mL) and continue to fast for 1 hour 
after each dose of cabozantinib. Participants should be instructed to swallow the tablets 
whole and not chew them prior to swallowing. Participants should record dosing time 


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and doses taken in a study drug dosing diary while on cabozantinib. If doses are 
withheld, the original schedule of assessments should be maintained when cabozantinib 
is restarted. The participant should be instructed to not make up the missed doses and to 
maintain the planned dosing schedule. As described in Appendix D, Participant’s 
Medication Diary, if it has been more than 12 hours since missing their scheduled dose, 
then the participants should not take the missed dose. However, if it has been less than 
12 hours since the missed dose, then the dose should be taken immediately and the 
participant should continue taking their dose at the regular time the next day. 
Participants must be instructed to not make up missed doses that are vomited. 
Participants should be instructed to wait until the next day to take the next scheduled 
dose and should be reminded to tell their doctor or nurse at their next visit which dose(s) 
were missed. 
5.4.2 Trastuzumab 
For HER2-positive patients, trastuzumab is administered intravenously in the outpatient 
setting. The dose for initial treatment with trastuzumab is 8 mg/kg IV unless the patient 
has received qweek dose (2mg/kg) trastuzumab ≤21 days or q3 week dose (6mg/kg) ≤ 
42 days from day 1 of treatment; patients who have received trastuzumab within these 
windows of initiation of therapy should receive an initial dose of 6 mg/kg IV. All 
subsequent doses are 6 mg/kg IV. There should be no dose adjustment for trastuzumab. 
Trastuzumab is administered concurrently with cabozantinib on Day 1 of each cycle. For 
patients who have not previously received trastuzumab, the initial infusion time of 
trastuzumab (loading dose 8 mg/kg) is approximately 90 minutes. 
  
The initial dose of trastuzumab will be administered over approximately 
90 minutes. If this first dose is well tolerated, subsequent infusion 
times may be shortened to approximately 30 minutes or given per 
participating site’s institutional SOP for trastuzumab administration. 
If the initial or a subsequent dose is not well tolerated (i.e. fevers, 
chills, or rigors), subsequent infusion times may be shortened only 
after a dose is well tolerated.  
 
5.5 
General Concomitant Medication and Supportive Care Guidelines 
If a participant requires additional systemic anticancer treatment, cabozantinib must be 
discontinued. These treatments include, but are not restricted to the following: 


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 Chemotherapy 
 Radiopharmaceuticals 
 Steroids (not including physiological replacement doses of steroids, equivalent to 
≤ 10 mg/day prednisone, or megestrol acetate used to treat constitutional 
symptoms) 
 Endocrine therapy for breast cancer (eg, tamoxifen, aromatase inhibitors) 
 Radiation therapy 
If the participant must use other concomitant medications during the study (including 
vitamins, herbal and nutritional supplements, and over-the-counter medications), it is the 
responsibility of the principal investigator (PI) to ensure that details regarding the 
medication are documented. 
At the discretion of the investigator and after the onset of symptoms, treatment (or 
prophylaxis) with anti-emetic and anti-diarrheal medications may be undertaken per 
standard clinical practice.  
Treatment with denosumab or a bisphosphonate is allowed while patient is on study. 
Colony stimulating factors (eg, erythropoietin, granulocyte colony-stimulating factors, 
and peg-filgrastim) are not allowed while patient is on study.  
Pain medications, transfusions, short-term systemic steroid treatment, and other 
supportive measures should be utilized as dictated by standard clinical practice while the 
participant is enrolled in the study.  
No concurrent investigational agents are permitted. 
5.6 
Potential Drug Interactions 
5.6.1 Cytochrome P450 
Data from a clinical drug interaction study (Study XL184 008) show that clinically 
relevant steady state concentrations of cabozantinib appear to have no marked effect on 
the area under the plasma drug concentration time curve (AUC) of co administered 
rosiglitazone, a CYP2C8 substrate. Therefore, cabozantinib is not anticipated to markedly 
inhibit CYP2C8 in the clinic, and by inference, is not anticipated to markedly inhibit other 


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CYP450 isozymes that have lower [I]/Ki values compared with CYP2C8 (ie, CYP2C9, 
CYP2C19, CYP2D6, CYP1A2, and CYP3A4). In vitro data indicate that cabozantinib is 
unlikely to induce cytochrome P450 enzymes, except for possible induction of CYP1A1 at 
high cabozantinib concentrations (30 μM).  
Cabozantinib is a CYP3A4 substrate and a weak substrate for CYP2C9 (but not a 
CYP2D6, CYP2C8, CYP2C19, CYP2B6, or CYP1A2 substrate), based on data from in 
vitro studies. Results from a clinical pharmacology study, XL184 006, showed that 
concurrent administration of cabozantinib with the strong CYP3A4 inducer, rifampin, 
resulted in an approximately 77% reduction in cabozantinib exposure (AUC values) after 
a single dose of cabozantinib in healthy volunteers. Chronic co-administration of 
cabozantinib with strong inducers of the CYP3A4 family (eg, dexamethasone, phenytoin, 
carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John’s Wort) may 
significantly decrease cabozantinib concentrations. The chronic use of strong CYP3A4 
inducers should be avoided. Other drugs that induce CYP3A4 should be used with caution 
because these drugs have the potential to decrease exposure (AUC) to cabozantinib. 
Selection of alternate concomitant medications with no or minimal CYP3A4 enzyme 
induction potential is recommended.  
Results from a clinical pharmacology study, XL184 007, showed that concurrent 
administration of cabozantinib with the strong CYP3A4 inhibitor, ketoconazole, resulted 
in a 38% increase in the cabozantinib exposure (AUC values) after a single dose of 
cabozantinib in healthy volunteers. Co-administration of cabozantinib with strong 
inhibitors of the CYP3A4 family (eg, ketoconazole, itraconazole, clarithromycin, 
indinavir, nefazodone, nelfinavir, and ritonavir) may increase cabozantinib concentrations. 
Grapefruit and Seville oranges may also increase plasma concentrations of cabozantinib 
and should be avoided. Strong CYP3A4 inhibitors should be avoided and other drugs that 
inhibit CYP3A4 should be used with caution because these drugs have the potential to 
increase exposure (AUC) to cabozantinib. Selection of alternate concomitant medications 
with no or minimal CYP3A4 enzyme inhibition potential is recommended.  
In addition, cimetidine should be avoided because of its potential to interfere with 
CYP3A4 mediated metabolism of cabozantinib. 
Please refer to the drug interaction tables at the following websites for lists of substrates, 
inducers, and inhibitors of selected CYP450 isozyme pathways: 


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http://medicine.iupui.edu/clinpharm/ddis/table.aspx 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInt
eractionsLabeling/ucm080499.htm   
5.6.2 Drugs Associated with QTc Prolongation 
Treatment with cabozantinib has been associated with a mild prolongation of the QTc 
interval.  Caution should be used when treating subjects on cabozantinib with other drugs 
associated with QTc prolongation (see http://www.qtdrugs.org).  Additional QTc 
monitoring is suggested for subjects who are treated concomitantly with QTc prolonging 
drugs. 
5.6.3 Protein Binding 
Cabozantinib is highly bound (≥ 99.7%) to human plasma proteins. Therefore, highly 
protein bound drugs should be used with caution with cabozantinib because there is a 
potential displacement interaction that could increase free concentrations of 
cabozantinib and/or a co-administered highly protein bound drug (and a 
corresponding increase in pharmacologic effect). 
5.6.4 Other Interactions 
Food may increase exposure levels of cabozantinib by 57%, fasting recommendations 
should be followed. In vitro data suggest that cabozantinib is unlikely to be a substrate 
for P glycoprotein, but it does appear to have the potential to inhibit the P-glycoprotein 
transport activity. Therefore, cabozantinib may have the potential to increase plasma 
concentrations of co-administered substrates of P-glycoprotein. Additional details 
related to these overall conclusions can be found in the investigator brochure. 
 
Additional details regarding potential drug interactions with cabozantinib can be found 
in the investigator brochure. 
 
5.7 
Compliance 
Drug accountability and subject compliance will be assessed with drug dispensing and 
return records.  


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5.8 
Study Drug Accountability 
The investigator will maintain accurate records of receipt of all cabozantinib, including 
dates of receipt. In addition, accurate records will be kept regarding when and how much 
cabozantinib is dispensed and used by each subject in the study. Reasons for deviation 
from the expected dispensing regimen must also be recorded. At completion of the 
study, to satisfy regulatory requirements regarding drug accountability, all unused 
cabozantinib will be reconciled and destroyed in accordance with applicable state and 
federal regulations. 
5.9 
Duration of Therapy 
Duration of therapy will depend on individual response, evidence of disease progression 
and tolerance. In the absence of treatment delays due to adverse events, treatment may 
continue until one of the following criteria applies: 
 Intolerable side effects the investigator feels may be due to cabozantinib 
 Specific conditions described in the medical management Section 6.2. 
 The investigator feels it is not in the best interest of the subject to continue on 
study  
 Necessity for treatment with non-protocol approved systemic anticancer therapy  
 If the subject does not recover from his or her toxicities to tolerable Grade ≤ 2 
within 6 weeks, the subject will have cabozantinib discontinued unless there is 
unequivocal evidence that the subject is benefitting.  In this situation, a subject 
may be able to restart therapy with a dose reduction upon resolution of the 
toxicity 
 Request by regulatory agencies for termination of treatment of an individual 
subject or all subjects under the protocol 
 Subject request to discontinue cabozantinib (with or without concurrent 
withdrawal of informed consent)  
 Significant noncompliance with the protocol schedule in the opinion of the 
investigator. 
 The minimum dose of cabozantinib will be 20 mg po qday. Subjects who cannot 
tolerate 20 mg po qday will have cabozantinib discontinued. 
 Disease progression 


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 Death 
 Intercurrent illness that prevents further administration of treatment 
 General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the opinion of the treating investigator. 
Participants will be removed from the protocol therapy when any of these criteria apply.  
The reason for removal from protocol therapy, and the date the participant was removed, 
must be documented in the case report form (CRF). Alternative care options will be 
discussed with the participant. 
 
A QACT Treatment Ended/Off Study Form will be filled out when a participant is 
removed from protocol therapy. This form can be found on the QACT website or obtained 
from the QACT registration staff. 
In the event of unusual or life-threatening complications, treating investigators must 
immediately notify the Principal Investigator, Sara Tolaney, phone: 617-632-2335, or 
email: stolaney@partners.org. 
 
5.10 
Duration of Follow Up  
Patients who are alive and free of disease progression when they are taken off protocol 
therapy will be followed until earliest occurrence of disease progression or death, 
whichever occurs first.  Patients who come off cabozantinib for reasons other than 
disease progression should have a staging scan at the time they go off cabozantinib, and 
scans should be performed every 9 weeks to look for disease progression. Patients 
removed from protocol therapy for unacceptable adverse event(s) will be followed until 
resolution or stabilization of the adverse event.  Patients will be followed up for survival 
after progression until death or lost to follow-up.   
5.11 
Criteria for Removal from Study 
Participants will be removed from study when any of the following criteria apply: 
 
 Lost to follow-up 
 Withdrawal of consent for data submission 
 Death 
 


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The reason for taking a participant off study, and the date the participant was removed, 
must be documented in the case report form (CRF). 
 
A QACT Treatment Ended/Off Study Form will be filled out when a participant comes 
off study. This form can be found on the QACT website or obtained from the QACT 
registration staff.  
 
6 
EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS 
DUE TO CABOZANTINIB 
Dose delays and modifications will be made using the following recommendations. 
Toxicity assessments will be done using the CTCAE Version 4.0 of the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) which is identified and located on 
the CTEP website at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
  
If possible, symptoms should be managed symptomatically. In the case of toxicity, 
appropriate medical treatment should be used (including anti-emetics, anti-diarrheals, 
etc.). 
All adverse events experienced by participants will be collected from the time of the first 
dose of cabozantinib, through the study and until the final study visit. Participants 
continuing to experience toxicity at the off study visit may be contacted for additional 
assessments until the toxicity has resolved or is deemed irreversible. 
 
6.1 
Anticipated Toxicities 
The general adverse event profile of cabozantinib includes GI symptoms (such as 
nausea, vomiting, and diarrhea), fatigue, anorexia, palmar-plantar erythrodysesthesia 
(PPE) syndrome, skin rash, elevated ALT and AST, increased pancreatic enzymes with 
rare cases of  pancreatitis, as well as side effects associated with inhibition of VEGF 
signaling such as thrombotic events (eg, pulmonary embolism [PE] and deep vein 
thrombosis [DVT]), hypertension, proteinuria, hemorrhagic events, and rare cases of 
gastrointestinal [GI] perforation and rectal/perirectal abscess. Arterial thromboembolism 
(transient ischemic attack [TIA], myocardial infarction [MI]) have been reported rarely. 
   
6.2 
Dose Modifications/Delays and Toxicity Management 


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Subjects will be monitored continuously for AEs throughout the study and for 30 days 
after the last dose of cabozantinib, and for any serious adverse event (SAE) assessed as 
related to cabozantinib or study procedures, even if the SAE occurs more than 30 days 
after the last dose of cabozantinib. 
 
Subjects will be instructed to notify their physician immediately of any and all AEs. 
Subjects experiencing one or more AEs due to the cabozantinib may require a dosing delay 
or reduction(s) in their dose in order to continue with cabozantinib. 
  
Re-escalating cabozantinib after a dose reduction: 
 
 Subjects who required a dose reduction for Grade 4 non-hematologic toxicity 
should not be re-escalated 
 For other related AEs, subjects may be re-escalated to the previous dose at the 
discretion of the investigator but not sooner than 2 weeks beyond the resolution 
to Grade ≤ 1 or to the baseline value of AEs. 
 If a subject has been dose-reduced , dose re-escalation can only occur to the next 
higher dose level. Further dose escalation to higher well-tolerated dose levels is 
allowed only if clinically indicated per investigator’s judgment and dose 
escalation criteria are met with each escalation (e.g. a minimum 2 week interval 
between escalations)  
 If the AEs that previously led to dose reduction(s) recur upon re-escalation, the 
dose should be reduced again and no further dose escalation will be permitted.  
 Dose re-escalation is not allowed for dose reduction triggered by neutropenia or 
thrombocytopenia.  
Additional information for dose delays or dose reductions: 
 Dose delays for reason(s) other than AEs related to cabozantinib, such as 
surgical procedures with no anticancer therapy intent, may be allowed with 
investigator approval. The acceptable length of interruption will be determined 
by the investigator. 
6.3 
Management of Adverse Events 


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In the absence of an unacceptable cabozantinib-related toxicity and/or clinical signs of 
disease progression, subjects may continue treatment at the discretion of the investigator. 
Subjects must be instructed to notify their physician immediately for any and all toxicities. 
Guidelines for the management of AEs (ie, dose interruptions and dose reductions) are 
presented in the next sections. Each dose reduction of cabozantinib should be to one 
dose level lower that the current dose (see Table 4 below).  Dose reductions of more 
than one dose level are acceptable if agreed to by the Investigator. If cabozantinib of 
cabozantinib is restarted after being withheld or interrupted, the subject should be 
instructed not to make up the missed doses of cabozantinib.  
The reason for treatment delay and reduced dose must be recorded on the case report form 
(CRF). 
Dosing may need to be interrupted for AEs considered not related to cabozantinib if this 
is clinically indicated or if causality is initially uncertain. Cabozantinib may be resumed 
at the same dose (or a lower dose per investigator judgment) if the AE is determined not 
to be related to cabozantinib once the investigator determines that retreatment is 
clinically appropriate and the subject meets the protocol re-treatment criteria. 
Table 4: Dose Reductions 
Starting Dose 
First Level dose Reduction 
Second Level dose 
Reduction 
60 mg cabozantinib 
Reduce to 40 mg 
cabozantinib 
Reduce to 20 mg  
cabozantinib 
 
6.3.1 General Guidelines for Non-Hematologic and Hematologic Adverse Events 
Guidelines for the management of AEs (ie, dose interruptions and dose reductions) are 
presented in the next sections. Each dose reduction of cabozantinib should be to one 
dose level lower that the current dose. Dose reductions of more than one dose level are 
acceptable if agreed to by the Investigator. All AEs should also be managed with 
supportive care at the earliest signs of toxicity considered related to the study treatment.  
If study treatment of cabozantinib is restarted after being withheld or interrupted, the 
subject should be instructed not to make up the missed doses of cabozantinib. The 


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reason for treatment delay and reduced dose must be recorded on the case report form 
(CRF). 
Dosing may need to be interrupted for AEs considered not related to cabozantinib if this 
is clinically indicated or if causality is initially uncertain. Study treatment may be 
resumed at the same dose (or a lower dose per investigator judgment) if the AE is 
determined not to be related to cabozantinib once the investigator determines that 
retreatment is clinically appropriate and the subject meets the protocol re-treatment 
criteria. 
Subjects receiving a daily dose of 20 mg may be restarted at the same dose if deemed 
safe at the discretion of the investigator. Subjects unable to tolerate a daily dose of 20 
mg should discontinue study treatment. 
Re-escalation to the previous dose, (but not higher than 60 mg/day) may be allowed at 
the discretion of the investigator but no sooner than 2 weeks beyond resolution of AEs 
that led to the dose reduction. Dose re-escalation is not allowed for a drug-related dose 
reduction triggered by myelosuppression or by Grade 4 AEs affecting major organs (eg, 
central nervous system, cardiac, hepatic, renal). 
The predicted effective plasma half-life of cabozantinib is 55 hours. Thus, when 
initiating therapy with cabozantinib, it will take most subjects 2 to 3 weeks to reach 
steady state. If AEs attributable to cabozantinib occur within the initial 3-week period of 
dosing, early intervention with dose modifications may be justified for AEs that, if 
worsened, could potentially be dangerous or debilitating, because without a dose 
adjustment, systemic exposure of cabozantinib might be expected to increase after the 
onset of the AE. 
Table 5: General Approach to the Management of Cabozantinib-Related Non-Hematologic 
Toxicities 


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CTCAE v4.0   
Guidelines/Intervention 
Grade 1: 
Add supportive care as indicated. Continue cabozantinib at the 
current dose level if the AE is manageable and tolerable. 
Grade 2 AEs which are tolerable 
and are easily managed 
Continue cabozantinib treatment at the current dose level with 
supportive care. 
Grade 2 AEs which are intolerable 
and cannot be adequately managed 
Interrupt cabozantinib treatment or dose reduction. Add 
supportive care as indicated. 
 
If cabozantinib dosing is interrupted, then upon resolution 
of the AE to baseline or Grade ≤ 1, cabozantinib may be 
resumed at either the same dose or with a dose reduction at 
the discretion of the investigator unless this is a recurring 
event at which time the dose should be reduced 
Grade 3 AEs which occurred 
without optimal prophylaxis or 
which is easily managed by 
medical intervention or resolved 
quickly  
Interrupt cabozantinib treatment and add supportive care as 
indicated: 
 
For AEs that are easily managed (eg, correction of 
electrolytes) with resolution to baseline or Grade ≤ 1 within 
24 hours, cabozantinib may be resumed at either the same 
dose or with a dose reduction at the discretion of the 
investigator unless this is a recurring event at which time the 
dose should be reduced 
 
For AEs that require supportive care, the dose should be held 
while supportive care is initiated and optimized. Then upon 
resolution of the AE to baseline or Grade ≤ 1, cabozantinib 
may be resumed at either the same dose or with a dose 
reduction at the discretion of the investigator unless this is a 
recurring event at which time the dose should be reduced 
Grade 3 AEs which occurred 
despite optimal prophylaxis or is 
not easily managed by medical 
intervention  
Interrupt cabozantinib treatment until recovery to ≤ Grade 1 or 
baseline.  Then resume treatment with a dose reduction. 
Grade 4 AEs (except easily 
corrected laboratory abnormalities) 
Permanently discontinue study treatment unless determined that 
the subject is unequivocally deriving clinical benefit. In this 
case, upon recovery to Grade ≤ 1 or baseline, the subject may be 
re-treated at a reduced dose that is to be determined by the 
treating investigator and Principal Investigator, but only with PI 
approval. 
Dose reductions or delays may occur in the setting of lower grade toxicity than defined above if 
the investigator believes that it is in the interest of the subject’s safety.  
 
 
 
 


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Table 6. General Approach to the Management of Hematologic Toxicities 
 
CTCAE v4.0 
Intervention 
Neutropenia 
 
Grade 3 neutropenia with 
infection requiring IV antibiotic, 
antifungal, or antiviral 
intervention 
 
Grade 3 neutropenia ≥ 7 days 
 
Grade 4 neutropenia  
Interrupt cabozantinib treatment until resolution to Grade ≤ 1, 
and resume cabozantinib treatment at a reduced dose.  
Thrombocytopenia 
Grade 3 thrombocytopenia with 
clinically significant bleeding or 
Grade 4 thrombocytopenia 
Interrupt cabozantinib treatment until platelet count is 
≥ 100,000/mm3, and resume cabozantinib treatment at a 
reduced dose. 
Febrile Neutropenia 
Grade 3 febrile neutropenia 
Interrupt cabozantinib treatment until recovery of ANC to 
Grade ≤ 1 and temperature to ≤ 38.0°C and resume 
cabozantinib treatment at a reduced dose. 
Grade 4 febrile neutropenia 
Permanently discontinue study treatment unless determined 
that the subject is unequivocally deriving clinical benefit. In 
this case, upon recovery to Grade ≤ 1 or baseline, the subject 
may be re-treated at a reduced dose that is to be determined by 
the investigator and Sponsor but only with Sponsor approval. 
Other Grade 4 Hematologic Toxicities 
Grade 4 hematologic toxicities  
other than anemia 
Permanently discontinue study treatment unless determined 
that the subject is clearly deriving clinical benefit. In this case, 
upon recovery to Grade ≤ 1 or baseline, the subject may be 
re-treated at a reduced dose that is to be determined by the 
treating investigator and Principal Investigator, and only with 
approval by the PI. 
Grade 4 anemia 
Permanent discontinuation for Grade 4 anemia is not 
mandated. Dose reductions or dose delays for anemia should 
be applied as clinically indicated. Supportive care such as red 
blood cell transfusions should be managed in accordance with 
institutional guidelines. 
ANC, absolute neutrophil count; LLN, lower limit of normal
Neutropenia: Grade 1 (ANC < LLN –  1.5  109/L); Grade 2 (ANC <1.5 x 109/L  – 1  109/L);  
Grade 3 (ANC <1  109/L –  0.5  109/L); Grade 4 (ANC <0.5  109/L ). 
Febrile Neutropenia: Grade 3 (present); Grade 4 (Life-threatening consequences; urgent intervention 
indicated). 
Thrombocytopenia: Grade 1 (Platelet count <LLN – 75 x 109/L); Grade 2 (Platelet count <75.0 – 50.0 x 
109/L); Grade 3 (Platelet count < 50 - 25  109/L); Grade 4 (Platelet count < 25  109/L). 
 


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6.3.2 Gastrointestinal Disorders 
The most common GI AEs reported in clinical studies with cabozantinib are diarrhea, oral 
pain, dyspepsia, stomatitis, and dysphagia.  
Diarrhea 
Subjects should be instructed to notify their physician immediately at the first signs of 
poorly formed or loose stool or an increased frequency of bowel movements. 
Administration of antidiarrheal/antimotility agents is recommended at the first sign of 
diarrhea as initial management. Some subjects may require concomitant treatment with 
more than one antidiarrheal agent. When therapy with antidiarrheal agents does not 
control the diarrhea to tolerable levels, study treatment should be temporarily interrupted 
or dose reduced. 
In addition, general supportive measures should be implemented including continuous oral 
hydration, correction of fluid and electrolyte abnormalities, small frequent meals, and 
stopping lactose-containing products, high fat meals, and alcohol.  
Nausea and Vomiting 
Antiemetic agents are recommended as clinically appropriate at the first sign of nausea 
and vomiting or as prophylaxis to prevent emesis, along with supportive care in 
accordance to clinical practice guidelines. The 5-HT3 receptor antagonists are 
recommended over chronic use of NK-1 receptor antagonists and dexamethasone (NK-1 
receptor antagonists can induce or inhibit CYP3A4, and glucocorticoids induce CYP3A4 
and thus could lower cabozantinib exposure). Caution is also recommended with the use 
of nabilone, which is a weak inhibitor of CYP3A4. When therapy with antiemetic agents 
does not control the nausea or vomiting to tolerable levels, study treatment should be 
temporarily interrupted or dose reduced. 
Stomatitis and Mucositis 
Preventive measures include a comprehensive dental examination to identify any potential 
complications before study treatment is initiated. Removal of local factors should be 
instituted as indicated, such as modification of ill-fitting dentures and appropriate care of 
gingivitis.  


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During treatment with cabozantinib good oral hygiene and standard local treatments such 
as nontraumatic cleansing and oral rinses (eg, with a weak solution of salt and baking 
soda) should be maintained. The oral cavity should be rinsed after meals, and dentures 
should be cleaned and brushed often to remove plaque. Local treatment should be 
instituted at the earliest onset of symptoms. Obtain bacterial/viral culture if oral infection 
is suspected and treat infection as indicated by local guidelines. When stomatitis interferes 
with adequate nutrition and local therapy is not adequately effective, dose reduction or 
temporary withholding of cabozantinib should be considered. 
6.3.3 Hepatobiliary Disorders 
Elevations of transaminases have also been observed during treatment with 
cabozantinib. In general, it is recommended that subjects with elevation of ALT, AST, 
and/or bilirubin have more frequent laboratory monitoring of these parameters. Other 
causes that may contribute to transaminase elevations should be considered.  If possible, 
hepatotoxic concomitant medications and alcohol should be discontinued in subjects 
who develop elevated transaminases.  
Because subjects may enter the study with elevations of AST/ALT at baseline, the 
following guidelines in Table 5 should be used for dose modifications: 
Table 7: Management of Transaminase Elevation 
Transaminase 
elevation CTCAE v4.0 
 
Intervention 
Subjects with AST and ALT less than or equal to the ULN at baseline 
Grade 1  
Continue cabozantinib with weekly monitoring of liver function 
tests (LFTs) for at least 4 weeks. Then resume the standard 
protocol-defined monitoring of liver function tests (LFTs). 
Grade 2 
Continue cabozantinib with at least twice weekly monitoring of 
LFTs for 2 weeks. Then weekly for 4 weeks. If LFTs continue to 
rise within Grade 2, interrupt cabozantinib treatment. Then continue 
with at least weekly LFTs until resolution to Grade ≤ 1. Study 
treatment may then be resumed at a one-dose-level reduction of 
cabozantinib 
Grade 3  
Interrupt cabozantinib treatment and monitor with at least twice 
weekly LFTs until Grade ≤ 2. Then continue with at least weekly 
LFTs until resolution to Grade ≤ 1. Cabozantinib may then be 
resumed at a one-dose-level reduction.  


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Cabozantinib treatment should also be interrupted when AST or ALT increases are 
accompanied by progressive elevations of total bilirubin, and/or elevations of coagulation 
tests (eg, International Normalized Ratio [INR]). Monitoring of transaminases should be 
intensified (2–3 times per week) and cabozantinib should be held until the etiology of the 
abnormalities is determined and these abnormalities are corrected or stabilize at clinically 
acceptable levels (INR < 1.5  upper limit of normal [ULN], total bilirubin < 1.5  ULN, 
aminotransferases ≤ baseline grade).  
Subjects must have cabozantinib permanently discontinued if transaminase elevations are 
accompanied by evidence of impaired hepatic function (bilirubin elevation > 2  ULN), in 
the absence of evidence of biliary obstruction (ie, significant elevation of alkaline 
phosphatase) or some other explanation of the injury (eg, viral hepatitis, alcohol hepatitis), 
because the combined finding (ie, Hy’s Law cases) represents a signal of a potential for 
the drug to cause severe liver injury. 
Grade 4 
Discontinue study treatment permanently. LFTs should be 
monitored as clinically indicated, at least 2 to 3 times per week, 
until resolution to Grade ≤ 1. If the subject was unequivocally 
deriving clinical benefit, the subject may be able to resume 
treatment at a lower dose of cabozantinib as determined by the 
treating investigator and Principal Investigator but only with PI 
approval. 
Subjects with AST or ALT above the ULN but ≤ 3.0 x ULN (ie, Grade 1) at baseline 
≥ 1.5 fold increase of 
AST or ALT AND 
both AST and ALT 
are ≤ 5.0 x ULN 
Continue cabozantinib treatment with at least twice weekly 
monitoring of LFTs for 4 weeks and weekly for 4 weeks. If LFTs 
continue to rise, interrupt study treatment. Then continue with at 
least weekly LFTs until resolution to Grade ≤ 1. Study treatment 
may then be resumed at a one-dose-level reduction of cabozantinib. 
≥ 1.5 fold increase of 
AST or ALT and at 
least one of AST or 
ALT is Grade 3 (ie, 
AST or ALT > 5.0 but 
≤ 20.0 x ULN) 
Interrupt study treatment and monitor with at least twice weekly 
LFTs until Grade ≤ 2. Then continue with at least weekly LFTs 
until resolution to Grade ≤ 1. Study treatment may then be resumed 
at a one-dose-level reduction of cabozantinib. 
Grade 4  
Discontinue study treatment permanently. LFTs should be 
monitored as clinically indicated, at least 2 to 3 times per week, 
until resolution to Grade ≤ 1. If the subject was unequivocally 
deriving clinical benefit, the subject may be able to resume 
treatment at a lower dose as determined by the treating investigator 
and Principal Investigator, but only with PI approval. 


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All subjects who develop isolated bilirubin elevations of Grade 3 should have study 
treatment held until recovered to Grade ≤ 1 or baseline (or lower). If this occurs within 
6 weeks of the dosing delay, study treatment may continue at a reduced dose. In subjects 
without biliary obstruction and Grade 4 bilirubin elevation, or with recurrence of Grade 
3 bilirubin elevation after a dose reduction, study treatment must be permanently 
discontinued. 
6.3.4 Fatigue, Anorexia and Weight Loss 
Fatigue has been reported during treatment with cabozantinib. Common causes of fatigue 
such as anemia, deconditioning, emotional distress (depression and/or anxiety), nutrition, 
sleep disturbance, and hypothyroidism should be ruled out and/or these causes treated in 
accordance to standard of care. Individual non-pharmacological and/or pharmacologic 
interventions directed to the contributing and treatable factors should be given. 
Pharmacological management with psychostimulants such as methylphenidate should be 
considered after disease specific morbidities have been excluded. Note: Chronic use of 
modafinil should be avoided because of its potential to reduce cabozantinib exposure (see 
Investigator’s Brochure).   
Anorexia and weight loss should be managed in accordance to local standard of care 
including nutritional support. Pharmacologic therapy such as megestrol acetate should be 
considered for appetite enhancement.  If fatigue, anorexia, or weight loss cannot be 
adequately managed, study treatment should be temporarily interrupted or dose reduced. 
6.3.5 Pancreatic Conditions 
Amylase and lipase elevations have been observed in clinical studies with cabozantinib. 
The clinical significance of asymptomatic elevations of enzymes is not known, but in 
general have not been associated with clinically apparent sequelae. It is recommended 
that subjects with lipase elevation and/or symptoms of pancreatitis have more frequent 
laboratory monitoring of lipase and/or amylase. Subjects with symptomatic pancreatitis 
should be treated with standard supportive measures. 
 
 
 
 
 
 


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Table 8: Asymptomatic Lipase or Amylase Elevations 
 
Asymptomatic Lipase or Amylase  Elevations 
Grade 1 or Grade 2 
Continue at current dose level.  More frequent monitoring is 
recommended 
Grade 3 
 Interrupt treatment 
 Monitor lipase and amylase weekly 
 Upon resolution to Grade ≤ 1 or baseline, cabozantinib may 
be restarted at the same dose or at a reduced dose provided 
that this occurs within 6 weeks. 
 If retreatment following Grade 3 lipase or amylase elevation 
is at the same dose and Grade 3 elevations recur, then 
treatment must be interrupted again until lipase and amylase  
levels have resolved to Grade ≤ 1 or baseline and 
retreatment must be at a reduced dose. 
Grade 4 
 Interrupt treatment 
 Monitor lipase and amylase weekly 
 Upon resolution to Grade ≤ 1 or baseline and if resolution 
occurred within 4 days, cabozantinib may be restarted at the 
same dose or a reduced dose.  If resolution took more than 4 
days, the dose must be reduced upon retreatment provided 
that resolution occurred within 6 weeks. 
 If retreatment following Grade 4 lipase or amylase elevation 
is at the same dose and Grade 3 or 4 elevations recur, then 
treatment must be interrupted again until lipase and amylase 
have resolved to Grade ≤ 1 or baseline and retreatment must 
be at a reduced dose. 
 


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Table 9:  Symptomatic Pancreatitis 
Pancreatitis 
Grade 2 
 Interrupt treatment 
 Monitor lipase and amylase weekly 
 Upon resolution to Grade ≤ 1 or baseline, cabozantinib may 
be restarted at the same dose or at a reduced dose provided 
that this occurs within 6 weeks. 
 If retreatment following Grade 2 pancreatitis is at the same 
dose and Grade 2 pancreatitis recurs, then treatment must be 
interrupted again until resolution to Grade ≤ 1 or baseline 
and retreatment must be at a reduced dose. 
Grade 3 
 Interrupt treatment 
 Monitor lipase and amylase weekly 
 Upon resolution to Grade ≤ 1 or baseline, cabozantinib may 
be restarted at a reduced dose if resolution occurred within 6 
weeks 
Grade 4 
Permanently discontinue treatment.  However, if the subject was 
unequivocally deriving benefit from cabozantinib therapy, 
treatment may resume at a reduced dose per investigator judgment. 
 
6.3.6 Skin Disorders 
Palmar-plantar erythrodysesthesia syndrome (also known as hand-foot syndrome), skin 
rash (including blisters, erythematous rash, macular rash, skin exfoliation, dermatitis 
acneiform, and papular rash), pruritus, dry skin, and erythema have been reported in 
cabozantinib-treated subjects. All subjects on study should be advised on prophylactic 
skin care. This includes the use of hypoallergenic moisturizing creams, ointment for dry 
skin, and sunscreen with sun protection factor ≥ 30, avoidance of exposure of hands and 
feet to hot water, protection of pressure-sensitive areas of hands and feet, and use of 
thick cotton gloves and socks to prevent injury and to keep the palms and soles dry. 
Subjects with skin disorders should be carefully monitored for signs of infection (eg, 
abscess, cellulitis, or impetigo). 
Early signs of hand-foot syndrome could be tingling, numbness, and slight redness or 
mild hyperkeratosis. Early manifestations include painful, symmetrical red and swollen 


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areas on the palms and soles. The lateral sides of the fingers or peri-ungual zones may 
also be affected. Adequate interventions are required to prevent worsening of skin 
symptoms such as blisters, desquamations, ulcerations, or necrosis of affected areas. 
Aggressive management of symptoms is recommended, including early dermatology 
referral. Treatment guidelines for PPE related to study treatment are presented in Table 
10. 
In the case of study treatment-related skin changes (eg, rash, hand-foot syndrome), the 
investigator may request that additional assessments be conducted with the subject’s 
consent. These assessments may include digital photographs of the skin changes and/or 
a biopsy of the affected skin and may be repeated until the skin changes resolve.  
Table 10: Hand-Foot Syndrome 
Hand-Foot Skin Reaction and Hand Foot Syndrome (PPE) 
Grade 1 
Continue cabozantinib at current dose. Start urea 20% cream twice 
daily and clobetasol 0.05% cream once daily. Assess subject at 
least weekly for changes in severity. Subjects should be instructed 
to notify investigator immediately if severity worsens. 
Grade 2 
If tolerable, continue cabozantinib at current dose. 
 
If intolerable, reduce cabozantinib dose to next lower level and/or 
interrupt dosing. Start/continue urea 20% cream twice daily and 
clobetasol 0.05% cream once daily. Add analgesics for pain control 
with NSAIDs/GABA agonists/narcotics if needed. Assess subject at 
least weekly for changes in severity. If treatment was interrupted 
(but not reduced), treatment may be restarted at the same dose or at 
one dose level lower when reaction decreases to Grade 1 or 0. If a 
treatment interruption is again required, the dose must be reduced 
when treatment resumes. 
 
Subjects should be instructed to notify investigator immediately if 
severity worsens. If severity worsens at any time, or affects 
self-care, proceed to the management guidelines for Grade 3 PPE. 
Grade 3 
Interrupt study treatment until severity decreases to Grade 1 or 0. 
Start/continue urea 20% cream twice daily and clobetasol 0.05% 
cream once daily. Pain control with NSAIDs/GABA 
agonists/narcotics. Treatment may restart at one dose level lower 
when reaction decreases to Grade 1 or 0. Permanently discontinue 
subject from study if reactions worsen or do not improve within 6 
weeks.  
GABA, γ-aminobutyric acid; NSAID, nonsteroidal anti-inflammatory drugs; PPE, palmar-plantar erythrodysesthesia 


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6.3.7 Thromboembolic Events 
Thromboembolic complications are frequent in cancer patients due to procoagulant 
changes induced by the malignancy or anticancer therapy including inhibitors of VEGF 
pathways. Deep vein thrombosis and PE have been observed in clinical studies with 
cabozantinib; including fatal events (please refer to the Investigator’s Brochure). 
Subjects who develop a PE or DVT should have cabozantinib treatment held until 
therapeutic anticoagulation with heparins (eg, low molecular weight heparin [LMWH]) 
is established. (Note: Therapeutic anticoagulation with oral anticoagulants, eg, warfarin, 
or oral platelet inhibitors such as clopidogrel is not allowed in this study). Cabozantinib 
treatment may be resumed in subjects who are stable and have uncomplicated PE or 
DVT and are deriving clinical benefit from cabozantinib treatment. During 
anticoagulation treatment, subjects need to be monitored on an ongoing basis for 
bleeding risk and signs of bleeding which may require additional or more frequent 
laboratory tests in accordance to institutional guidelines. If there are any signs of 
clinically significant bleedings, cabozantinib treatment should be permanently 
discontinued. 
Arterial thrombotic events (eg, transient ischemic attack, myocardial infarction) have 
been observed in studies with cabozantinib. Subjects should be evaluated for preexisting 
risk factors for arterial thrombotic events such as diabetes mellitus, hyperlipidemia, 
hypertension, coronary artery disease, history of tobacco use, and cardiac or 
thromboembolic events that occurred before initiation of study treatment. Cabozantinib 
treatment should be discontinued in subjects who develop an acute myocardial infarction 
or any other clinically relevant arterial thromboembolic complication. 
 
6.3.8 Hypertension 
Hypertension is a common class effect of drugs that inhibit VEGF pathways and has 
been reported among subjects treated with cabozantinib. 
Blood pressure should be monitored in a constant position at each visit (either sitting or 
supine). Treatment guidelines for hypertension deemed related to cabozantinib are 
presented in Table 11. In general, subjects with known hypertension should be optimally 
managed before study entry. Decisions to decrease or hold the dose of study treatment 
must be based on blood pressure readings taken by a medical professional and must be 
confirmed with a second measurement at least 5 minutes after the first measurement. 


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Other than for hypertension requiring immediate therapy, the presence of new or 
worsened hypertension should be confirmed at a second visit before taking therapeutic 
action. It is recommended that this second visit occurs within 1 week. 
 
Table 11:  Management of Hypertension Related to Cabozantinib 
Criteria for Dose Modifications 
Treatment/cabozantinib Dose Modification 
Subjects not receiving optimized anti-hypertensive therapy 
> 150 mm Hg (systolic) and < 160 
mm Hg 
or 
> 100 mm Hg (diastolic) and < 110 
mm Hg 
 
 
 Increase antihypertension therapy (ie, increase 
dose of existing medications and/or add new 
antihypertensive medications) ; 
 Maintain dose of cabozantinib; 
 If optimal antihypertensive therapy (usually to 
include 3 agents) does not result in blood pressure 
< 140 systolic or < 90 diastolic, or if the subject is 
symptomatic, the dose of cabozantinib should be 
interrupted and/or reduced. 
≥ 160 mm Hg (systolic) and < 180 
mm Hg 
or 
≥ 110 mm Hg (diastolic) and < 120 
mm Hg 
 Interrupt and/or reduce cabozantinib by one dose 
level; 
 Increase antihypertension therapy (ie, increase 
dose of existing medications and/or add new 
antihypertensive medications) ; 
 Monitor subject closely for hypotension; 
 If optimal antihypertensive therapy (usually to 
include 3 agents) does not result in blood pressure 
< 150 systolic or < 100 diastolic, dose of 
cabozantinib should be reduced further. 
≥ 180 mm Hg (systolic) 
or 
≥ 120 mm Hg (diastolic ) 
 Interrupt treatment with cabozantinib Add new or 
additional anti-hypertensive medications and/or 
increase dose of existing medications; 
 Monitor subject closely for hypotension; 
 When SBP < 150 and DBP < 100, restart 
cabozantinib treatment at one dose level lower; 
 If optimal antihypertensive therapy (usually to 
include 3 agents) does not result in blood pressure 
< 150 systolic or < 100 diastolic, dose of 
cabozantinib should be reduced further. 
Hypertensive emergency or 
hypertensive encephalopathy 
Discontinue all study treatment 
BP, blood pressure, SBP systolic blood pressure, DBP diastolic blood pressure 
NOTE: If SBP and DBP meet different criteria in table, manage per higher dose-modification criteria 
 
 


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6.3.9 Proteinuria 
Proteinuria is an anticipated AE with the inhibition of VEGF pathways and has been 
observed in cabozantinib clinical studies, and nephrotic syndrome has been reported 
with cabozantinib and other inhibitors of VEGF pathways. Management guidelines are 
provided in Table 12. 
  Table 12: Management of Treatment Emergent Proteinuria 
Severity of 
Proteinuria 
(UPCR) 
Action To Be Taken 
≤ 1 mg/mg  
(≤ 113.1 mg/mmol) 
 No change in cabozantinib treatment or monitoring. 
> 1 and < 3.5 mg/mg 
(> 113.1 and 
< 395.9 mg/mmol) 
 No change in cabozantinib treatment required;  
 Consider confirming with a 24-hour protein assessment 
within 7 days; 
 Repeat UPCR within 7 days and once per week. If 
UPCR < 1 on 2 consecutive readings, UPCR monitoring 
can revert to protocol-specific times. (Second reading is 
confirmatory and can be done within 1 week of first 
reading). 
≥ 3.5 mg/mg 
(≥ 395.9 mg/mmol) 
 
 Hold cabozantinib treatment pending repeat UPCR 
within 7 days and/or 24-hour urine protein; 
 If ≥ 3.5 on repeat UPCR, continue to hold cabozantinib 
treatment and check UPCR every 7 days. If UPCR 
decreases to < 2, restart cabozantinib treatment at a 
reduced dose and monitoring of urine protein/creatinine 
should continue weekly until the UPCR decreases to < 1. 
Nephrotic syndrome  Discontinue cabozantinib treatment. 
UPCR, urine protein to creatinine ratio. 
 
6.3.10 Hemorrhage 
Hemorrhagic events have been reported with approved drugs that inhibit VEGF 
pathways as well as with cabozantinib. In order to mitigate risk of severe hemorrhage, 
subjects should be evaluated for potential bleeding risk factors before initiating 
cabozantinib treatment and monitored for bleeding events with serial complete blood 
counts and physical examination while on study. Risk factors for hemorrhagic events 
may include (but may not be limited to) the following: 


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 
Tumor of the lung with cavitary lesions or tumor lesions which invades, 
encases, or abuts major blood vessels. The anatomic location and 
characteristics of tumor as well as the medical history must be carefully 
reviewed in the selection of subjects for treatment with cabozantinib; 
 
Recent or concurrent radiation to the thoracic cavity; 
 
Active peptic ulcer disease, ulcerative colitis, and other inflammatory GI 
diseases; 
 
Underlying medical conditions which affect normal hemostasis (eg, 
deficiencies in clotting factors and/or platelet function, or thrombocytopenia); 
 
Concomitant medication with anticoagulants or other drugs which affect 
normal hemostasis; 
 
History of clinically significant hemoptysis. 
Discontinue cabozantinib treatment in subjects who have been diagnosed with a 
severe bleeding complication. 
6.3.11 Rectal and Perirectal Abscess 
Rectal and perirectal abscesses have been reported, sometimes in subjects with 
concurrent diarrhea. These should be treated with appropriate local care and antibiotic 
therapy. Cabozantinib should be held until adequate healing has taken place. 
6.3.12 GI Perforation/Fistula and Non-GI Fistula Formation 
GI perforation/fistula and non-GI fistula formation have been reported with approved 
drugs that inhibit VEGF pathways as well as with cabozantinib. Carefully monitor for 
episodes of abdominal pain, especially among subjects with known risk factors for 
developing GI perforation/fistula, and carefully monitor subjects with known risk factors 
for non-GI fistula, to allow for early diagnosis. Such risk factors include (but may not be 
limited to) the following: 
GI perforation/fistula: 
 Intra-abdominal tumor/metastases invading GI mucosa; 


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 Active peptic ulcer disease, inflammatory bowel disease, diverticulitis, cholecystitis 
or symptomatic cholangitis, or appendicitis; 
 History of abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal 
abscess; 
 Prior GI surgery (particularly when associated with delayed or incomplete healing). 
Complete healing after abdominal surgery or resolution of intra-abdominal abscess 
must be confirmed before initiating treatment with cabozantinib. 
Additional risk factors include concurrent chronic use of steroid treatment or nonsteroidal 
anti-inflammatory drugs. Constipation indicative of bowel obstruction should be 
monitored and effectively managed.  
Non-GI fistula: 
Complications from radiation therapy has been identified as a possible predisposing risk 
factor for non-GI fistula formation among subjects undergoing treatment with VEGF 
pathway inhibitors (eg, bevacizumab). Patients with endotracheal or endobronchial tumor 
should not be treated with cabozantinib 
Discontinue cabozantinib treatment in subjects who have been diagnosed with GI or 
non-GI perforation/fistula. 
6.3.13 Wound Healing and Surgery 
VEGFR inhibitors can cause wound healing complications and wound dehiscence which 
may occur even long after a wound has been considered healed. Therefore, surgical and 
traumatic wounds must have completely healed before starting cabozantinib treatment and 
be monitored for wound dehiscence or wound infection while the subject is being treated 
with cabozantinib. If possible, cabozantinib treatment should be stopped for at least 28 
days prior to major surgery. 
6.3.14 Hypophosphatemia 
Hypophosphatemia has been reported during treatment with cabozantinib. Serum 
phosphorus should be monitored frequently while receiving cabozantinib. Other causes of 
hypophosphatemia should be ruled out and/or these causes treated in accordance to 
standard of care. Mild to moderate hypophosphatemia should be managed by oral 


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replacement including food that are high in phosphate (diary items, meats, beans) and/or 
oral phosphate supplements in accordance to standard clinical practice guidelines.  
Clinically relevant hypophosphatemia should be managed in accordance to the dose 
modification guidelines. 
6.3.15 Thyroid Function Disorders 
Changes in thyroid function tests (TFTs) and hypothyroidism have been reported with 
cabozantinib and other tyrosine kinase inhibitor treatment as a result of altered thyroid 
hormone regulation by mechanisms that seem to be specific for each agent (Torino et al. 
2009). Preliminary data from ongoing studies indicate that treatment-emergent elevation 
of thyroid stimulating hormone (TSH) by cabozantinib may be dose-dependent in fashion. 
Hyperthyroidism has also been reported. Currently available data are insufficient to 
determine the mechanism of TFT alterations and its clinical relevance. Routine monitoring 
of thyroid function and assessments for signs and symptoms associated with thyroid 
dysfunction is recommended before initiation and during treatment with cabozantinib. 
Management of thyroid dysfunction (eg, symptomatic hypothyroidism) should follow 
accepted clinical practice guidelines and dose modification guidelines. 
6.3.16 Guidelines for Prevention of Osteonecrosis of the Jaw 
Osteonecrosis of the jaw (ONJ) has been reported with use of anti-angiogenic drugs and 
bisphosphonates and denosumab in cancer patients. Additional risk factors for ONJ have 
been identified such as use of corticosteroids, chemotherapy, local radiotherapy, poor oral 
hygiene, smoking, dental or orofacial surgery procedures, and cancer disease itself. 
Osteonecrosis has been reported among subjects treated with cabozantinib, the details of 
which are provided in the current version of Investigator’s Brochure. As a preventive 
measure, invasive dental procedures should be avoided if possible in subjects who have 
previously been treated with or concomitantly receive bisphosphonates or denosumab. 
In cases where dental procedures are unavoidable, the risks and benefits of a dental 
procedure and the extent of the procedure as well as the risk of developing ONJ need to be 
considered when deciding on the duration of a temporary treatment interruption of 
cabozantinib. If clinically possible, treatment with cabozantinib should be held for 
approximately 4 weeks before a dental procedure and resumed after complete healing has 
occurred. 


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Subjects with any documented case of osteonecrosis should have study treatment 
interrupted, and appropriate clinical management should be initiated. Reinitiation of 
study treatment must be discussed with and approved by the Sponsor on a case-by-case 
basis. 
6.3.17 Guidelines for Management of Treatment-Emergent Corrected QT (QTc) 
The effect of orally administered cabozantinib at 140 mg/day (free-base equivalent) on 
QTc interval was evaluated in a randomized, double-blinded, placebo-controlled phase 3 
study in patients with medullary thyroid carcinoma. A mean increase in QTcF of 10 - 15 
ms was observed at 4 weeks after initiating cabozantinib. A concentration-QTc 
relationship could not be definitively established. Changes in cardiac wave form 
morphology or new rhythms were not observed. Accordingly, subjects in this study will 
be monitored for potential QT effects. 
Other factors which may contribute to QTc prolongation include: 
 Treatment with other drugs associated with QTc prolongation (see 
http://www.qtdrugs.org); 
 Treatment with CyP 3A4 inhibitors (which may increase cabozantinib drug 
levels); 
 Electrolyte changes (hypokalemia, hypocalcemia, hypomagnesemia); 
 Medical conditions which can alter electrolyte status eg, severe or prolonged 
diarrhea. 
Subjects having any of these additional risk factors while on cabozantinib must have 
electrocardiograms (ECGs) performed approximately one week after the onset of these 
factors. 
If at any time on study there is an increase in QTc to an absolute value > 500 msec, two 
additional ECGs should be performed within 30 minutes after the initial ECG with 
intervals not less than 3 minutes apart. If the average QTc calculated by the Friderica 
formula (QTcF) from the three ECGs is > 500 msec, study treatment must be withheld 
and the following actions should be taken: 


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 Check electrolytes, especially potassium, magnesium and calcium. Correct 
abnormalities as clinically indicated; 
 If possible, discontinue any QTc-prolonging concomitant medications; 
 Repeat ECG triplets hourly until the average QTcF is ≤ 500 msec or otherwise 
determined by consultation with a cardiologist. 
The Sponsor should be notified immediately of any QTc prolongation event: 
Subjects with QTc prolongation and symptoms must be monitored closely until the QTc 
elevation has resolved. Cardiology consultation is recommended for evaluation and 
subject management. Symptomatic subjects must be treated in accordance with standard 
clinical practice. No additional study treatment is to be given to the subject until after the 
event has resolved, the subject has been thoroughly evaluated, and further treatment has 
been agreed to by the Sponsor. If any additional study treatment is given (eg, after 
correction of electrolyte abnormalities and normalization of QTcF), it will be at a 
reduced dose as agreed to by the investigator and the Sponsor. 
7 
EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS 
DUE TO TRASTUZUMAB 
There are no reductions in the trastuzumab dose. If adverse events occur that require 
holding trastuzumab, the dose will remain the same once treatment resumes. 
7.1 
Recommendations for Dose Modification of Trastuzumab Based on Cardiac 
Monitoring 
 
Asymptomatic 
LVEF drop 
CTCv3 Grade 3 
CTCv4 Grade 4 
Trastuzumab 
≥10% AND below 
LLN-Hold, repeat EF 
in 4-6 weeks, restart 
if in normal range 
Discontinue 
permanently 
Discontinue 
permanently 
 


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 LVEF can be determined by echocardiogram or MUGA but the same method 
should be used for that patient for all determinations. 
 LVEF of greater than 75% at baseline should be re-reviewed and/or at least 
repeated as it may be falsely elevated. 
 Trastuzumab may be restarted if the 4-6 week repeat LVEF has improved such 
that the hold parameters would no longer apply. 
 Patients who have two consecutive or three intermittent “holds” of trastuzumab 
should have trastuzumab discontinued permanently. 
 If trastuzumab is discontinued, patients may still remain on study and receive 
cabozantinib, if parameters are met for administration of this agent. 
7.2 
Management of Acute Infusion Syndrome 
During the first infusion with trastuzumab, a symptom complex consisting of chills and/or 
fever is observed commonly in patients. Other signs and/or symptoms may include 
nausea, vomiting, pain, rigors, headache, cough, dizziness, rash, and asthenia. These 
symptoms are usually mild to moderate in severity, and occur infrequently with 
subsequent trastuzumab infusion. These symptoms can be treated with an 
analgesic/antipyretic such as meperidine, or an antihistamine such as diphenhydramine. 
Serious adverse reactions to trastuzumab infusion including dyspnea, hypotension, 
wheezing, bronchospasm, tachycardia, reduced oxygen saturation and respiratory distress 
have been reported infrequently. In rare cases, these events were associated with a clinical 
course culminating in a fatal outcome. Serious reactions have been treated with supportive 
therapy such as oxygen, beta-agonists, corticosteroids, and withdrawal of trastuzumab as 
indicated. 
If patients develop an infusion reaction: 
 Stop trastuzumab infusion and notify physician. 
 Assess vital signs. 
 Administer acetaminophen 650 mg PO. 


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 Consider administration of: meperidine (Demerol®) 50 mg IM, Benadryl® 50 mg 
IV, Ranitidine 50 mg IV or cimetidine 300 mg IV, and dexamethasone 10 mg IV.  
It is acceptable to administer meperidine (Demerol®) intravenously. 
 If vital signs stable, resume trastuzumab infusion. 
 Patients tend not to develop infusion syndromes with subsequent cycles. No 
standard premedication is required for future treatments if patients have developed 
an infusion syndrome. Patients may be given acetaminophen prior to treatments. 
 If a grade 3 or 4 toxicity occurs during an infusion of trastuzumab, the infusion 
must be immediately stopped. The patient must be monitored for a minimum of 1 
hour after the infusion is stopped. If an outpatient, the patient must be admitted to 
the hospital for monitoring if the toxicity does not resolve within 3 hours. 
 If a grade 3 or 4 toxicity occurs during the post-infusion observation period, the 
patient must be evaluated for a minimum of 1 hour from the time the toxicity was 
first noticed. If an outpatient, the patient must be admitted to the hospital for 
monitoring if the toxicity does not resolve within that hour. 
8 
DRUG FORMULATION AND STORAGE 
8.1 
Cabozantinib 
8.1.1  Description 
Chemical Name: N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N’-(4-
fluorophenyl)cyclopropane-1,1-dicarboxamide, (2S)-hydroxybutanedioate 
8.1.2 Form – Cabozantinib Tablets 
Exelixis internal number: XL184 
Exelixis will provide each investigator with adequate supplies of cabozantinib, which 
will be supplied as 60-mg, and 20-mg yellow film-coated tablets. The 60-mg tablets are 
oval, and the 20-mg tablets are round. The components of the tablets are listed in Table 
13. 
 
 


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Table 13: Cabozantinib Tablet Components and Composition 
 
 
 
 
 
 
 
 
 
8.1.3 Storage & Stability 
Cabozantinib must be stored at controlled room temperature 
8.1.4 Compatibility 
Ingredient  
Function 
% w/w
Cabozantinib Drug Substance (25% drug load 
as free base) 
Active Ingredient 
31.7 
Microcrystalline Cellulose (Avicel PH-102) 
Filler 
38.9 
Lactose Anhydrous (60M) 
Filler 
19.4 
Hydroxypropyl Cellulose (EXF) 
Binder 
3.0 
Croscarmellose Sodium (Ac-Di-Sol) 
Disenegrant 
6.0 
Colloidal Silicon Dioxide, 
Glidant 
0.3 
Magnesium Stearate 
Lubricant 
0.75 
Opadry Yellow Film Coating which includes: 
- 
HPMC 2910 / Hypromellose 6 cp  
- 
Titanium dioxide  
- 
Triacetin  
- 
Iron Oxide Yellow 
Film Coating 
4.00 


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Not applicable 
8.1.5 Availability 
Cabozantinib is an investigational agent and will be supplied free-of-charge from 
Exelixis. 
8.1.6 Preparation 
Not applicable 
8.1.7 Ordering 
Cabozantinib will be provided by Exelixis. 
8.1.8 Accountability 
The investigator, or a responsible party designated by the investigator, must maintain 
a careful record of the inventory and disposition of cabozantinib using the NCI Drug 
Accountability Record or another comparable drug accountability form.  
8.1.9 Destruction and Return 
At the end of the study, unused supplies of cabozantinib should be destroyed 
according to institutional policies. Destruction will be documented in the Drug 
Accountability Record Form. 
8.2 
Trastuzumab 
8.2.1 Product Description 
Trastuzumab is commercially available. Trastuzumab Lyophilized Formulation is 
supplied as a freeze-dried preparation at a nominal content of either 440 mg or 150 mg 
per vial for parenteral administration (may vary based upon commercial availability). 
The drug is formulated in histidine, trehalose, and polysorbate 20. 
8.2.2 Formulation 
 
Each 440 mg vial is reconstituted with 20mL of Bacteriostatic Water for Injection 
(BWI), USP (containing 1.1% benzyl alcohol), which is supplied with each vial. The 
reconstituted solution contains 21 mg/mL Herceptin and will be added to 250 mL of 


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0.9% Sodium Chloride Injection, USP.  The reconstituted formulation (440 mg vial) is 
designed for multiple use.  Unused drug may be stored for 28 days at 2ºC-8ºC (36ºF-
46ºF).   
Each 150 mg vial is reconstituted with 7.4 mL of Sterile Water for Injection (SWFI). 
The reconstituted solution contains 21 mg/mL trastuzumab and will be added to 250 ml 
of 0.9% Sodium Chloride Injection, USP. Use the Herceptin solution immediately 
following reconstitution with SWFI, as it contains no preservative. If not used 
immediately, store the reconstituted Herceptin solution for up to 24 hours at 2ºC-8ºC  ; 
discard any unused Herceptin after 24 hours. 
8.2.3 Storage 
 
DO NOT FREEZE. Trastuzumab may be sensitive to shear-induced stress (e.g. agitation 
or rapid expulsion from a syringe). DO NOT SHAKE. Vigorous handling of solutions 
trastuzumab results in aggregation of the protein and may create cloudy solutions. 
 
Reconstituted trastuzumab should be clear to slightly opalescent and colorless to pale 
yellow. 
 
9 
CORRELATIVE / SPECIAL STUDIES METHODS 
9.1 
Evaluate c-Met and phosphor-c-Met expression in FFPE tumor tissue (and optional 
baseline tumor biopsies, if available) 
FFPE tissue sections will be deparaffinized prior to antigen retrieval, blocking, and 
incubation with primary antibodies. Patients will be dichotomized as to whether or not 
their tumor expresses c-Met and the association between expression and response to 
cabozantinib will be evaluated. 
 
Please refer to Appendix F for archival tissue guidelines. 
 
9.2 
Evaluate the incidence of c-Met positive circulating tumor cells at baseline 
Peripheral blood will be collected at baseline for evaluation of c-met amplification in 
circulating tumor cells (CTCs). Two tubes of whole blood will be collected in CellSave 
tubes.  CTCs will be collected using the automated CellSearch processing technique 
(Veridex).  The captured cells are permeabilized and labeled with cytokeratin CD45 


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specific antibodies, and the nuclear stain ‘4-6-Diamidino-2-phenylindole (DAPI), and 
analyzed by semi-automated counting of appropriately labeled CTCs (Riethdorf et al, 
2007). CTCs are defined as CD45 negative and positive for cytokeratin and DAPI. 
Stained cells are collected by the Veridex system in a “MagNest” cartridge. This 
cartridge is automatically scanned. Semi-automated counting is performed according to 
the manufacturer’s instructions by a trained pathologist. The MET/CEP 7 bacterial 
artificial chromosome (BAC) probe will be obtained from Vysis Molecular (Abbot Park, 
Illinois). BAC MET (RP11-95I20) will be obtained from CHORI (Children’s Hospital 
of Oakland Research Hospital). Labeling will be completed with the Nick Translation 
Kit (Vysis Molecular (Abbot Park, Illinois). Slides will be maintained in a horizontal 
position throughout the entire hybridization and washing procedure.  Briefly, cells are 
fixed with methanol-acetic acid (3:1), dehydrated in an alcohol series (50%, 75%, 90%, 
100%) and air-dried. Five microliters of the probe mixture are applied, and the slides are 
covered with cover glass and sealed with rubber cement. Pre-hybridization is done with 
hybridization buffer without dextran sulfate for 1 hour at 37oC. Denaturation is 
performed at 94oC for 5 minutes. Hybridization is completed overnight at 37oC. 
Following hybridization, slides are washed in 1x SSC 3 times for 10 minutes each at 
37oC (maintaining the horizontal position), briefly air dried, and counterstained with 
Vectashield/DAPI (Vector). Two-color FISH slides will be created for each MET 
amplification analysis. Manual quantification of tumor cells will be performed by 
determining the total number of whole nuclei (DAPI-positive signals).  This will be 
performed in Dr. Cloud Paweletz’s laboratory at Dana-Farber Cancer Institute. 
Patients will be grouped as to whether or not their tumor has amplified Met and the 
association between amplification and response to cabozantinib will be evaluated. 
Please refer to Appendix F for specimen collection and shipping 
guidelines. 
 
9.3 
Evaluate potential plasma biomarkers of cabozantinib 
Exploratory analyses of potential biomarkers of cabozantinib activity will be performed by 
measuring proteins in the plasma and circulating cells at baseline, on day 8, day 1 of each cycle 
of therapy, and, if available, at the end of treatment. 8cc of blood will be collected in purple top 
(plasma EDTA) vacutainers, with a minimum of 5cc required. Each sample will be shipped on 
wet ice to the Steele Laboratory at MGH. Blood will be separated by centrifugation into plasma 
and a cellular phase by standard methods. The plasma will be prepared in standard fashion and 
stored at –78 degrees Celsius until analysis. After plasma separation, we will use the cellular 


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fraction for flow cytometric analyses of lymphocytes and myeloid cell populations. We will 
enumerate cells using CD3, CD4, CD8, CD14, CD25, CD34, CD45, CD56, CD117, CD127 and 
CD133, using established protocols and an LSR-II flow cytometer available in the Steele 
Lanboratories. Plasma analysis will be carried out for a panel of circulating angiogenic and 
inflammatory molecules previously identified as potential biomarkers of response to anti-VEGF 
therapy in breast cancer patients. They include vascular endothelial growth factor (VEGF), 
placental-derived growth factor (PlGF), soluble (s)VEGFR1, and basic fibroblast growth factor 
(bFGF), using 1 multiplex (4-plex) protein array from Meso-Scale Discovery (Gaithersburg, 
MD), and stromal-derived factor 1 (SDF1) using ELISA from R&D Systems (Minneapolis, 
MN). In addition, we will measure the plasma concentration of biomarkers that are related to 
cabozantinib activity: HGF, s-MET, s-c-KIT and sVEGFR2 using ELISA from R&D Systems 
(Minneapolis, MN). Finally, we will evaluate biomarkers of tumor hypoxia, by measuring 
plasma carbonic anhydrase IX (CAIX) levels as well as biomarkers of osteoclast and osteoblast 
activity (plasma C-telopeptide and total alkaline phosphatase) using ELISA from R&D Systems 
(Minneapolis, MN). Samples will be run in duplicate. The number of circulating cells will be 
evaluated by using cell counters at routine visits and by flow cytometry in fresh blood samples 
collected at the same time-points as for plasma measurements.  
 
Please refer to Appendix F for specimen collection and shipping 
guidelines. 
 
9.4 
Cerebral blood volume, blood flow, vessel size, tumor infiltration 
Two broad approaches have been taken to assess the vascularity of tumors: T1-based, 
dynamic contrast enhanced (DCE) MRI; and T2-based, termed dynamic susceptibility 
contrast (DSC) MRI. There are limitations to DCE-MRI, because enhancement depends 
on multiple factors (blood flow, blood volume, permeability and surface area of the 
capillary bed). It is therefore important to measure both blood flow and blood volume.  
The following measurements will be described at baseline and following the first cycle of 
cabozantinib (on Cycle 2 Day 1). These analyses are exploratory and hypothesis-
generating only. Any promising findings will be further studied in future clinical trials. 
 Perfusion MRI Markers 
We will quantitatively describe relative cerebral blood volume/flow (rCBS, rCBF), 
mean transit time (MTT), and mean vessel diameter from perfusion-weighted MRI 
(PWI) and arterial spin labeling.  
 Permeability 


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We will measure the permeability surface area product on a voxel-by-voxel basis 
as well other permeability imaging parameters such as Ve, the volume of 
extravascular extracellular space.  
 Diffusion 
We will measure the full water self-diffusion tensor on a voxel-by-voxel basis. 
Water mobility can regionally increase due to tissue edema, increased matrix 
degradation caused by tumor invasion, and/or tumor necrosis. We will also 
measure tensor fractional anisotropy (FA); FA can be used to define white matter 
tract directions, and tumor invasion may induce effects like displacement, 
infiltration, or disruption of white matter tracts. 
 Resting State (optional) 
We will measure the default mode connectivity using functional MRI to assess the 
infiltration, or disruption of white matter tracts. 
 MR Spectroscopy (optional) 
We will obtain MRS to look at tumor metabolites and tumor infiltration 
9.5 
Pain Assessments 
For the purpose of determining the effect of cabozantinib treatment on pain and 
analgesic medication usage, pain will be assessed by a participant-reported 
questionnaire, and daily analgesic medication usage will be recorded during regular 
intervals.  All participants are required to complete assessments, regardless of whether 
pain is present or analgesic medications are being taken at baseline. 
Pain assessments will consist of patient-reported responses to a questionnaire (see 
Appendix B), administered by paper, in which participants will be asked to rate their 
pain and degree of interference in daily activities due to pain over the prior 24 hours. 
The participant will complete this pain questionnaire each day for a 7-day interval 
within 14 days before the first dose of cabozantinib and at 7-day intervals during Week 
3 and the last week of the cycles that patients are scanned on ( ie end of cycle 2, 4, 6, 9, 12, etc.) 
until the date of the participant’s last follow-up visit.    


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Analgesic medications will be recorded on a daily participant diary matching the dates 
of the pain questionnaire (described above). Analgesic medications to be recorded on the 
diary include narcotics and corticosteroids used to treat pain symptoms.  Every effort 
should be made to collect responses for every day during the 7 day assessment interval.  
However, collection of a minimum of 4 out of the 7 days in the interval (need not be 
consecutive) will be deemed sufficient for assessment completion. 
The pain questionnaire and analgesic medication diary will be due on the last 
week of the cycles that patients are scanned on ( ie end of cycle 2, 4, 6, 9, 12, etc.)until the date 
of the participant’s last follow-up visit. The first pain questionnaire completed can be used 
to report pain that the participant experienced the week prior to the date of the study consent 
signature.   
9.6 
Tumor biopsies 
With agreement of the investigator and with the participant’s consent tumor tissue 
samples may be optionally collected, preferentially, during the screening period 
(preferably 1-2 weeks prior to initiation of cabozantinib treatment).  
Please refer to Appendix F for specimen collection and shipping guidelines. 
 
Tumor analyses may involve evaluation of the signaling pathways related to 
cabozantinib targets (eg, VEGFR, MET, KIT, RET) and include methods such as 
genotyping, fluorescence in situ hybridization (FISH) and/or Immuno-histochemistry 
(IHC). Mutation and/or amplification status of disease-specific tumor-promoters or 
suppressors may also be determined to characterize the potential impact on response or 
resistance to cabozantinib (eg, HER2, EGFR, KRAS, NRAS, BRAF, PTEN, PIK3CA, 
TP53). Broader genome-wide copy number and mutation profiling may also be 
conducted. For paired tumor biopsies pharmacodynamic markers such as pMET/MET, 
pVEGFR2/VEGFR2, pERK/ERK, pAKT/AKT and pKIT/KIT may also be analyzed by 
IHC. 
9.7 
Blood sample collection 
Blood will be collected at baseline and the end of treatment for the analysis of cfDNA 
and to be processed by the DF/HCC Clinical Trials Core Laboratory and then banked in 
the DF/HCC Clinical Trials Core laboratory for future research purposes.   


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One 10 ml of whole blood will be collected in Streck Tubes.  The blood sample will be 
collected and processed at baseline and at the end of treatment for evaluation of cfDNA.  
Tubes are provided by the Sponsor as needed.   
If the blood collection is missed at baseline or at the time of progression, then the blood 
will be collected at a future appointment.  The banked samples will be used to analyze 
DNA, RNA and protein in future studies. 
Please refer to Appendix F for specimen collection and shipping guidelines and 
Appendix H for additional processing details specific to the laboratories at Dana-Farber 
Cancer Institute.      
 


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10 
STUDY CALENDAR 
All assessments must be performed prior to administration of any study medication.  
Table 14: Study Calendar 
 
Pre-
treatment 
21 Day Cycles 
Assessments/ 
Procedures 
ScreeningA   
C1 D1 
 
C1 D8  
(± 2 days) 
C 2 D1 
(± 4 days) 
C3 D1 and Subsequent 
Odd Cycles Day 1  
(± 4 days) 
C4 D1 
(± 4 days) 
C6 D1 and Subsequent 
Even Cycles Day 1  
(± 4 days) 
Every 2 
Cycles  
(days 16-22) 
Every 4 
Cycles 
(days 16-22) 
End of 
Cabozantinib 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/ 
exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical and 
cancer history 
X 
 
 
X 
X 
X 
X 
 
 
X 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Complete 
physical 
examination 
X 
XB 
X 
X 
X 
X 
X 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Vital signsC 
X 
XB 
X 
X 
X 
X 
X 
 
 
X 
ECOG 
performance 
status 
X 
XB 
X 
X 
X 
X 
X 
 
 
X 
12-lead EKG D 
X 
 
 
X 
 
X 
 
 
 
 
MUGA or 
echocardiogramE 
X 
 
 
 
 
 
 
 
XE 
 
Neurological 
examinationF 
X 
 
X 
X 
X 
X 
X 
 
 
X 
CBC w/ 
differential and 
platelets 
X 
XB 
X 
X 
X 
X 
X 
 
 
X 
Coagulation 
studies (PT/INR 
and PTT) 
X 
XB 
 
X 
X 
X 
 
X 
 
 
X 
Serum 
chemistryG 
X 
XB 
X 
X 
X 
X 
X 
 
 
X 
Amylase/lipase 
X 
XB 
 
X 
X 
X 
X 
 
 
X 
Urine protein and 
creatinineH 
X 
XB 
 
 
X 
 
 
 
 
X 


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Pre-
treatment 
21 Day Cycles 
Assessments/ 
Procedures 
ScreeningA   
C1 D1 
 
C1 D8  
(± 2 days) 
C 2 D1 
(± 4 days) 
C3 D1 and Subsequent 
Odd Cycles Day 1  
(± 4 days) 
C4 D1 
(± 4 days) 
C6 D1 and Subsequent 
Even Cycles Day 1  
(± 4 days) 
Every 2 
Cycles  
(days 16-22) 
Every 4 
Cycles 
(days 16-22) 
End of 
Cabozantinib 
TSH 
X 
XB 
 
 
X 
 
 
 
 
X 
Research blood 
draw for CTC 
collectionI 
X 
 
 
 
 
 
 
 
 
 
Research blood 
draw for Plasma 
biomarkersJ 
X 
 
X 
X 
XJ 
XJ 
 
XJ 
 
XJ 
Research blood 
draw for cfDNAK 
X 
 
 
 
 
 
 
 
 
XK 
Serum/urine 
pregnancy testL 
X 
 
 
 
 
 
 
 
 
 
Baseline 
Findings  
(CTCAE v.4.0) 
X 
 
 
 
 
 
 
 
 
 
Brain MRIM 
X 
 
 
 
X 
 
 
XM 
 
 
Research MRI  
sequencesN 
X 
 
 
X 
 
 
 
 
 
 
Non-CNS tumor 
evaluation (MRI 
or CT and 
clinical 
assessment of 
visible, palpable 
lesions)M 
X 
 
 
 
X 
 
 
XM 
 
 
Bone scan O 
 
 
 
 
X 
 
 
X M 
 
X M 
CA 27.29 or 
CA15.3 
X 
XB 
 
X 
X 
X 
X 
 
 
X 
Adverse eventsP 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Drug diary  
 
X 
X 
X 
X 
X 
X 
 
 
 
Survival 
 follow-up 
 
 
 
 
 
 
 
 
 
XQ 
Optional biopsyR 
X 
 
 
 
 
 
 
 
 
 
7-day pain 
questionnaireS 
X 
 
 
X 
X S 
 
 
 
 
 
7-day analgesic 
medication 
 diary S 
X 
 
 
X 
X S 
 
 
 
 
 
CabozantinibT 
 
X 
X 
X 
X 
X 
X 
 
 
 


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Pre-
treatment 
21 Day Cycles 
Assessments/ 
Procedures 
ScreeningA   
C1 D1 
 
C1 D8  
(± 2 days) 
C 2 D1 
(± 4 days) 
C3 D1 and Subsequent 
Odd Cycles Day 1  
(± 4 days) 
C4 D1 
(± 4 days) 
C6 D1 and Subsequent 
Even Cycles Day 1  
(± 4 days) 
Every 2 
Cycles  
(days 16-22) 
Every 4 
Cycles 
(days 16-22) 
End of 
Cabozantinib 
TrastuzumabU 
 
X 
 
X 
X 
X 
X 
 
 
 
A   Laboratory tests must occur within 14 days before initial dose of cabozantinib. All other screening assessments must occur within 28 days 
before initial dose of cabozantinib (with the exception of the baseline research MRI sequences, which must be < 7 days of C1D1 dose).  
Informed consent must be provided before any study-specific procedures are performed and within 28 days of registration.    
B  If performed <7 days before the first dose of cabozantinib, these screening procedures do not need to be repeated on Cycle 1 Day 1. If these 
procedures are performed on Cycle 1 Day 1, then the results must be available and reviewed by the treating physician prior to administering 
cabozantinib.  All pre-treatment criteria listed in Section 5.2 must be met in order to begin cabozantinib on Cycle 1 of Day 1. 
C  Includes blood pressure, pulse, respiratory rate, temperature, weight 
D  Three EKGs must be performed at screening. To be eligible, the patient must have an average QTcF of ≤ 500 msec on three consecutive 
results. 
E Only performed in HER2-positive patients currently taking trastuzumab. Evaluation of LVEF to occur at baseline and every 4 cycles. When 
possible, the same modality (e.g. MUGA or ECHO) should be performed for consistency in measurements. 
F    Neurologic examination worksheet (Appendix E) to be completed at baseline and at each study visit, except for Cycle 1 Day 1 the neurological 
examination will be on Cycle 1 Day 8. 
G   Complete serum chemistry panel includes albumin, alkaline phosphatase, ALT, AST, BUN, calcium, chloride, creatinine, glucose, magnesium, 
potassium, phosphorus, sodium, total bilirubin, total protein. Electrolytes do not need to be collected as part of the eligibility assessment (K, 
Phos, Ca, Mg). 
H Spot urine protein and urine creatinine 
I  At baseline, 2 tubes of whole blood will be collected in 10 ml CellSave tubes for CTC analysis.  If this is not performed at screening, then it can 
be collected on C1D1 prior to the start of treatment. 
J    At baseline and at C1D8, C2D1, C3D1, C4D1, C5D1, C6D1 and then every 2 cycles, and at end of treatment, two 10 ml purple top tubes 
(plasma EDTA) will be collected (minimum of 5 cc of blood in each) at each visit.  The purple top tubes will be shipped on wet ice to the 
Steele Laboratory at MGH.  If this is not performed at screening, then it can be collected on C1D1 prior to the start of treatment.  After 18 
weeks (6 cycles) research blood collection for plasma biomarkers should occur at the same time scans are reviewed after a restaging. After 18 
weeks, frequency of restaging scans is reduced to once every 3 cycles (item M above), therefore draws will occur on C7D1, C10D1, C13D1, 
etc. 


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K At baseline and at the end of treatment, 1 tube of whole blood will be collected in a 10 ml Streck tube for cfDNA analysis.  If sample collection 
is missed for any reason at baseline or at the end of treatment then the sample should be drawn at a future appointment.   
L   For women of child bearing potential.  This must be performed within 14 days of C1D1. 
M  Clinical Brain MRI at screening and non-CNS tumor evaluation must be performed within 28 days of Cycle 1 Day 1.  Clinical Brain MRI and 
non-CNS tumor evaluation scans will then be completed within 7 days prior to Cycle 3 Day 1, Cycle 5 Day 1, and Cycle 7 Day 1. Patients 
with stable or responsive disease after completion of 6 cycles may have the frequency of restaging scans reduced to once every 3 
cycles.  For patients who come off cabozantinib for any reason other than disease progression, they will need to undergo a scan at the time 
they come off cabozantinib, and continue undergoing scans every 9 weeks.  They will also need to have a follow-up visit every 6 months. 
N  The research MRI sequences will be performed at Massachusetts General Hospital, Charlestown Navy Yard at Baseline (< 7 days of Cycle 1 
Day 1), and at Cycle 2 day 1 (prior to dose treatment that day). The study coordinator will obtain a copy of the MRI scan to be archived at 
DFCI.  Contact name for Massachusetts General Hospital Charlestown Navy Yard is Stephanie Salcedo (ssalcedo@partners.org).   
O  Bone scans should be performed in any patient with known bone metastases.    
P Adverse events information will be collected at study visits and may, in addition, be collected over the phone. For patients who come off 
cabozantinib for progressive disease, an end of Study Visit should be completed within 30 days (+/- 7 days) of last dose of study drug. 
Q  Follow-up every 6 months or until death 
R For patients that consent to optional biopsy only, preferentially performed 1-2 weeks prior to receiving first dose of study drug. 
S The participant will complete the pain diary and medication diary each day for a 7-day interval within 14 days of the first dose of cabozantinib 
and at 7-day intervals during Week 3 and the last week of the cycles that patients are scanned on ( ie end of cycle 2, 4, 6, 9, 12, etc). Pain 
Questionnaire and Analgesic Medication Diary will also be due  the last week of cycles that patients are scanned on (end of Cycle 2, 4, 6, 9, 12, 
etc.)The first pain questionnaire completed can be used to report pain that the participant experienced the week prior to the date of the study 
consent signature.  Analgesic medications to be recorded on the diary include narcotics and corticosteroids used to treat pain symptoms.  
T   Cabozantinib will be given orally once daily  
U    Trastuzumab will be given to HER2- positive patients (cohorts 1)


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11 
MEASUREMENT OF EFFECT 
Response in the CNS and non-CNS will use RECIST 1.1. Volumetric assessments of 
CNS response will also be conducted. Response and progression in non-CNS sites 
will be evaluated in this study using the new international criteria proposed by the 
Response Evaluation Criteria in Solid Tumors (RECIST) Committee (Therasse, 
2000). Changes in only the largest diameter (unidimensional measurement) of the 
tumor lesions are used in the RECIST 1.1 criteria. For the purposes of this study, 
participants should be re-evaluated for response every 6 weeks. Patients with stable or 
responsive disease after completion of 6 cycles may have the frequency of restaging 
scans reduced to once every 3 cycles. In addition to a baseline scan, confirmatory 
scans should also be obtained 3 weeks following initial documentation of objective 
response. 
Response in the CNS and in non-CNS sites will be evaluated and recorded separately 
in this trial. 
11.1 
Definitions 
Evaluable for toxicity. All participants who receive at least one dose of cabozantinib 
will be evaluable for toxicity from the time of their first treatment. 
Evaluable for objective response. Only those participants who have received at 
least one dose of therapy will be considered evaluable for response. These 
participants will have their response classified according to the definitions stated 
below. (Note: Participants who exhibit objective disease progression or die prior to 
the end of cycle 1 will also be considered evaluable.) All participants who receive at 
least one dose of cabozantinib will be considered in the denominator for calculation 
of objective response rate.  
11.2 
Disease Parameters 
Measurable disease.  
Measurable disease is the presence of at least one (1) lesion that can be 
accurately measured in at least one dimension with longest diameter  >20 millimeters 
(mm) using conventional techniques (CT, MRI, x-ray) or  >10 mm with spiral CT 


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scan. Measurable lesions must be at least 2 times the slice thickness in mm. All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
A lesion in a previously irradiated area is not eligible for measurable disease 
unless there is objective evidence of progression of the lesion prior to study 
enrollment. Lesions in previously irradiated areas must be clearly identified as 
such. 
Clinical lesions. Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes).  
Malignant lymph nodes.  
To be considered pathologically enlarged and measurable, a lymph node must be > 
15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the 
short axis will be measured and followed. 
Non-measurable disease.  
All other lesions (or sites of disease), including small lesions (longest diameter <10 mm 
or pathological lymph nodes with > 10 to < 15mm short axis, are considered non-
measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, abdominal masses 
identified by physical exam that are not measurable by reproducible imaging techniques, 
and cystic lesions are all considered non-measurable. 
Target lesions.  
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and 
recorded and measured at baseline. Lesions must be accurately measured in 1 
dimension. Nodes must have a short axis > 15 mm. The short axis should be included 
in the sum of the lesions in the calculation of response. Nodes that shrink to < 10 mm 
are considered normal. 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).  For CNS and non-CNS 
sites, the sum of the longest diameter (LD) for all target lesions will be calculated 


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and reported as the baseline sum LD.  The baseline sum LD will be used as reference 
by which to characterize the objective tumor response in CNS and non-CNS sites.  
RECIST 1.1 criteria will be used to assess overall response rates for CNS target 
lesions as the primary endpoint. In addition, we will also report non-CNS response 
rates according to RECIST 1.1 criteria and CNS lesion responses according to 
volumetric and composite criteria.  
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross sectional imaging techniques such as CT or MRI can be 
considered target lesions if the soft tissue component meets the definition of measurability 
as defined above. Cystic lesions thought to represent cystic metastases can be considered 
as target lesions. However, if non-cystic lesions are present, these are preferred for 
selection as target lesions. Lesions in previously irradiated areas or areas subject to other 
loco-regional therapy are usually not considered measurable unless there has been 
demonstrated progression of that lesion.  
Non-target lesions.  
All other lesions including small lesions < 10 mm or pathological lymph nodes 
measuring > 10 mm to < 15 mm in short axis, as well as truly non-measurable 
lesions, which include bone lesions that do not meet the requirements of the last 
paragraph, leptomeningeal disease, ascites, pleural or pericardial effusion, 
inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses identified by physical exam that are not measurable by reproducible imaging 
techniques are considered non-target lesions. 
11.3 
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation, using a ruler, calipers, 
or digital measurement tool. All baseline non-CNS 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.  Clinical brain MRI at screening will be performed within 28 
days of Cycle 1 Day 1 and research MRI sequences will be performed within 7 days of 
Cycle 1 Day 1. 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 


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evaluation is preferred to evaluation by clinical examination when both methods have 
been used to assess the anti-tumor effect of a treatment. 
Methods of Evaluation for CNS Measurable Disease 
MRI Brain: Imaging with MRI brain is required for all participants on study to 
evaluate brain lesions. MRI images will include T1-weighted images with and 
without gadolinium contrast, T2-weighted images, and FLAIR (fluid attenuated 
inversion recovery) images. 
 
Methods of Evaluation for Non-CNS Measurable Disease 
Clinical lesions. Measurable skin lesions will be documented by color photography, 
including use of a ruler to estimate the size of the lesion. 
Chest x-ray. Lesions on chest x-ray are acceptable as measurable lesions when they 
are clearly defined and surrounded by aerated lung; however, CT is preferable. 
Conventional CT and MRI. These techniques 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. 
Ultrasound (US). When the primary endpoint of the study is objective response 
evaluation, 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. 
FDG PET and PET/CT. The acquisition of FDG PET and FDG PET/CT scans should 
follow the NCI Guidelines for using FDG PET as an indicator of therapeutic response 
(Shankar et al., 2006). Patients should avoid strenuous exercise and be on a low 
carbohydrate diet for 24 hours prior to the scan. Patients should fast for 4 hours or 
longer prior to the FDG injection and should have a serum glucose of less than 200 
mg/dL at the time of FDG injection. A 10-20 mCi dose of FDG should be injected for 
typical adult patients. For longitudinal studies with multiple scans, particular attention 


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should be paid to ensure consistent patient preparation and acquisition parameters 
between the follow-up scan and the baseline scan.  
Endoscopy, Laparoscopy. The utilization of these techniques for objective tumor 
evaluation has not yet been fully and widely validated. Their uses in this specific 
context require sophisticated equipment and a high level of expertise that may only be 
available in some centers. Therefore, the utilization of such techniques for objective 
tumor response should be restricted to validation purposes in reference centers. 
However, such techniques may be useful to confirm complete pathological response 
when biopsies are obtained. 
Tumor markers. Tumor markers alone cannot be used to assess response.  
11.4 
Response Criteria 
11.4.1 Response Criteria for Target Lesions (RECIST 1.1) 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study).  In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm.  (Note:  the appearance of one or 
more new lesions is also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
11.4.2 Response Criteria for Non-Target Lesions (RECIST 1.1) 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization of 
tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm short 
axis). 


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Note:  If tumor markers are initially above the upper normal limit, they must normalize 
for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance 
of tumor marker level above the normal limits. 
Progressive Disease (PD):  Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not 
normally trump target lesion status.  It must be representative of overall disease status 
change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of 
the treating physician should prevail in such circumstances, and the progression status 
should be confirmed at a later time by the review panel (or Principal Investigator). 
 
11.4.3 Evaluation of New Lesions 
 
The finding of a new lesion should be unequivocal (i.e. not due to difference in scanning 
technique, imaging modality, or findings thought to represent something other than 
tumor (for example, some ‘new’ bone lesions may be simply healing or flare of pre-
existing lesions). However, a lesion identified on a follow-up scan in an anatomical 
location that was not scanned at baseline is considered new and will indicate PD. If a 
new lesion is equivocal (because of small size etc.), follow-up evaluation will clarify if it 
truly represents new disease and if PD is confirmed, progression should be declared 
using the date of the initial scan on which the lesion was discovered. 
 
11.4.4 CNS Volumetric & Composite Response Criteria 
 
RECIST 1.1 criteria will be used to determine response but volumetric/composite 
response will also be done as an exploratory study. 
CNS Complete Response (CR): All of the following must be satisfied: 
 Complete resolution of all measurable (≥ 1 cm diameter) and non-measurable 
brain metastases 
 No new CNS lesions (new lesion defined as ≥ 6 mm diameter) 
 Stable or decreasing steroid dose 
 No new/progressive tumor-related neurologic signs or symptoms 


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 No progression of systemic (non-CNS) disease as assessed by RECIST 
CNS Partial Response (PR): All of the following must be satisfied: 
 ≥ 50% reduction in the volumetric sum of all measurable (≥ 1 cm diameter) brain 
metastases compared to baseline 
 No progression of non-measurable lesions 
 No new lesions (new lesion defined as ≥ 6 mm) 
 Stable or decreasing steroid dose 
 No new/progressive tumor-related neurologic signs or symptoms 
 No progression of systemic (non-CNS) disease as assessed by RECIST 
CNS Stable Disease (SD): All of the following must be satisfied: 
 < 50% reduction in the volumetric sum of all measurable (≥ 1 cm diameter) brain 
metastases compared to baseline, and not fulfilling the criteria for progressive 
disease 
 No progression of non-measurable lesions 
 No new lesions (new lesion defined as ≥ 6 mm) 
 Stable or decreasing steroid dose 
 No new/progressive tumor-related neurologic signs or symptoms 
 No progression of systemic (non-CNS) disease as assessed by RECIST 
Note: CNS lesions were initially evaluable (≥ 1 cm diameter) at baseline and have 
decreased in size on trial therapy to < 1 cm diameter will continue to be assessed 
volumetrically for response. 
CNS Progression (PD): Patients will be considered to have PD if ANY of the following 
are satisfied: 
 ≥40% increase in the volumetric sum of all measurable lesions as compared to 
the smallest volume since protocol-based therapy was initiated, OR 
 Progression of non-measurable lesions*, OR 
 New lesions (new lesion defined as ≥ 6 mm), OR 
 Increasing steroid requirement (As CNS progression is an eligibility requirement, 
increasing steroid dose within 4 weeks after study entry will not necessarily 
constitute disease progression), OR 
 New/progression tumor-related neurologic signs and symptoms (NSS) except for 
transient worsening lasting ≤ 14 days. (As CNS progression is an eligibility 


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requirement, worsening of NSS within 4 weeks after study entry will not 
necessarily constitute disease progression), OR 
 Progression of systemic (non-CNS) disease as assessed by RECIST 
*Note: Progression of non-measurable (non-target) CNS lesions is defined as 
follows: 
 A lesion initially at baseline ≤ 5 mm in diameter that increases to ≥ 10 mm in 
diameter, or 
 A lesion initially at baseline 6-9 mm in diameter that increases by at least 5 
mm in diameter. 
These criteria were chosen to minimize classifying subjects as having progressive 
disease due to MRI sampling error, given an MRI slice thickness of 3 mm. 
Table 15: Summary of Composite Criteria for CNS Response 
 
Complete 
Response 
Partial 
Response 
Stable 
Disease 
Progressive 
Disease 
Qualifying Criteria 
All 
All 
All 
Any 
Brain lesions (volumetric MRI) 
Target 
CR 
≥ 50% volume 
decrease 
< 50% volume 
decrease 
≥ 40% volume 
increase 
Non-target 
None/CR 
None/no progression 
Progression 
New 
None 
Yes 
Steroids 
Stable or decreasing 
Increasing dose 
Neurological 
signs/symptoms 
Stable or improving 
New or 
worsening 
Systemic disease 
(RECIST 1.1) 
No progression 
Progression 
 
11.4.5 Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started). The participant's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria based on RECIST 1.1. 


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Table 16: Criteria for Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response for 
when Confirmation is 
Required: 
CR 
CR 
No 
CR 
>4 wks confirmation 
CR 
Non-CR/Non-PD 
No 
PR 
>4 wks confirmation 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/Not evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/Not evaluated 
No 
SD 
Documented at least once 
>4 wks from baseline 
PD 
Any 
Yes or No
PD 
No prior SD, PR or CR 
Any 
PD* 
Yes or No
PD 
Any 
Any 
Yes 
PD 
* 
In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression. 
Note:   Participants with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
"symptomatic deterioration". Every effort should be made to document the objective progression 
even after discontinuation of treatment. 
 
11.4.6 Duration of Response 
 
Duration of overall response: The duration of overall response is measured from the 
time measurement criteria are met for CR or PR (whichever is first recorded) until the 
first date that recurrence or PD is objectively documented, taking as reference for PD 
the smallest measurements recorded since the treatment started. 
 
Duration of overall complete response: The duration of overall CR is measured from 
the time measurement criteria are first met for CR until the first date that recurrent 
disease is objectively documented. 
 


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Duration of stable disease: Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started. 
 
11.4.7 Progression-Free Survival 
 
Progression-Free Survival (PFS) is defined as the duration of time from start of treatment to 
time of objective disease progression or time of death from any cause, whichever comes 
first.  Included in the definition of progression for PFS are: objective progression of CNS 
lesions on MRI, neurologic deterioration leading to study discontinuation, global 
deterioration of health status requiring discontinuation of treatment, and death. For 
neurologic symptoms, the default will be to assume that worsening of neurologic 
symptoms requiring discontinuation of treatment is related to progressive disease. 
However, it is anticipated that some patients may discontinue due to peripheral 
neuropathy or other neurologic symptoms that are more likely related to cumulative drug 
toxicity rather than CNS progression. For patients who are taken off of protocol treatment 
for a reason(s) other than progression, the date of PFS will be censored at the date of last 
staging study (either while on or off protocol therapy) on which the patient is documented 
not to have progressed, or the date of initiation of alternative anti-cancer therapy, 
whichever comes first. 
11.4.8 Response Review 
 
All CNS and non-CNS responses will be reviewed by an independent radiologist as part 
of the DF/HCC Tumor Imaging Metrics Core (TIMC) facility. CNS response will be 
assessed centrally using the RECIST 1.1 and volumetric criteria outlined. Non-CNS 
scans will also be assessed centrally using RECIST 1.1 and recorded in the CRF by 
individual site personnel.  
 
11.5 
Neurological Signs and Symptoms (NSS) 
Tumor-associated NSS will be recorded on Appendix E at each study visit. 
Improvement or worsening of non-tumor associated NSS will not constitute a change in 
NSS. 
Improvement of NSS will be defined if all of the following are satisfied: 


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 Decrease by 1 or more grades from baseline of any tumor-related NSS, with 
confirmation at least 3 weeks (1 cycle) later 
 No development or worsening in any tumor related NSS during this interval 
 Stable or decreasing steroids during this interval 
In addition, Appendix E contains a global question for the treating investigator, asking 
whether a patient’s neurological status is improved, stable or worse. The response to this 
question will be analyzed in relation to the itemized portion of the NSS worksheet, in 
order to further evaluate the utility of the worksheet in evaluating NSS longitudinally 
over time. 
12 
ADVERSE EVENT REPORTING REQUIREMENTS 
12.1 
Definitions 
12.1.1 Adverse Event (AE) 
An adverse event (AE) is any undesirable sign, symptom or medical condition or 
experience that develops or worsens in severity after starting the first dose of cabozantinib 
or any procedure specified in the protocol, even if the event is not considered to be related 
to the study.  
Abnormal laboratory values or diagnostic test results constitute adverse events only if they 
induce clinical signs or symptoms or require treatment or further diagnostic tests.  
12.1.2 Serious adverse event (SAE) 
A serious adverse event (SAE) is any adverse event, occurring at any dose and regardless 
of causality that:  
 Results in death 
 Is life-threatening. Life-threatening means that the person was at immediate risk 
of death from the reaction as it occurred, i.e., it does not include a reaction which 
hypothetically might have caused death had it occurred in a more severe form. 
 Requires or prolongs inpatient hospitalization (i.e., the event required at least a 
24-hour hospitalization or prolonged a hospitalization beyond the expected 


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length of stay). Hospitalization admissions and/or surgical operations scheduled 
to occur during the study period, but planned prior to study entry are not 
considered SAEs if the illness or disease existed before the person was enrolled 
in the trial, provided that it did not deteriorate in an unexpected manner during 
the trial (e.g., surgery performed earlier than planned). 
 Results in persistent or significant disability/incapacity. Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions. 
 Is a congenital anomaly or birth defect; or 
 Is an important medical event when, based upon appropriate medical judgment, 
it may jeopardize the participant and require medical or surgical intervention to 
prevent one of the outcomes listed above. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home; blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
Events not considered to be serious adverse events are hospitalizations for: 
 Routine treatment or monitoring of the studied indication, not associated with 
any deterioration in condition, or for elective procedures 
 Elective or pre-planned treatment for a pre-existing condition that did not worsen 
 Emergency outpatient treatment for an event not fulfilling the serious criteria 
outlined above and not resulting in inpatient admission 
 Respite care 
12.1.3 Expectedness 
Adverse events can be 'Expected' or 'Unexpected.'  
Expected Adverse Event 
Expected adverse events are those that have been previously identified as resulting from 
administration of the agent. For the purposes of this study, an adverse event is 
considered expected when it appears in the current adverse event list, the Investigator’s 


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Brochure, the package insert or is included in the informed consent document as a 
potential risk.   
Refer to Section 6.1 for a listing of expected adverse events associated with the study 
agent(s). 
Unexpected Adverse Event 
For the purposes of this study, an adverse event is considered unexpected when it varies 
in nature, intensity or frequency from information provided in the current adverse event 
list, the Investigator’s Brochure, the package insert or when it is not included in the 
informed consent document as a potential risk.   
12.1.4 Attribution 
Assessment of the relationship of the AE to the cabozantinib by the investigator is based 
on the following two definitions: 
 
Not Related: A not-related AE is defined as an AE that is not associated with the 
cabozantinib and is attributable to another cause. 
 
Related: A related AE is defined as an AE where a causal relationship between 
the event and the cabozantinib is a reasonable possibility. A reasonable causal 
relationship is meant to convey that there are facts (eg, evidence such as 
dechallenge/ rechallenge) or other clinical arguments to suggest a causal 
relationship between the AE and cabozantinib. 
12.2 
Procedures for AE and SAE Recording and Reporting 
Participating investigators will assess the occurrence of AEs and SAEs at all participant 
evaluation time points during the study.  
All AEs and SAEs whether reported by the participant, discovered during questioning, 
directly observed, or detected by physical examination, laboratory test or other means, 
will be recorded in the participant’s medical record and on the appropriate study-specific 
case report forms.  


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The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. All 
appropriate treatment areas should have access to a copy of the CTCAE version 4.0. 
A copy of the CTCAE version 4.0 can be downloaded from the CTEP website at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
12.3 
Expedited SAE Reporting Guidelines 
12.3.1 DF/HCC Expedited Reporting Guidelines 
 
Investigative sites within DF/HCC and DF/PCC will report SAEs directly to the DFCI 
Office for Human Research Studies (OHRS) per the DFCI IRB reporting policy.  
 
All serious adverse events that occur after the initial dose of cabozantinib, during 
treatment, or within 30 days of the last dose of treatment must be reported to the 
DF/HCC Overall Principal Investigator on the local institutional SAE form. 
 
Participating investigators must report each serious adverse event to the DF/HCC 
Overall Principal Investigator within 1 business day of learning of the occurrence. In the 
event that the participating investigator does not become aware of the serious adverse 
event immediately (e.g., participant sought treatment elsewhere), the participating 
investigator is to report the event within 1 business day after learning of it and document 
the time of his or her first awareness of the adverse event. Report serious adverse events 
by telephone, email or facsimile to: 
 
 
Sara Tolaney, MD, MPH 
 
 
Phone: 617-632-2335  
 
 
 
Email: stolaney@partners.org 
 
 
Fax: 617-632-1930 
 
12.3.2 Serious Adverse Event Reporting to Exelixis 
 
All serious adverse events that occur after the initial dose of cabozantinib, during 
treatment, or within 30 days of the last dose of treatment that meet the criteria per 
DF/HCC AE policy must be reported to Exelixis on the local institutional SAE form.  
Forms should be sent to the following within two business days: 


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Exelixis Drug Safety: 
Email: drugsafety@exelixis.com 
Fax: 650-837-7392 
 
 This report must be submitted by the study site to Exelixis or designee within 
two business days, even if it is not felt to be drug related.   
 The investigator agrees to provide supplementary information requested by the 
Exelixis Drug Safety personnel or designee. 
 Pregnancy, although not itself an SAE, should also be reported on an SAE 
form or pregnancy form and be followed up to determine outcome, including 
spontaneous or voluntary termination, details of birth, and the presence or 
absence of any birth defects or congenital abnormalities. 
12.3.3 Non-Serious Adverse Event Reporting 
 
Non-serious adverse events will be reported to the DF/HCC Overall Principal 
Investigator on the toxicity Case Report Forms.   
12.4 
Reporting to the Institutional Review Board (IRB) 
Investigative sites within DF/HCC will report all serious adverse events directly to the 
DFCI Office for Human Research Studies (OHRS). 
12.5 
Reporting to the Food and Drug Administration (FDA) 
The DF/HCC Overall Principal Investigator, as holder of the IND, will be responsible 
for all communication with the FDA. The DF/HCC Overall Principal Investigator will 
report to the FDA, regardless of the site of occurrence, any adverse event that is serious, 
unexpected and reasonably related (i.e., possible, probable, definite) to the cabozantinib. 
Unexpected fatal or life-threatening experiences associated with the use of the 
cabozantinib will be reported to FDA as soon as possible but in no event later than 7 
calendar days after initial receipt of the information. 
All other serious unexpected experiences associated with the use of the cabozantinib will 
be reported to FDA as soon as possible but in no event later than 15 calendar days after 
initial receipt of the information. 


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Events will be reported to the FDA by telephone (1-800-FDA-1088) or by fax (1-800-
FDA-0178) using Form FDA 3500A (Mandatory Reporting Form for investigational 
agents). Forms are available at http://www.fda.gov/medwatch/getforms.htm.  A hard 
copy of the form will also be submitted to the FDA. 
12.6 
Reporting to the Hospital Risk Management 
Participating investigators will report to their local Risk Management office any subject 
safety reports or sentinel events that require reporting according to institutional policy. 
12.7 
Monitoring of Adverse Events and Period of Observation 
All adverse events, both serious and non-serious, and deaths that are encountered from 
initiation of study intervention, throughout the study, and within 30 days of the last 
study intervention should be followed to their resolution, or until the participating 
investigator assesses them as stable, or the participating investigator determines the 
event to be irreversible, or the participant is lost to follow-up. The presence and 
resolution of AEs and SAEs (with dates) should be documented on the appropriate case 
report form and recorded in the participant’s medical record to facilitate source data 
verification.  
For some SAEs, the study sponsor or designee may follow-up by telephone, fax, and/or 
monitoring visit to obtain additional case details deemed necessary to appropriately 
evaluate the SAE report (e.g., hospital discharge summary, consultant report, or autopsy 
report).  
Participants should be instructed to report any serious post-study event(s) that might 
reasonably be related to participation in this study. Participating investigators should 
notify the DF/HCC Overall Principal Investigator and their respective IRB of any 
unanticipated death or adverse event occurring after a participant has discontinued or 
terminated study participation that may reasonably be related to the study.   
13 
DATA AND SAFETY MONITORING 
13.1 
Data Reporting 
13.1.1 Method 
 
The QACT will collect, manage, and monitor data for this study. 


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 13.1.2 
Data Submission 
 
The schedule for completion and submission of case report forms (paper or electronic) to 
the QACT is as follows: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
13.2 
Safety Meetings 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor 
toxicity and accrual data from this trial. The committee is composed of clinical 
specialists with experience in oncology and who have no direct relationship with the 
study. Information that raises any questions about participant safety will be addressed 
with the Principal Investigator and study team. 
The DSMC will meet quarterly and/or more often if required to review toxicity and 
accrual data.  Information to be provided to the committee may include:  up-to-date 
participant accrual; current dose level information; DLT information; all grade 2 or 
higher unexpected adverse events that have been reported; summary of all deaths 
occurring within 30 days for Phase I or II protocols; for gene transfer protocols, 
summary of all deaths while being treated and during active follow-up; any response 
information; audit results, and a summary provided by the study team. Other information 
(e.g. scans, laboratory values) will be provided upon request. 
  
Form 
Submission Timeline 
Eligibility Checklist 
Complete prior to registration with QACT 
On Study Form 
Within 14 days of registration 
Baseline Assessment Form 
Within 14 days of registration 
Treatment Form 
Within 10 days of the last day of the cycle 
Adverse Event Report Form 
Within 10 days of the last day of the cycle 
Response Assessment Form 
Within 10 days of the completion of the cycle required for 
response evaluation 
Off Treatment/Off Study Form 
Within 14 days of completing treatment or being taken off 
study for any reason 
Follow up/Survival Form 
Within 14 days of the protocol defined follow up visit date 
or call 


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13.3 
Monitoring 
Involvement in this study as a participating investigator implies acceptance of potential 
audits or inspections, including source data verification, by representatives designated 
by the DF/HCC Overall Principal Investigator (or Protocol Chair) or DF/HCC. The 
purpose of these audits or inspections is to examine study-related activities and 
documents to determine whether these activities were conducted and data were 
recorded, analyzed, and accurately reported in accordance with the protocol, 
institutional policy, and any applicable regulatory requirements.  
All data will be monitored for timeliness of submission, completeness, and adherence 
to protocol requirements. Monitoring will begin at the time of participant registration 
and will continue during protocol performance and completion.  
14 
REGULATORY CONSIDERATIONS 
14.1 
Protocol Review and Amendments 
This protocol, the proposed informed consent and all forms of participant information 
related to the study (e.g., advertisements used to recruit participants) and any other 
necessary documents must be submitted, reviewed and approved by a properly 
constituted IRB governing each study location.  
Any changes made to the protocol must be submitted as amendments and must be 
approved by the IRB prior to implementation. Any changes in study conduct must be 
reported to the IRB. The DF/HCC Overall Principal Investigator (or Protocol Chair) 
will disseminate protocol amendment information to all participating investigators.  
All decisions of the IRB concerning the conduct of the study must be made in 
writing. 
14.2 
Informed Consent 
All participants must be provided a consent form describing this study and 
providing sufficient information for participants to make an informed decision 
about their participation in this study. The formal consent of a participant, using 
the IRB approved consent form, must be obtained before the participant is 
involved in any study-related procedure. The consent form must be signed and 
dated by the participant or the participant’s legally authorized representative, and 


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by the person obtaining the consent. The participant must be given a copy of the 
signed and dated consent document. The original signed copy of the consent 
document must be retained in the medical record or research file.  
14.3 
Ethics 
This study is to be conducted according to the following considerations, which 
represent good and sound research practice: 
 US Code of Federal Regulations (CFR) governing clinical study conduct 
and ethical principles that have their origin in the Declaration of Helsinki 
o Title 21 Part 50 – Protection of Human Subjects 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr50_02.html  
o Title 21 Part 54 – Financial Disclosure by Clinical Investigators 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr54_02.html  
o Title 21 Part 56 – Institutional Review Boards 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr56_02.html  
o Title 21 Part 312 – Investigational New Drug Application 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr312_02.html  
 State laws 
 DF/HCC research policies and procedures        
http://www.dfhcc.harvard.edu/clinical-research-support/clinical-research-
unit-cru/policies-and-procedures/  
It is understood that deviations from the protocol should be avoided, except when 
necessary to eliminate an immediate hazard to a research participant. In such case, 
the deviation must be reported to the IRB according to the local reporting policy.  
14.4 
Study Documentation 
The investigator must prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each 
research participant. This information enables the study to be fully documented and the 
study data to be subsequently verified. 
Original source documents supporting entries in the case report forms include but are 
not limited to hospital records, clinical charts, laboratory and pharmacy records, 


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recorded data from automated instruments, microfiches, photographic negatives, 
microfilm or magnetic media, and/or x-rays.  
14.5 
Records Retention 
All study-related documents must be retained for the maximum period required by 
applicable federal regulations and guidelines or institutional policies.  
15 
STATISTICAL CONSIDERATIONS 
15.1 
Study Design / Endpoints 
This is a two-stage phase 2 study of XL184 for HER2-positive metastatic breast cancer 
with known brain metastases, and a pilot study of XL184 for ER+ and TN breast cancer 
with known brain metastases. 
  
The primary endpoint is response, defined as a confirmed CR or confirmed PR per CNS 
objective response.  Patients who do not achieve a confirmed CR or confirmed PR will 
be considered non-responders. Assuming the study does not terminate early and all 
patients enrolled begin protocol therapy, the 95% CI for the response rate will be 
determined accounting for the two-stage design. 
 
All other analyses are exploratory with no plans for formal hypothesis testing given the 
limited sample size. Analyses will treat as categorical variables c-MET amplification in 
CTC’s, or marker levels that can be categorized using established cutpoints. Variables 
will be tabulated by RECIST response. For markers without an established cutpoint, 
analyses will involve summary statistics by RECIST response. PFS and OS, as defined 
in Section 11.4.5, will be described using the method of Kaplan-Meier.  The point 
estimate of median PFS and OS, as well as estimates of PFS and OS at other time points, 
will be presented with 95% confidence intervals derived using log(-log(PFS)) 
methodology. 
 
15.2 
Sample Size / Accrual Rate 
There are no data on the response rate to XL184 in patients with metastatic breast cancer 
and brain metastases.  A true rate of 30% among predominantly pretreated patients with 
HER2-positive metastatic breast cancer would be considered worthy of further study. A 
true rate of 5% or less would not be of clinical interest. This is a one-arm two-stage 


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design to evaluate the efficacy of XL184 in patients with HER2-positive metastatic breast 
cancer and brain metastases.  The sample size was chosen to have high power (90%) with 
a Type I error no more than 10%. 
  
In the first stage, 7 patients will be enrolled. If there is at least 1 response, accrual will 
continue to the second stage where up to 14 additional patients will be enrolled. If at least 
3 of these 21 patients have a response rate, the regimen will be considered worthy of 
further study.  With this design, the probability of stopping the trial early is 70% if the 
true response rate is 5%, and 8% if the true response rate is 30%. If the true response rate 
is 5%, the chance the regimen is declared worthy of further study is 10% and if the true 
response rate is 30% the chance that the regimen is declared worthy of further study is 
90%. 
 
Update: As of October 20, 2015, there have been no confirmed CNS objective responses 
by RECIST 1.1 in the first seven patients enrolled in the HER2+ cohort.  There has been 
one volumetric partial response (PR) in the brain, along with a partial response (PR) in 
the body (Table 17). In addition, patients have remained on trial for a significant amount 
of time, with two of seven patients on study for 9 cycles, and one on for 8 cycles, with 
continued stable disease. Given that there seems to be t meaningful clinical benefit 
received with the agent, we felt further study of this agent is warranted in this population.  
Thus, an additional 14 patients will be enrolled to a maximum of 21 HER2+ patients in 
order to have more precise estimates of the efficacy of cabozantinib  in patients with 
metastatic breast cancer and brain metastases. 
 
Table 17: Data for the HER2+ Cohort as of October 20, 2015 
 
RECIST
Volume
‐/‐/+
Off
2
N
SD (‐13.1) SD (‐43.9) PD (75.2) Body PD
+/+/+
Off
9
Y (20mg)
SD (‐5.9)
SD (6.3)
SD (‐8.9) Brain and body PD
‐/‐/+
Off
5
N
SD (‐9.8) SD (‐39.5) SD (0.0) Clinical PD
+/+/+
Off
9
Y (40mg)
SD (‐21.7) SD (‐46.3) NP (0.0) Brain PD
+/‐/+
Off
4
Y (40mg)
SD (‐6.8) SD (‐41.3) PR (‐42) Vol. PD and clinical PD
‐/‐/+
On
8
N
SD (‐0.3) SD (‐17.5) NP (0.0) N/A
+/‐/+
On
5
Y (40mg)
SD (‐8.7) PR (‐72.6) SD (0.0) N/A
HER2+ Cohort
Body
ER/PR/HER2 status On/off Cycles Dose red (Y/N)
TIMC best response (%)
Reason Off
Brain


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101 
The primary analysis will declare that under the Simon two-stage design, we are unable 
to reject the null hypothesis for the true CNS objective response rate in HER2+ patients. 
Secondary analysis will be estimation-only, and report all endpoints of clinical activity 
(best overall response by RECIST, best overall CNS volumetric response, best response 
in the body, progression-free survival) with 95% confidence intervals. With 21 evaluable 
HER2+ patients, the maximum half-width of a confidence interval for response rates is 
0.22.    
 
Eight patients with ER-positive metastatic breast cancer and brain metastases and 8 
patients with triple-negative metastatic breast cancer and brain metastases will be 
enrolled in two pilot cohorts for studying the efficacy of XL184 in patients with those 
two subtypes of metastatic breast cancer. If the true response rate is 30% in ER+ and TN 
disease, the probability that no responses are seen in 8 patients is 5.7%. The table below 
gives exact 95% confidence intervals for seeing 1 to 3 responses in 8 patients. Even if the 
regimen is concluded as ineffective in interim analysis of the HER2-positive cohort, 
accrual in pilot cohorts will continue until reaching the goal accrual. 
    
Table 18: Estimated 95% Confidence Interval for Events 
Sample Size 
Number of Response 
Response Rate 
95% CI 
8 
1 
12.5% 
0.3-52.7% 
8 
2 
25.0% 
3.2-65.1% 
8 
3 
37.5% 
8.5-75.5% 
 
Accrual is estimated to be 1-2 patients per month. Total accrual time is estimated to be 
approximately 18-24 months.  
15.2.1 Evaluation of toxicity 
 
All participants will be evaluable for toxicity from the time of their first treatment. 
 
 
 


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15.2.2 Evaluation of response 
 
All participants included in the study must be assessed for response to treatment, even if 
there are major protocol treatment deviations. Ineligible patients will be excluded. Each 
participant should be assigned one of the following categories: 1) complete response, 2) 
partial response, 3) stable disease, 4) progressive disease, 5) early death from malignant 
disease, 6) early death from toxicity, 7) early death because of other cause, or 9) unknown 
(not assessable, insufficient data). By arbitrary convention, category 9 usually designates 
the "unknown" status of any type of data in a clinical database.              
16 
PUBLICATION PLAN 
The Principal Investigator (Protocol Chair) holds the primary responsibility for publication of the 
study results; provided that the Principal Investigator will provide any such publication to 
Exelixis, Inc. for review at least sixty (60) days prior to submission and also comply with any 
provisions regarding publication as are agreed to between the Principal Investigator’s institution 
(e.g., Dana Farber/Partners Cancer Care, Inc.) and Exelixis, Inc. in the Clinical Trial Agreement 
related to this study. The results will be made public within 24 months of the end of data 
collection. However, if a report is planned to be published in a peer-reviewed journal, then that 
initial release may be an abstract that meets the requirements of the International Committee of 
Medical Journal Editors. In any event, a full report of the outcomes should be made public no 
later than three (3) years after the end of data collection. Authorship for abstracts and 
manuscripts resulting from this study will be determined according to guidelines established by 
the International Committee of Medical Journal Editors. 
 
 
 


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


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Pain Questionnaire and Analgesic Medication Diary Due Dates for Appendix B and Appendix C 
The participant will complete the pain diary and analgesic medication diary each day for a 7-day interval 
within 14 days of the first dose of cabozantinib and at 7-day intervals during Week 3 and the last week of 
the cycles that patients are scanned on ( ie end of cycle 2, 4, 6, 9, 12, etc) The pain questionnaire and 
analgesic medication diary will also be due  the last week of cycles that patients are scanned on (end of 
Cycle 2, 4, 6, 9, 12, etc.) The first pain questionnaire completed can be used to report pain that the 
participant experienced the week prior to the date of the study consent signature.  Analgesic medications 
to be recorded on the diary include narcotics and corticosteroids used to treat pain symptoms.  As follows 
the pain questionnaire and analgesic medication diary should be completed by the participant and then 
brought with them to next appointment: 
 
Questionnaire and diary completed during Cycle 1 Day 15-21 (Week 3); then they will be due on 
Cycle 2 Day 1 (Week 4). 
 
Question and diary completed during Cycle 2 Day 15-21 (Week 6); then they will be due on 
Cycle 3 Day 1 (Week 7). 
 
Questionnaire and diary completed during Cycle 4 Day 15-21 (Week 12); then they will be due 
on Cycle 5 Day 1 (Week 13). 
 
Questionnaire and diary completed during Cycle 6 Day 15-21 (Week 18); then they will be due 
on Cycle 7 Day 1 (Week 19).  
  
 


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APPENDIX B:  PAIN QUESTIONNAIRE 
Participant ID number: 
Date: ____________________    Participant Signature: ____________________________ 
 
1.   People with cancer frequently have symptoms that are caused by their disease or by their 
treatment. We ask you to rate how severe the following symptoms have been in the last 24 hours. 
Please fill in the circle below from 0 (symptom has not been present) to 10 (the symptom was as 
bad as you can imagine it could be) for each item.   
 
Not Present 
As Bad As You 
Can Imagine 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
a. Your pain at its WORST? 
○○ ○ ○ ○ ○ ○ ○ ○ ○ ○ 
 
b. Your disturbed sleep at its   
WORST?  
○○ ○ ○ ○ ○ ○ ○ ○ ○ ○ 
 
2.   Symptoms frequently interfere with how we feel and function. How much have your 
symptoms interfered with the following items in the last 24 hours:  
 
Did Not 
Interfere 
Interfered 
Completely 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
a. General activity? 
○○ ○ ○ ○ ○ ○ ○ ○ ○ ○ 
 
 
 
 


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Participant ID number:_________                                         Date: ________________ 
3. Compared to the last time I completed this questionnaire, my pain in the last 24 hours was:  
 
 Very much worse 
 Moderately worse 
 A little worse 
 About the same 
 A little better 
 Moderately better 
 Very much better 
 Not Applicable (first time completing this form) 
  
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX C:  7-DAY ANALGESIC MEDICATION DIARY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient Signature:___________: Date:_____________________ 
 


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APPENDIX D:  PARTICIPANT’S MEDICATION DIARY 
 
Participant’s Name____________________ (initials acceptable) 
Participant ID________ 
Protocol #: ______ Cycle #: _____ Study Drug: CABOZANTINIB   Your Dose:     _____ 
 
 
 
 
 
Participant’s signature _____________________________________       Date: __________________
INSTRUCTIONS FOR TAKING YOUR CABOZANTINIB: 
1. 
Complete one form for each cycle of treatment (Cycle = 21 days). 
2. 
You will take CABOZANTINIB tablets via mouth once a day.  You should take the tablets each morning after 
you have fasted for 2 hours (no food or drink with the exception of water). You should continue to fast for 1 
hour after taking your CABOZANTINIB.  CABOZANTINIB should be taken with a full glass of water (8 oz 
minimum) and consumed over as short a time as possible. Please swallow the tablets as a whole and do not 
crush, chew or dissolve in water.  Grapefruit and Seville oranges must be avoided while on study. 
3. 
If you forget to take your daily CABOZANTINIB dose: 
 If it has been more than 12 hours since missing your scheduled dose, do NOT take your missed dose. 
 If it has been less than 12 hours since missing your scheduled dose, take your dose immediately and 
continue taking your dose at your regular time the next day. 
4.    If you vomit your dose, do NOT retake your dose.  Wait until the next day to take your next scheduled dose.  
Remember to tell your study doctor or nurse at your next visit which dose(s) you missed. 
INSTRUCTIONS FOR COMPLETING THIS FORM: 
Record the date, the number of tablets of each size of tablet that you took, and when you took them.  If you have 
any comments or notice any side effects, please record them in the Comments column.  Please bring this 
form and your bottles (even if they are empty) of CABOZANTINIB when you return for each 
appointment. 
 
Day 
 
Date 
 
Time of 
dose  
# of tablets taken
Comments
 mg 
 mg 
  
 
1 
 
 
 
 
 
2 
 
 
 
 
 
3 
 
 
 
 
 
4 
 
 
 
 
 
5 
 
 
 
 
 
6 
 
 
 
 
 
7 
 
 
 
 
 
8 
 
 
 
 
 
9 
 
 
 
 
 
10 
 
 
 
 
 
11 
 
 
 
 
 
12 
 
 
 
 
 
13 
 
 
 
 
 
14 
 
 
 
 
 
15 
 
 
 
 
 
16 
 
 
 
 
 
17 
 
 
 
 
 
18 
 
 
 
 
 
19 
 
 
 
 
 
20 
 
 
 
 
 
21 
 
 
 
 
 


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APPENDIX E:  NEUROLOGICAL SIGNS AND SYMPTOMS 
Neurological Examination Worksheet 
(to be completed at baseline and at the end of each 3-week cycle) 
 
Please note if signs/symptoms are thought related or not-related to patient’s brain metastases 
 
Patient ____________________  
Examiner __________________ 
Date________________ 
 
Level of consciousness (check one) 
___ Normal 
___ Somnolence or sedation not interfering with function 
___ Somnolence or sedation interfering with function, but not interfering with ADLs 
___ Obtundation or stupor, difficult to arouse; interfering with ADLs 
___ Coma 
 
Neurological Symptoms (check if present, and specify CTCAE grade) 
** if asymptomatic, check here  ___ 
Headache  
 
 
 
 
 
 
___  present, specify grade _____ 
Dizziness/lightheadness 
 
 
___ present, specify grade _____ 
Vertigo  
 
 
 
 
 
 
 
___ present, specify grade _____ 
Nausea/vomiting  
 
 
 
 
___ present, specify grade _____ 
Visual problems  
 
 
 
 
___ present, specify grade _____ 
Seizure  
 
 
 
 
 
 
 
___ present, specify grade _____ 
Other  
 
 
 
 
 
 
 
 
___ absent,   ___ present, specify grade _____ 
 
Cranial nerves II – XII+ 
___ Normal 
___ Present, not interfering with ADLs 
___ Present, interfering with ADLs 
___ Life-threatening, disabling 
+  
If abnormal, please specify which cranial nerve(s) affected ________________________ 
 
Language 
___ Absence of dysphasia or aphasia 
___ Awareness of receptive or expressive aphasia, not impairing ability to communicate 
___ Receptive or expressive dysphasia, impairing ability to communicate 
___ Inability to communicate 
 
Sensation** 
___ Normal 
___ Loss of deep tendon reflexes or paresthesia, but not interfering with function 
___ Objective sensory loss or paresthesia interfering with function, but not with ADLs 
___ Sensory loss or paresthesia interfering with ADLs 
___ Permanent sensory loss that interferes with function 
**  
If abnormal, please specify location/distribution _________________________________ 
 
 


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114 
Neurological Examination Worksheet 
(pg. 2 of 2) 
 
Patient ____________________  
Examiner __________________ 
Date________________ 
 
Strength* 
R upper extremity 
 
___ Normal 
 
 
___ Abnormal; please specify _________________ 
L upper extremity 
 
___ Normal 
 
 
___ Abnormal; please specify _________________ 
R lower extremity 
 
___ Normal 
 
 
___ Abnormal; please specify _________________ 
L lower extremity 
 
___ Normal 
 
 
___ Abnormal; please specify _________________ 
 
*If abnormal, please specify muscle group and grade according to the scale below: (e.g., biceps, 
grade 2) 
 Grade 1 = asymptomatic with weakness on physical exam 
 Grade 2 = symptomatic and interfering with function, but not interfering with ADLs 
 Grade 3 = symptomatic and interfering with activities of daily living 
 Grade 4 = bedridden or disabling 
 
Ataxia*** 
R upper extremity (finger-to-nose testing) 
___ Normal 
 
___ Abnormal; specify grade ___ 
L upper extremity (finger-to-nose testing) 
___ Normal 
 
___ Abnormal; specify grade ___ 
Gait  
 
 
 
 
 
 
 
 
 
 
 
 
___ Normal 
 
___ Abnormal; specify grade ___ 
Balance (Romber)  
 
 
 
 
 
 
 
___ Normal 
 
___ Abnormal; specify grade ___ 
 
*** If any of above abnormal, please assign grade using the following criteria 
 Grade 1 = asymptomatic but abnormal on physical exam, and not interfering with 
function 
 Grade 2 = mild symptoms interfering with function, but not interfering with ADLs 
 Grade 3 = moderate symptoms interfering with ADLs 
 Grade 4 = bedridden or disabling 
 
In the opinion of the treating physician, overall are the patients tumor-related neurological 
signs and symptoms worsening, stable or improved (please check one)? 
___ Worsening 
___ Stable 
___ Improved 
 
Is the patient currently taking corticosteroids? 
___ Yes 
___ No 
 
If yes, please list name of medication and dose (e.g. decadron, 4 mg QD) ________________ 
 
 
 


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APPENDIX F:  RESEARCH SPECIMEN COLLECTION/SHIPPING GUIDELINES 
 
Procedures for Collecting and Shipping Circulating Tumor Cells (CTCs): 
Automated CellSearch™ processing technique (Veridex). 8 mls of whole blood is collected in 10 
ml CellSave tubes™. Samples must be kept at room temperature and must be PROCESSED 
within 96 hours of draw. 
 
SAMPLE COLLECTION 
1. Ensure that peripheral blood collection occurs prior to administration of i.v. therapy. 
2. The blood sample must be collected in a CellSave preservative tube. Label the tube with the 
sample identifier/number, protocol number, and submitting investigator. 
3. Collect at least 8 ml of blood. Gently invert the tube 8 times to prevent clotting immediately 
after filling the tube. 
4. Do not submit clotted samples. 
 
SAMPLE SHIPPING 
1. The blood sample must be transported and stored at room temperature (15-30C) until 
processing. Do NOT refrigerate or freeze the sample. 
2. Samples must be processed within 96 hours of collection, but best results are obtained if the 
sample is processed as soon as possible. 
3. Overnight ship the tube (along with the baseline CTC sample) AT ROOM TEMPERATURE 
to: 
 
For sample drawn at institution other than DFCI, ship to: 
Madeline Tenenbaum450 Brookline Ave., Mailstop DA157 
Boston, MA 02215 
 
 Please email Madeline Tenenbaum(madeline_tenenbaum@dfci.harvard.edu) the day 
before with sample information and tracking information. 
 CTC blood samples should not be drawn the day before a holiday weekend. 
 Email CTC core and cc Elena Ivanova and Masahiko Yanagita to co-ordinate (if sample 
coming from site other than DFCI, also cc DFCI CRCMadeline Tenenbaum), 
BWHPathologyCTCLab@partners.org; evivanova@partners.org; 
myanagita@partners.org; madeline_tenenbaum@dfci.harvard.edu 
 
Please include the following info in the email: 
 
Protocol: 14-359 
Patient: ____________ 
MRN: _____________ 
Time point: BL / C1D1 
Date of draw: __________ 
Time of draw: __________  
Enumeration, profile, or both: Profile kit (tube) 
 


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 DFCI CRC will take tubes and requisition to CTC core for same day or next day early 
morning processing. (For Friday patients tubes may be processed at CTC core on Monday 
depending on whether Elena prefers that)  
 CTC core should email Elena when tubes are ready for pick up.  Samples will be processed 
in Dr. Cloud Paweletz’s laboratory at the Dana-Farber Cancer Institute. 
 
Procedures for Collecting and Shipping Plasma Biomarkers 
Exploratory analyses of potential biomarkers of cabozantinib activity will be 
performed by measuring proteins in the plasma and circulating cells at the following timepoints: 
 Baseline 
 Cycle 1 Day 8 
 Day 1 of each cycle of therapy (Cycles 1-6) 
 When scans are reviewed after restaging after Cycle 6 (Day 1 every 3 cycles after 18 
weeks have passed) 
 At the end of treatment (if available) 
 
8cc of blood will be collected in purple top (plasma EDTA) vacutainers, with a 
minimum of 5cc required. Each sample will be de-identified and shipped on wet ice to the Steele 
Laboratory at MGH (via courier from DFCI).   
 
CRC to Email Anna Khachatryan (akhachatryan@partners.org) and Julia Kahn 
(jakahn@partners.org) a list of expected samples for next week. For example: 
 
12-431 
00011 
R-W 
C3D1 
2 purple tops 
11/11/2013 
10:20 AM 
 
Procedures for Collecting and Shipping cfDNA: 
One 10 ml Streck tube will be collected and processed at baseline and at the end of treatment for 
evaluation of cfDNA.  Fill the Streck tube completely and immediately mix by gentle inversion 8 
to 10 times.  Inadequate or delayed mixing may result in accurate results.  Ship within 24 hours 
of collection at ambient temperature overnight to: 
 
Madeline Tenenbaum 
450 Brookline Avenue, DA157 
Boston, MA 02215  
Ph:  617-632-2342 
Fax:  617-632-3550  
madeline_tenenbaum@dfci.harvard.edu 
 
Email Madeline Tenenbaum with the sample information and tracking information the day 
before shipping specimens: madeline_tenenbaum@dfci.harvard.edu 
 
Tube precautions: 


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 If samples cannot be shipped within 24 hours of collection, contact DFCI.  DO NOT 
FREEZE OR REFRIDGERATE TUBES as this could result in cfDNA breakage.  Blood 
collected in the Streck tube can be stored for 14 days between 6-37 degrees Celsius.  
 Do not use tubes after expiration date. 
 Fill the tube completely; overfilling or underfilling of tubes will result in an incorrect 
blood-to-additive ratio and may lead to incorrect analytical results. 
 
Shipping Note:  Streck tube samples are sent ambient.  Frozen and ambient specimens obtained 
and shipped on the same day to Madeline Tenenbaum(e.g., Progression or Off Study Biopsy 
Specimens, Streck Tubes, and Circulating Tumor Cells) may be placed in a combination 
shipping box which contains separate compartments for frozen and ambient samples.  If a 
combination shipping box is not available, two shipping boxes should be used.   
 
Please refer to Appendix H for additional processing details specific to the laboratories at 
Dana-Farber Cancer Institute. 
 
Procedures for Collecting and Shipping Optional Research Biopsy Tissue 
Tissue specimens will be collected from recurrent or metastatic lesions using standard 
institutional procedures. The amount of tissue collected will follow the guidelines listed below: 
 
Breast: A goal of 3-6 core biopsy specimens will be obtained using standard institutional 
guidelines for a diagnostic core biopsy of a breast mass. 
 
Skin/chest wall: A goal of 1-2 5-mm punch biopsies will be obtained. 
 
Lymph node: A goal of 3-6 core biopsy specimens will be obtained using an 18-gauge needle. 
 
Liver: A goal of 3-6 core biopsy specimens will be obtained using an 18-gauge needle. 
 
Lung: Because of the risk of pneumothorax associated with core needle biopsies of lung nodules, 
no core biopsies of lung nodules will be performed on this protocol; unless if they are clinically 
indicated.  
 
Bone: Because the yield of malignant tissue from bone biopsies tends to be relatively low, if a 
patient has another accessible site of disease (i.e. skin, lymph node, liver), that site should be 
biopsied preferentially. If bone is the only biopsy-accessible site, then a goal of 3-6 core biopsy 
specimens will be obtained using an 11-13 gauge needle. 
 
Pleural Fluid: A goal of 500 cc of pleural fluid will be obtained with a standard thoracentesis 
procedure, with or without image guidance, according to the clinical judgment of the treating 
physician and clinician performing the procedure. Less than the goal amount is acceptable, and 
should be based upon the clinical judgment of the Investigator and the clinician performing the 
procedure. If more than the goal amount of fluid is obtained, then the entire specimen (with the 
exception of what is needed for clinical purposes, if applicable) will be stored in the tissue bank. 
 


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Ascites fluid:  A goal of 500 cc of ascites fluid will be obtained with a standard paracentesis 
procedure, with or without image guidance, according to the clinical judgment of the treating 
physician and clinician performing the procedure. Less than the goal amount is acceptable, and 
should be based upon the clinical judgment of the Investigator and the clinician performing the 
procedure. If more than the goal amount of fluid is obtained, then the entire specimen (with the 
exception of what is needed for clinical purposes, if applicable) will be stored in the tissue bank. 
 
Please note that the above are guidelines for the amount of tissue to be obtained, and are 
not meant to replace clinical judgment at the time the procedure is performed. Less than the 
goal quantity of tissue is accepted for each type of biopsy, and will be left to the clinical 
judgment of the physician performing the procedure. If ascites or pleural fluid is to be used as the 
investigational biopsy specimen, consideration should be given to confirming the malignant 
nature of the ascites or pleural fluid prior to study entry. 
 
If a patient is undergoing resection of a lesion for clinical reasons (i.e. wedge resection of a 
new lung lesion for confirmation of diagnosis or re-testing of hormone receptor or HER2 status; 
or, resection of a chest wall lesion; or, resection of a lymph node), then the patient may opt to 
have a portion of that tissue (roughly equivalent to the goal amount of tissue listed in the 
guidelines above, i.e. the equivalent of two 5-mm punch biopsies of the skin, or 3-6 18-gauge 
core biopsies) stored for research at the time of the procedure (provided that the tissue is 
processed as specified), in which case, the patient would not be required to undergo a separate 
research biopsy for entry into this protocol. 
 
Half of the cores should be frozen in OCT and the other half should be placed in formalin 
and made into paraffin blocks. 
 
Specimens will be shipped to the Clinical Research Coordinator, the frozen sample in OCT will 
be shipped on dry ice and the ones in formalin or paraffin will be shipped ambient, who will then 
deliver tissues to pathology lab: 
 
Madeline Tenenbaum 
450 Brookline Avenue, DA157 
Boston, MA 02215  
Ph:  617-632-2342 
Fax:  617-632-3550  
Madeline_tenenbaum@dfci.harvard.edu 
 
Guidelines for Archival Tissue  
Archival tissue from the most recent procedure is preferred, if available. 
 15 unstained slides and 1 H&E OR 1 block and 1 H&E 
 Thickness of slides should be 4-5 µm 
 
 


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APPENDIX G:  STUDY DRUG ORDER FORM   
 


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APPENDIX H:  STRECK COLLECTION AND PROCESSING INSTRUCTIONS – FOR 
OUTSIDE OF DFCI LAB USE ONLY   
 


Protocol #13-359 D: 8/5/2014 KAJ; F: 9/22/2014 LK;  
 
DANA-FARBER CANCER INSTITUTE 
Nursing Protocol Education Sheet 
Protocol Number: 
14-359 
Protocol Name: 
A Phase II Study of cabozantinib alone or in combination with trastuzumab in breast 
cancer patients with brain metastases 
DFCI Site PI: 
Sara Tolaney, MD, MPH 
DFCI Research Nurse: 
Peg Haldoupis, RN; Liz Kasparian, RN; Mary O’Driscoll, RN; Kathy Roche, RN; Myra St. Amand, 
RN 
Page the DFCI research nurse or DFCI site PI if there are any questions/concerns about the protocol.   
Please also refer to ONC 15: Oncology Nursing Protocol Education Policy 
*** Remember to check the ALERT PAGE*** 
              SPECIAL NURSING CONSIDERATIONS UNIQUE TO THIS PROTOCOL 
Study Design 
 
It is estimated that approximately 10-15% of women with metastatic breast cancer will eventually develop brain 
metastases. Recent data suggests that anti-angiogenic therapy can be safely given to patients with brain 
metastases and clinical activity has been noted.  Evidence from studies suggests that cabozantinib has anti-
angiogenic activity, CNS penetration, activity in breast cancer and could be efficacious in the treatment of brain 
metastases from breast cancer.  In this study, participants with HER2-positive will also be treated with 
trastuzumab (humanized anti-HER2 antibody). Study Design – Section 1.1; Study Rationale – Section 2.6; A 
cycle is 21 days – Section 1.1 
Dose 
Calc. 
 
Cabozantinib is fixed dosing in mg; no calculation is required – Section 5.4.1 
 
Trastuzumab is dosed in mg/kg – Section 5.4.2 
 
Study Drug  
Administration 
Cabozantinib – Sections 5.1 and 5.4.1  
 
Pre-treatment criteria – Section 5.2 
 
Oral, taken once per day each morning with a full glass of water (minimum 8oz/240mL) – Section 5.4.1 
 
Must fast 2 hours before and 1 hour after dose; Tablets must be swallowed whole & not chewed – Section 5.4.1
 
Missed doses may taken up to 12 hours after scheduled dosing time – Section 5.4.1 
 
Vomited doses are not re-taken – Section 5.4.1 
 
Grapefruit and Seville oranges must be avoided while on study – Section 5.6.1 
Trastuzumab – Section 5.1 and 5.4.2   
 
IV, administered on Day 1 of each cycle – Section 5.4.2 
 
A loading may be required for some participants.  Please see Section 5.4.2 for guidelines on loading doses and 
rate(s) of infusion. 
 
Infusion reactions – see Section 7.2 for management and required observation periods post-reaction. 
 
Dose 
Modifications 
& Toxicity 
Dose Modifications/Dosing Delay for Toxicity are in Sections 6 (cabozantinib) and Section 7 (trastuzumab) 
 
This protocol uses NCI CTCAE criteria, version 4.0 – Section 6 
 
The definition of a DLT (for the cabozantinib + trastuzumab cohort) is in Section 5.3 
 
Clinical experience of cabozantinib is in Section 2.3 
 
Safety profile of trastuzumab is in Section 2.4.2 
Con 
Meds 
Concomitant Therapy Guidelines are in Sections 5.5 and 5.6 
 
Please review the cited sections for permitted, prohibited, and “use with caution” medications/therapies/foods 
Required  
Data  
Study Calendar and Assessment Required data are outlined in Sections 9 and 10  
 
Please review the study calendar in Section 10 
Charting Tips 
All study drugs require documentation of exact administration time. 
Please be sure to DOCUMENT study medication actual UP/DOWN times in medical record (e.g. LMR, eMAR, 
nursing notes). Edit eMAR as needed to match the exact time given. 
 If there is a discrepancy in the infusion time, delay in administration, or infusion takes longer than is permitted 
by the guidelines of the protocol, please document the reason for the discrepancy in the medical record. 
Please also DOCUMENT any required observation periods (i.e. if an infusion reaction occurs), any additional vital 
signs, routes of administration. 
 
 


1 
 
HIGHLIGHTS OF PRESCRIBING INFORMATION 
These highlights do not include all the information needed to use 
Herceptin safely and effectively.  See full prescribing information for 
Herceptin. 
 
HERCEPTIN® (trastuzumab) for injection, for intravenous use  
Initial U.S. Approval:  1998 
 
WARNING: CARDIOMYOPATHY, INFUSION REACTIONS, 
EMBRYO-FETAL TOXICITY, and PULMONARY TOXICITY 
 
See full prescribing information for complete boxed warning 
Cardiomyopathy: Herceptin can result in subclinical and clinical cardiac 
failure manifesting as CHF, and decreased LVEF, with greatest risk 
when administered concurrently with anthracyclines. Evaluate cardiac 
function prior to and during treatment. Discontinue Herceptin for 
cardiomyopathy. (2.3, 5.1) 
 
Infusion Reactions, Pulmonary Toxicity: Discontinue Herceptin for 
anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory 
distress syndrome. (5.2, 5.4) 
 
Embryo-Fetal Toxicity: Exposure to Herceptin during pregnancy can 
result in oligohydramnios, in some cases complicated by pulmonary 
hypoplasia and neonatal death. Advise patients of these risks and the 
need for effective contraception.  (5.3, 8.1, 8.3) 
-----------------------------RECENT MAJOR CHANGES------------------------- 
 
 
Dosage and Administration (2.1) 
04/2017 
Warnings and Precautions (5.3) 
03/2016 
---------------------------INDICATIONS AND USAGE---------------------------- 
Herceptin is a HER2/neu receptor antagonist indicated for: 
• 
The treatment of HER2-overexpressing breast cancer. (1.1, 1.2) 
• 
The treatment of HER2-overexpressing metastatic gastric or 
gastroesophageal junction adenocarcinoma. (1.3) 
Select patients for therapy based on an FDA-approved companion diagnostic 
for Herceptin (1, 2.1). 
------------------------DOSAGE AND ADMINISTRATION---------------------- 
For intravenous (IV) infusion only.  Do not administer as an IV push or 
bolus. (2.2)  
Do not substitute Herceptin (trastuzumab) for or with ado-trastuzumab 
emtansine. (2.2) 
Perform HER2 testing using FDA-approved tests by laboratories with 
demonstrated proficiency. (1, 2.1) 
 
Adjuvant Treatment of HER2-Overexpressing Breast Cancer (2.2) 
Administer at either: 
• Initial dose of 4 mg/kg over 90 minute IV infusion, then 2 mg/kg over 
30 minute IV infusion weekly for 12 weeks (with paclitaxel or docetaxel) 
or 18 weeks (with docetaxel/carboplatin).  One week after the last weekly 
dose of Herceptin, administer 6 mg/kg as an IV infusion over 30−90 
minutes every three weeks to complete a total of 52 weeks of therapy, or 
• Initial dose of 8 mg/kg over 90 minutes IV infusion, then 6 mg/kg over 
30−90 minutes IV infusion every three weeks for 52 weeks. 
Metastatic HER2-Overexpressing Breast Cancer (2.2) 
• Initial dose of 4 mg/kg as a 90 minute IV infusion followed by subsequent 
weekly doses of 2 mg/kg as 30 minute IV infusions. 
Metastatic HER2-Overexpressing Gastric Cancer (2.2) 
• Initial dose of 8 mg/kg over 90 minutes IV infusion, followed by 6 mg/kg 
over 30 to 90 minutes IV infusion every 3 weeks.  
---------------------DOSAGE FORMS AND STRENGTHS---------------------- 
• For Injection: 150 mg lyophilized powder in a single-dose vial for 
reconstitution 
• For Injection: 420 mg lyophilized powder in a multiple-dose vial for 
reconstitution 
------------------------------CONTRAINDICATIONS------------------------------ 
• None. (4) 
-----------------------WARNINGS AND PRECAUTIONS------------------------ 
• Exacerbation of Chemotherapy-Induced Neutropenia. (5.5, 6.1) 
------------------------------ADVERSE REACTIONS------------------------------ 
Adjuvant Breast Cancer  
• Most common adverse reactions (≥ 5%) are headache, diarrhea, nausea, and 
chills. (6.1) 
Metastatic Breast Cancer  
• Most common adverse reactions (≥ 10%) are fever, chills, headache, 
infection, congestive heart failure, insomnia, cough, and rash. (6.1) 
Metastatic Gastric Cancer 
• Most common adverse reactions (≥ 10%) are neutropenia, diarrhea, fatigue, 
anemia, stomatitis, weight loss, upper respiratory tract infections, fever, 
thrombocytopenia, mucosal inflammation, nasopharyngitis, and dysgeusia. 
(6.1) 
To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 
1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 
----------------------USE IN SPECIFIC POPULATIONS---------------------- 
Females and Males of Reproductive Potential: Verify the pregnancy status of 
females prior to initiation of Herceptin (8.3). 
 
See 17 for PATIENT COUNSELING INFORMATION. 
Revised: 04/2017 
 
 
 
FULL PRESCRIBING INFORMATION:  CONTENTS* 
WARNING − CARDIOMYOPATHY, INFUSION REACTIONS, 
EMBRYO-FETAL TOXICITY, and PULMONARY TOXICITY 
1 
INDICATIONS AND USAGE 
1.1 
Adjuvant Breast Cancer 
1.2 
Metastatic Breast Cancer 
1.3 
Metastatic Gastric Cancer  
2 
DOSAGE AND ADMINISTRATION 
2.1 
Patient Selection 
2.2 
Recommended Doses and Schedules 
2.3 
Important Dosing Considerations 
2.4 
Preparation for Administration 
3 
DOSAGE FORMS AND STRENGTHS 
4 
CONTRAINDICATIONS 
5 
WARNINGS AND PRECAUTIONS 
5.1 
Cardiomyopathy 
5.2 
Infusion Reactions 
5.3 
Embryo-Fetal Toxicity 
5.4 
Pulmonary Toxicity  
5.5 
Exacerbation of Chemotherapy-Induced Neutropenia  
6 
ADVERSE REACTIONS 
6.1 
Clinical Trials Experience 
6.2 
Immunogenicity 
6.3 
Post-Marketing Experience 
7 
DRUG INTERACTIONS 
8 
USE IN SPECIFIC POPULATIONS 
8.1 
Pregnancy 
8.2 
Lactation 
8.3 
Females and Males of Reproductive Potential 
8.4 
Pediatric Use 
8.5 
Geriatric Use 
10 OVERDOSAGE 
11 DESCRIPTION 
12 CLINICAL PHARMACOLOGY 
12.1 
Mechanism of Action 
12.2 
Pharmacodynamics 
12.3 
Pharmacokinetics 
13 NONCLINICAL TOXICOLOGY 
13.1 
Carcinogenesis, Mutagenesis, Impairment of Fertility 
14 CLINICAL STUDIES 
14.1 Adjuvant Breast Cancer 
14.2 
Metastatic Breast Cancer 
14.3 
Metastatic Gastric Cancer 
16 HOW SUPPLIED/STORAGE AND HANDLING 
16.1 
How Supplied 
16.2 
Stability and Storage 
17 PATIENT COUNSELING INFORMATION 
 
* Sections or subsections omitted from the full prescribing information are not 
listed. 


 
2 
FULL PRESCRIBING INFORMATION 
1 
WARNING: CARDIOMYOPATHY, INFUSION REACTIONS, EMBRYO-FETAL 
2 
TOXICITY, and PULMONARY TOXICITY  
3 
Cardiomyopathy 
4 
 Herceptin administration can result in sub-clinical and clinical cardiac failure.  The 
5 
incidence and severity was highest in patients receiving Herceptin with 
6 
anthracycline-containing chemotherapy regimens. 
7 
 Evaluate left ventricular function in all patients prior to and during treatment with 
8 
Herceptin.  Discontinue Herceptin treatment in patients receiving adjuvant therapy and 
9 
withhold Herceptin in patients with metastatic disease for clinically significant decrease in left 
10 
ventricular function [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)]. 
11 
Infusion Reactions; Pulmonary Toxicity 
12 
 Herceptin administration can result in serious and fatal infusion reactions and pulmonary 
13 
toxicity.  Symptoms usually occur during or within 24 hours of Herceptin administration.  
14 
Interrupt Herceptin infusion for dyspnea or clinically significant hypotension.  Monitor 
15 
patients until symptoms completely resolve.  Discontinue Herceptin for anaphylaxis, 
16 
angioedema, interstitial pneumonitis, or acute respiratory distress syndrome [see Warnings 
17 
and Precautions (5.2, 5.4)]. 
18 
Embryo-Fetal Toxicity  
19 
 Exposure to Herceptin during pregnancy can result in oligohydramnios and 
20 
oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and 
21 
neonatal death. Advise patients of these risks and the need for effective contraception [see 
22 
Warnings and Precautions (5.3) and Use in Specific Populations (8.1, 8.3)]. 
23 
 
24 
1 INDICATIONS AND USAGE 
25 
1.1 Adjuvant Breast Cancer 
26 
 
Herceptin is indicated for adjuvant treatment of HER2 overexpressing node positive or node 
27 
negative (ER/PR negative or with one high risk feature [see Clinical Studies (14.1)]) breast cancer  
28 
• 
as part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either 
29 
paclitaxel or docetaxel 
30 
• 
as part of a treatment regimen with docetaxel and carboplatin  
31 
• 
as a single agent following multi-modality anthracycline based therapy.   
32 
 
Select patients for therapy based on an FDA-approved companion diagnostic for Herceptin [see 
33 
Dosage and Administration (2.1)]. 
34 
1.2 Metastatic Breast Cancer 
35 
 
Herceptin is indicated: 
36 
• 
In combination with paclitaxel for first-line treatment of HER2-overexpressing metastatic 
37 
breast cancer 
38 
• 
As a single agent for treatment of HER2-overexpressing breast cancer in patients who have 
39 
received one or more chemotherapy regimens for metastatic disease. 
40 
 
Select patients for therapy based on an FDA-approved companion diagnostic for Herceptin [see 
41 
Dosage and Administration (2.1)]. 
42 
1.3 Metastatic Gastric Cancer  
43 
 
Herceptin is indicated, in combination with cisplatin and capecitabine or 5-fluorouracil, for the 
44 
treatment of patients with HER2-overexpressing metastatic gastric or gastroesophageal junction 
45 
adenocarcinoma who have not received prior treatment for metastatic disease. 
46 


 
3 
 
Select patients for therapy based on an FDA-approved companion diagnostic for Herceptin [see 
47 
Dosage and Administration (2.1)]. 
48 
 
49 
2 DOSAGE AND ADMINISTRATION 
50 
2.1 Patient Selection 
51 
Select patients based on HER2 protein overexpression or HER2 gene amplification in tumor 
52 
specimens [see Indications and Usage (1) and Clinical Studies (14)].  Assessment of HER2 protein 
53 
overexpression and HER2 gene amplification should be performed using FDA-approved tests 
54 
specific for breast or gastric cancers by laboratories with demonstrated proficiency.  Information on 
55 
the FDA-approved tests for the detection of HER2 protein overexpression and HER2 gene 
56 
amplification is available at:  http://www.fda.gov/CompanionDiagnostics. 
57 
 Assessment of HER2 protein overexpression and HER2 gene amplification in metastatic gastric 
58 
cancer should be performed using FDA-approved tests specifically for gastric cancers due to 
59 
differences in gastric vs. breast histopathology, including incomplete membrane staining and more 
60 
frequent heterogeneous expression of HER2 seen in gastric cancers.  
61 
Improper assay performance, including use of suboptimally fixed tissue, failure to utilize 
62 
specified reagents, deviation from specific assay instructions, and failure to include appropriate 
63 
controls for assay validation, can lead to unreliable results. 
64 
2.2 Recommended Doses and Schedules 
65 
• 
Do not administer as an intravenous push or bolus. Do not mix Herceptin with other 
66 
drugs. 
67 
• 
Do not substitute Herceptin (trastuzumab) for or with ado-trastuzumab emtansine. 
68 
Adjuvant Treatment, Breast Cancer 
69 
Administer according to one of the following doses and schedules for a total of 52 weeks of 
70 
Herceptin therapy: 
71 
 During and following paclitaxel, docetaxel, or docetaxel/carboplatin: 
72 
• 
Initial dose of 4 mg/kg as an intravenous infusion over 90 minutes then at 2 mg/kg as an 
73 
intravenous infusion over 30 minutes weekly during chemotherapy for the first 12 weeks 
74 
(paclitaxel or docetaxel) or 18 weeks (docetaxel/carboplatin). 
75 
• 
One week following the last weekly dose of Herceptin, administer Herceptin at 6 mg/kg as an 
76 
intravenous infusion over 30−90 minutes every three weeks. 
77 
As a single agent within three weeks following completion of multi-modality, 
78 
anthracycline-based chemotherapy regimens:  
79 
• 
Initial dose at 8 mg/kg as an intravenous infusion over 90 minutes  
80 
• 
Subsequent doses at 6 mg/kg as an intravenous infusion over 30−90 minutes every 
81 
three weeks [see Dosage and Administration (2.3)]. 
82 
• 
Extending adjuvant treatment beyond one year is not recommended [see Adverse Reactions 
83 
(6.1)]. 
84 
Metastatic Treatment, Breast Cancer 
85 
• 
Administer Herceptin, alone or in combination with paclitaxel, at an initial dose of 4 mg/kg as 
86 
a 90-minute intravenous infusion followed by subsequent once weekly doses of 2 mg/kg as 
87 
30-minute intravenous infusions until disease progression. 
88 
Metastatic Gastric Cancer  
89 
• Administer Herceptin at an initial dose of 8 mg/kg as a 90-minute intravenous infusion 
90 
followed by subsequent doses of 6 mg/kg as an intravenous infusion over 30–90 minutes every 
91 
three weeks until disease progression [see Dosage and Administration (2.3)]. 
92 


 
4 
2.3 Important Dosing Considerations 
93 
If the patient has missed a dose of Herceptin by one week or less, then the usual maintenance dose 
94 
(weekly schedule: 2 mg/kg; three-weekly schedule: 6 mg/kg) should be administered as soon as 
95 
possible.  Do not wait until the next planned cycle.  Subsequent Herceptin maintenance doses should 
96 
be administered 7 days or 21 days later according to the weekly or three-weekly schedules, 
97 
respectively. 
98 
If the patient has missed a dose of Herceptin by more than one week, a re-loading dose of 
99 
Herceptin should be administered over approximately 90 minutes (weekly schedule: 4 mg/kg; three-
100 
weekly schedule: 8 mg/kg) as soon as possible.  Subsequent Herceptin maintenance doses (weekly 
101 
schedule: 2 mg/kg; three-weekly schedule 6 mg/kg) should be administered 7 days or 21 days later 
102 
according to the weekly or three-weekly schedules, respectively. 
103 
Infusion Reactions 
104 
[See Boxed Warning, Warnings and Precautions (5.2)] 
105 
• 
Decrease the rate of infusion for mild or moderate infusion reactions 
106 
• 
Interrupt the infusion in patients with dyspnea or clinically significant hypotension 
107 
• 
Discontinue Herceptin for severe or life-threatening infusion reactions. 
108 
Cardiomyopathy 
109 
[See Boxed Warning, Warnings and Precautions (5.1)] 
110 
 Assess left ventricular ejection fraction (LVEF) prior to initiation of Herceptin and at regular 
111 
intervals during treatment.  Withhold Herceptin dosing for at least 4 weeks for either of the 
112 
following: 
113 
• 
 ≥ 16% absolute decrease in LVEF from pre-treatment values 
114 
• 
LVEF below institutional limits of normal and ≥ 10% absolute decrease in LVEF from 
115 
pretreatment values. 
116 
 Herceptin may be resumed if, within 4−8 weeks, the LVEF returns to normal limits and the 
117 
absolute decrease from baseline is ≤ 15%. 
118 
 Permanently discontinue Herceptin for a persistent (> 8 weeks) LVEF decline or for suspension of 
119 
Herceptin dosing on more than 3 occasions for cardiomyopathy. 
120 
2.4 Preparation for Administration 
121 
 To prevent medication errors, it is important to check the vial labels to ensure that the drug being 
122 
prepared and administered is Herceptin (trastuzumab) and not ado-trastuzumab emtansine. 
123 
420 mg Multiple-dose vial 
124 
Reconstitution 
125 
 Reconstitute each 420 mg vial of Herceptin with 20 mL of Bacteriostatic Water for Injection 
126 
(BWFI), USP, containing 1.1% benzyl alcohol as a preservative to yield a multiple-dose solution 
127 
containing 21 mg/mL trastuzumab that delivers 20 mL (420 mg trastuzumab).  In patients with 
128 
known hypersensitivity to benzyl alcohol, reconstitute with 20 mL of Sterile Water for Injection 
129 
(SWFI) without preservative to yield a single use solution. 
130 
 Use appropriate aseptic technique when performing the following reconstitution steps: 
131 
• 
Using a sterile syringe, slowly inject the 20 mL of diluent into the vial containing the 
132 
lyophilized cake of Herceptin.  The stream of diluent should be directed into the lyophilized 
133 
cake. The reconstituted vial yields a solution for multiple-dose use, containing 21 mg/mL 
134 
trastuzumab. 
135 
• 
Swirl the vial gently to aid reconstitution.  DO NOT SHAKE. 
136 
• 
Slight foaming of the product may be present upon reconstitution.  Allow the vial to stand 
137 
undisturbed for approximately 5 minutes. 
138 


 
5 
• 
Parenteral drug products should be inspected visually for particulate matter and discoloration 
139 
prior to administration, whenever solution and container permit.  Inspect visually for 
140 
particulates and discoloration.  The solution should be free of visible particulates, clear to 
141 
slightly opalescent and colorless to pale yellow. 
142 
• 
Store reconstituted Herceptin in the refrigerator at 2○C to 8○C (36°F to 46°F); discard unused 
143 
Herceptin after 28 days.  If Herceptin is reconstituted with SWFI without preservative, use 
144 
immediately and discard any unused portion. Do not freeze. 
145 
Dilution 
146 
• 
Determine the dose (mg) of Herceptin [see Dosage and Administration (2.2)].  Calculate the 
147 
volume of the 21 mg/mL reconstituted Herceptin solution needed, withdraw this amount from 
148 
the vial and add it to an infusion bag containing 250 mL of 0.9% Sodium Chloride Injection, 
149 
USP.  DO NOT USE DEXTROSE (5%) SOLUTION. 
150 
• 
Gently invert the bag to mix the solution. 
151 
• 
The solution of Herceptin for infusion diluted in polyvinylchloride or polyethylene bags 
152 
containing 0.9% Sodium Chloride Injection, USP, should be stored at 2°C to 8°C (36°F to 
153 
46°F) for no more than 24 hours prior to use. Do not freeze. 
154 
 
155 
150 mg Single-dose vial 
156 
Reconstitution 
157 
 Reconstitute each 150 mg vial of Herceptin with 7.4 mL of Sterile Water for Injection (SWFI) 
158 
(not supplied) to yield a single-dose solution containing 21 mg/mL trastuzumab that delivers 7.15 
159 
mL (150 mg trastuzumab). 
160 
 Use appropriate aseptic technique when performing the following reconstitution steps: 
161 
• 
Using a sterile syringe, slowly inject 7.4 mL of SWFI (not supplied) into the vial containing 
162 
the lyophilized 150 mg Herceptin, directing the diluent stream into the lyophilized cake. The 
163 
reconstituted vial yields a solution for single-dose use, containing 21 mg/mL trastuzumab. 
164 
• 
Swirl the vial gently to aid reconstitution.  DO NOT SHAKE.  
165 
• 
Slight foaming of the product may be present upon reconstitution.  Allow the vial to stand 
166 
undisturbed for approximately 5 minutes.  
167 
• 
Parenteral drug products should be inspected visually for particulate matter and discoloration 
168 
prior to administration, whenever solution and container permit.  Inspect visually for 
169 
particulates and discoloration.  The solution should be free of visible particulates, clear to 
170 
slightly opalescent and colorless to pale yellow. 
171 
• 
Use the Herceptin solution immediately following reconstitution with SWFI, as it contains no 
172 
preservative and is intended for single-dose only. If not used immediately, store the 
173 
reconstituted Herceptin solution for up to 24 hours at 2○C to 8○C (36○F to 46○F); discard any 
174 
unused Herceptin after 24 hours.  Do not freeze.  
175 
Dilution 
176 
• 
Determine the dose (mg) of Herceptin [see Dosage and Administration (2.1)].   
177 
• 
Calculate the volume of the 21 mg/mL reconstituted Herceptin solution needed. 
178 
• 
Withdraw this amount from the vial and add it to an infusion bag containing 250 mL of 
179 
0.9% Sodium Chloride Injection, USP.  DO NOT USE DEXTROSE (5%) SOLUTION. 
180 
• 
Gently invert the bag to mix the solution. 
181 
• 
The solution of Herceptin for infusion diluted in polyvinylchloride or polyethylene bags 
182 
containing 0.9% Sodium Chloride Injection, USP, should be stored at 2°C to 8°C (36°F to 
183 
46°F) for no more than 24 hours prior to use.  Discard after 24 hours.  This storage time is 
184 
additional to the time allowed for the reconstituted vials.  Do not freeze. 
185 
 
186 


 
6 
3 DOSAGE FORMS AND STRENGTHS 
187 
• For injection: 150 mg lyophilized powder in a single-dose vial 
188 
• For injection: 420 mg lyophilized powder in a multiple-dose vial. 
189 
 
190 
4 CONTRAINDICATIONS 
191 
 None. 
192 
 
193 
5 WARNINGS AND PRECAUTIONS 
194 
5.1 Cardiomyopathy 
195 
 Herceptin can cause left ventricular cardiac dysfunction, arrhythmias, hypertension, disabling 
196 
cardiac failure, cardiomyopathy, and cardiac death [see Boxed Warning: Cardiomyopathy].  
197 
Herceptin can also cause asymptomatic decline in left ventricular ejection fraction (LVEF). 
198 
 There is a 4−6 fold increase in the incidence of symptomatic myocardial dysfunction among 
199 
patients receiving Herceptin as a single agent or in combination therapy compared with those not 
200 
receiving Herceptin.  The highest absolute incidence occurs when Herceptin is administered with an 
201 
anthracycline. 
202 
 Withhold Herceptin for ≥ 16% absolute decrease in LVEF from pre-treatment values or an LVEF 
203 
value below institutional limits of normal and ≥ 10% absolute decrease in LVEF from pretreatment 
204 
values [see Dosage and Administration (2.3)].  The safety of continuation or resumption of 
205 
Herceptin in patients with Herceptin-induced left ventricular cardiac dysfunction has not been 
206 
studied. 
207 
 Patients who receive anthracycline after stopping Herceptin may also be at increased risk of 
208 
cardiac dysfunction [see Drug Interactions (7) and Clinical Pharmacology (12.3)].   
209 
Cardiac Monitoring 
210 
 
Conduct thorough cardiac assessment, including history, physical examination, and determination 
211 
of LVEF by echocardiogram or MUGA scan.  The following schedule is recommended: 
212 
• 
Baseline LVEF measurement immediately prior to initiation of Herceptin 
213 
• 
LVEF measurements every 3 months during and upon completion of Herceptin 
214 
• 
Repeat LVEF measurement at 4 week intervals if Herceptin is withheld for significant left 
215 
ventricular cardiac dysfunction [see Dosage and Administration (2.3)] 
216 
• 
LVEF measurements every 6 months for at least 2 years following completion of Herceptin as 
217 
a component of adjuvant therapy. 
218 
 
In Study 1, 15% (158/1031) of patients discontinued Herceptin due to clinical evidence of 
219 
myocardial dysfunction or significant decline in LVEF after a median follow-up duration of 
220 
8.7 years in the AC-TH arm.  In Study 3 (one-year Herceptin treatment), the number of patients who 
221 
discontinued Herceptin due to cardiac toxicity at 12.6 months median duration of follow-up was 
222 
2.6% (44/1678).  In Study 4, a total of 2.9% (31/1056) of patients in the TCH arm (1.5% during the 
223 
chemotherapy phase and 1.4% during the monotherapy phase) and 5.7% (61/1068) of patients in the 
224 
AC-TH arm (1.5% during the chemotherapy phase and 4.2% during the monotherapy phase) 
225 
discontinued Herceptin due to cardiac toxicity. 
226 
 Among 64 patients receiving adjuvant chemotherapy (Studies 1 and 2) who developed congestive 
227 
heart failure, one patient died of cardiomyopathy, one patient died suddenly without documented 
228 
etiology, and 33 patients were receiving cardiac medication at last follow-up.  Approximately 24% 
229 
of the surviving patients had recovery to a normal LVEF (defined as ≥ 50%) and no symptoms on 
230 
continuing medical management at the time of last follow-up.  Incidence of congestive heart failure 
231 
(CHF) is presented in Table 1.  The safety of continuation or resumption of Herceptin in patients 
232 
with Herceptin-induced left ventricular cardiac dysfunction has not been studied. 
233 
 
234 


 
7 
Table 1  
Incidence of Congestive Heart Failure in Adjuvant Breast Cancer Studies 
 
Incidence of CHF 
Study 
Regimen 
Herceptin  
Control  
1 & 2a 
ACb→Paclitaxel+Herceptin 
3.2% (64/2000)c 
1.3% (21/1655) 
3d 
Chemo → Herceptin  
2% (30/1678) 
0.3% (5/1708) 
4  
ACb→Docetaxel+Herceptin 
2% (20/1068) 
0.3% (3/1050) 
4  
Docetaxel+Carbo+Herceptin 
0.4% (4/1056) 
0.3% (3/1050) 
  a Median follow-up duration for studies 1 and 2 combined was 8.3 years in the AC→TH arm.    
   b Anthracycline (doxorubicin) and cyclophosphamide. 
   c Includes 1 patient with fatal cardiomyopathy and 1 patient with sudden death without documented 
etiology. 
   d Includes NYHA II-IV and cardiac death at 12.6 months median duration of follow-up in the one-year 
Herceptin arm.  
 
235 
 In Study 3 (one-year Herceptin treatment), at a median follow-up duration of 8 years, the incidence 
236 
of severe CHF (NYHA III & IV) was 0.8%, and the rate of mild symptomatic and asymptomatic left 
237 
ventricular dysfunction was 4.6%. 
238 
 
239 
Table 2  
Incidence of Cardiac Dysfunctiona in Metastatic Breast Cancer Studies 
Study 
Event 
Incidence 
NYHA I−IV  
NYHA III−IV  
Herceptin 
Control 
Herceptin 
Control 
5 
(AC)b 
Cardiac Dysfunction 
28% 
7% 
19% 
3% 
5 
(paclitaxel) 
Cardiac Dysfunction 
11% 
1% 
4% 
1% 
6 
Cardiac Dysfunctionc 
7%  
N/A 
5% 
N/A 
 a Congestive heart failure or significant asymptomatic decrease in LVEF. 
 b Anthracycline (doxorubicin or epirubicin) and cyclophosphamide. 
 c Includes 1 patient with fatal cardiomyopathy. 
 
240 
 In Study 4, the incidence of NCI-CTC Grade 3/4 cardiac ischemia/infarction was higher in the 
241 
Herceptin containing regimens (AC-TH: 0.3% (3/1068) and TCH: 0.2% (2/1056)) as compared to 
242 
none in AC-T. 
243 
5.2 Infusion Reactions 
244 
 Infusion reactions consist of a symptom complex characterized by fever and chills, and on 
245 
occasion included nausea, vomiting, pain (in some cases at tumor sites), headache, dizziness, 
246 
dyspnea, hypotension, rash, and asthenia [see Adverse Reactions (6.1)]. 
247 
 In post-marketing reports, serious and fatal infusion reactions have been reported.  Severe 
248 
reactions, which include bronchospasm, anaphylaxis, angioedema, hypoxia, and severe hypotension, 
249 
were usually reported during or immediately following the initial infusion.  However, the onset and 
250 
clinical course were variable, including progressive worsening, initial improvement followed by 
251 
clinical deterioration, or delayed post-infusion events with rapid clinical deterioration.  For fatal 
252 
events, death occurred within hours to days following a serious infusion reaction. 
253 


 
8 
 Interrupt Herceptin infusion in all patients experiencing dyspnea, clinically significant 
254 
hypotension, and intervention of medical therapy administered (which may include epinephrine, 
255 
corticosteroids, diphenhydramine, bronchodilators, and oxygen).  Patients should be evaluated and 
256 
carefully monitored until complete resolution of signs and symptoms.  Permanent discontinuation 
257 
should be strongly considered in all patients with severe infusion reactions. 
258 
 There are no data regarding the most appropriate method of identification of patients who may 
259 
safely be retreated with Herceptin after experiencing a severe infusion reaction.  Prior to resumption 
260 
of Herceptin infusion, the majority of patients who experienced a severe infusion reaction were 
261 
pre-medicated with antihistamines and/or corticosteroids.  While some patients tolerated Herceptin 
262 
infusions, others had recurrent severe infusion reactions despite pre-medications. 
263 
5.3 Embryo-Fetal Toxicity  
264 
 Herceptin can cause fetal harm when administered to a pregnant woman. In post-marketing 
265 
reports, use of Herceptin during pregnancy resulted in cases of oligohydramnios and 
266 
oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and 
267 
neonatal death.  
268 
 Verify the pregnancy status of females of reproductive potential prior to the initiation of 
269 
Herceptin. Advise pregnant women and females of reproductive potential that exposure to 
270 
Herceptin during pregnancy or within 7 months prior to conception can result in fetal harm.  Advise 
271 
females of reproductive potential to use effective contraception during treatment and for 7 months 
272 
following the last dose of Herceptin [see Use in Specific Populations (8.1, 8.3) and Clinical 
273 
Pharmacology (12.3)]. 
274 
5.4 Pulmonary Toxicity 
275 
 Herceptin use can result in serious and fatal pulmonary toxicity.  Pulmonary toxicity includes 
276 
dyspnea, interstitial pneumonitis, pulmonary infiltrates, pleural effusions, non-cardiogenic 
277 
pulmonary edema, pulmonary insufficiency and hypoxia, acute respiratory distress syndrome, and 
278 
pulmonary fibrosis.  Such events can occur as sequelae of infusion reactions [see Warnings and 
279 
Precautions (5.2)].  Patients with symptomatic intrinsic lung disease or with extensive tumor 
280 
involvement of the lungs, resulting in dyspnea at rest, appear to have more severe toxicity. 
281 
5.5 Exacerbation of Chemotherapy-Induced Neutropenia 
282 
 In randomized, controlled clinical trials, the per-patient incidences of NCI-CTC Grade 3−4 
283 
neutropenia and of febrile neutropenia were higher in patients receiving Herceptin in combination 
284 
with myelosuppressive chemotherapy as compared to those who received chemotherapy alone.  The 
285 
incidence of septic death was similar among patients who received Herceptin and those who did not 
286 
[see Adverse Reactions (6.1)]. 
287 
 
288 
6 ADVERSE REACTIONS 
289 
 The following adverse reactions are discussed in greater detail in other sections of the label: 
290 
• 
Cardiomyopathy [see Warnings and Precautions (5.1)] 
291 
• 
Infusion Reactions [see Warnings and Precautions (5.2)] 
292 
• 
Embryo-Fetal Toxicity [see Warnings and Precautions (5.3)] 
293 
• 
Pulmonary Toxicity [see Warnings and Precautions (5.4)] 
294 
• 
Exacerbation of Chemotherapy-Induced Neutropenia [see Warnings and Precautions (5.5)] 
295 
 
296 
 The most common adverse reactions in patients receiving Herceptin in the adjuvant and metastatic 
297 
breast cancer setting are fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased 
298 
cough, headache, fatigue, dyspnea, rash, neutropenia, anemia, and myalgia.  Adverse reactions 
299 
requiring interruption or discontinuation of Herceptin treatment include CHF, significant decline in 
300 


 
9 
left ventricular cardiac function, severe infusion reactions, and pulmonary toxicity [see Dosage and 
301 
Administration (2.3)]. 
302 
 In the metastatic gastric cancer setting, the most common adverse reactions (≥ 10%) that were 
303 
increased (≥ 5% difference) in the Herceptin arm as compared to the chemotherapy alone arm were 
304 
neutropenia, diarrhea, fatigue, anemia, stomatitis, weight loss, upper respiratory tract infections, 
305 
fever, thrombocytopenia, mucosal inflammation, nasopharyngitis, and dysgeusia.  The most 
306 
common adverse reactions which resulted in discontinuation of treatment on the Herceptin-
307 
containing arm in the absence of disease progression were infection, diarrhea, and febrile 
308 
neutropenia. 
309 
6.1 Clinical Trials Experience 
310 
 Because clinical trials are conducted under widely varying conditions, adverse reaction rates 
311 
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of 
312 
another drug and may not reflect the rates observed in practice. 
313 
Adjuvant Breast Cancer Studies 
314 
 The data below reflect exposure to one-year Herceptin therapy across three randomized, 
315 
open-label studies, Studies 1, 2, and 3, with (n = 3678) or without (n = 3363) trastuzumab in the 
316 
adjuvant treatment of breast cancer. 
317 
 The data summarized in Table 3 below, from Study 3, reflect exposure to Herceptin in 
318 
1678 patients; the median treatment duration was 51 weeks and median number of infusions was 18.  
319 
Among the 3386 patients enrolled in the observation and one-year Herceptin arms of Study 3 at a 
320 
median duration of follow-up of 12.6 months in the Herceptin arm, the median age was 49 years 
321 
(range: 21 to 80 years), 83% of patients were Caucasian, and 13% were Asian. 
322 
 
323 


 
10 
Table 3  
Adverse Reactions for Study 3a, All Gradesb 
   
Adverse Reaction 
One Year Herceptin 
(n = 1678) 
Observation 
(n = 1708) 
Cardiac 
Hypertension 
64 (4%) 
35 (2%) 
Dizziness 
60 (4%) 
29 (2%) 
Ejection Fraction Decreased 
58 (3.5%) 
11 (0.6%) 
Palpitations 
48 (3%) 
12 (0.7%) 
Cardiac Arrhythmiasc 
40 (3%) 
17 (1%) 
Cardiac Failure Congestive 
30 (2%) 
5 (0.3%) 
Cardiac Failure 
9 (0.5%) 
4 (0.2%) 
Cardiac Disorder 
5 (0.3%) 
0 (0%) 
Ventricular Dysfunction 
4 (0.2%) 
0 (0%) 
Respiratory Thoracic Mediastinal Disorders 
Cough 
81 (5%) 
34 (2%) 
Influenza 
70 (4%) 
9 (0.5%) 
Dyspnea 
57 (3%) 
26 (2%) 
URI 
46 (3%) 
20 (1%) 
Rhinitis 
36 (2%) 
6 (0.4%) 
Pharyngolaryngeal Pain 
32 (2%) 
8 (0.5%) 
Sinusitis 
26 (2%) 
5 (0.3%) 
Epistaxis 
25 (2%) 
1 (0.06%) 
Pulmonary Hypertension 
4 (0.2%) 
0 (0%) 
Interstitial Pneumonitis 
4 (0.2%) 
0 (0%) 
Gastrointestinal Disorders 
Diarrhea 
123 (7%) 
16 (1%) 
Nausea 
108 (6%) 
19 (1%) 
Vomiting 
58 (3.5%) 
10 (0.6%) 
Constipation 
33 (2%) 
17 (1%) 
Dyspepsia 
30 (2%) 
9 (0.5%) 
Upper Abdominal Pain 
29 (2%) 
15 (1%) 
Musculoskeletal & Connective Tissue Disorders 
Arthralgia 
137 (8%) 
98 (6%) 
Back Pain 
91 (5%) 
58 (3%) 
Myalgia 
63 (4%) 
17 (1%) 
Bone Pain 
49 (3%) 
26 (2%) 
Muscle Spasm 
46 (3%) 
3 (0.2%) 
Nervous System Disorders 
Headache 
162 (10%) 
49 (3%) 
Paraesthesia 
29 (2%) 
11 (0.6%) 
Skin & Subcutaneous Tissue Disorders 
Rash 
70 (4%) 
10 (0.6%) 
Nail Disorders 
43 (2%) 
0 (0%) 
Pruritus 
40 (2%) 
10 (0.6%) 
 
324 


 
11 
Table 3 (cont’d) 
Adverse Reactions for Study 3a, All Gradesb 
Adverse Reaction 
One Year Herceptin 
(n = 1678) 
Observation 
(n = 1708) 
General Disorders 
Pyrexia 
100 (6%) 
6 (0.4%) 
Edema Peripheral 
79 (5%) 
37 (2%) 
Chills 
85 (5%) 
0 (0%) 
Asthenia 
75 (4.5%) 
30 (2%) 
Influenza-like Illness 
40 (2%) 
3 (0.2%) 
Sudden Death 
1 (0.06%) 
0 (0%) 
Infections 
Nasopharyngitis 
135 (8%) 
43 (3%) 
UTI 
39 (3%) 
13 (0.8%) 
Immune System Disorders 
Hypersensitivity 
10 (0.6%) 
1 (0.06%) 
Autoimmune Thyroiditis 
4 (0.3%) 
0 (0%) 
 a Median follow-up duration of 12.6 months in the one-year Herceptin 
treatment arm. 
 b The incidence of Grade 3 or higher adverse reactions was <1% in both 
arms for each listed term. 
 c Higher level grouping term. 
 
325 
 In Study 3, a comparison of 3-weekly Herceptin treatment for two years versus one year was also 
326 
performed.  The rate of asymptomatic cardiac dysfunction was increased in the 2-year Herceptin 
327 
treatment arm (8.1% versus 4.6% in the one-year Herceptin treatment arm).  More patients 
328 
experienced at least one adverse reaction of Grade 3 or higher in the 2-year Herceptin treatment arm 
329 
(20.4%) compared with the one-year Herceptin treatment arm (16.3%). 
330 
 The safety data from Studies 1 and 2 were obtained from 3655 patients, of whom 2000 received 
331 
Herceptin; the median treatment duration was 51 weeks.  The median age was 49 years (range: 
332 
24−80); 84% of patients were White, 7% Black, 4% Hispanic, and 3% Asian.   
333 
 In Study 1, only Grade 3−5 adverse events, treatment-related Grade 2 events, and Grade 2−5 
334 
dyspnea were collected during and for up to 3 months following protocol-specified treatment.  The 
335 
following non-cardiac adverse reactions of Grade 2−5 occurred at an incidence of at least 2% greater 
336 
among patients receiving Herceptin plus chemotherapy as compared to chemotherapy alone:  fatigue 
337 
(29.5% vs. 22.4%), infection (24.0% vs. 12.8%), hot flashes (17.1% vs. 15.0%), anemia (12.3% vs. 
338 
6.7%), dyspnea (11.8% vs. 4.6%), rash/desquamation (10.9% vs. 7.6%), leukopenia (10.5% vs. 
339 
8.4%), neutropenia (6.4% vs. 4.3%), headache (6.2% vs. 3.8%), pain (5.5% vs. 3.0%), edema (4.7% 
340 
vs. 2.7%), and insomnia (4.3% vs. 1.5%).  The majority of these events were Grade 2 in severity.  
341 
 In Study 2, data collection was limited to the following investigator-attributed treatment-related 
342 
adverse reactions: NCI-CTC Grade 4 and 5 hematologic toxicities, Grade 3−5 non-hematologic 
343 
toxicities, selected Grade 2−5 toxicities associated with taxanes (myalgia, arthralgias, nail changes, 
344 
motor neuropathy, and sensory neuropathy) and Grade 1−5 cardiac toxicities occurring during 
345 
chemotherapy and/or Herceptin treatment.  The following non-cardiac adverse reactions of 
346 
Grade 2−5 occurred at an incidence of at least 2% greater among patients receiving Herceptin plus 
347 
chemotherapy as compared to chemotherapy alone:  arthralgia (12.2% vs. 9.1%), nail changes 
348 
(11.5% vs. 6.8%), dyspnea (2.4% vs. 0.2%), and diarrhea (2.2% vs. 0%).  The majority of these 
349 
events were Grade 2 in severity. 
350 
 Safety data from Study 4 reflect exposure to Herceptin as part of an adjuvant treatment regimen 
351 
from 2124 patients receiving at least one dose of study treatment [AC-TH: n = 1068; TCH: n = 1056].  
352 


 
12 
The overall median treatment duration was 54 weeks in both the AC-TH and TCH arms.  
353 
The median number of infusions was 26 in the AC-TH arm and 30 in the TCH arm, including 
354 
weekly infusions during the chemotherapy phase and every three week dosing in the monotherapy 
355 
period.  Among these patients, the median age was 49 years (range 22 to 74 years).  In Study 4, the 
356 
toxicity profile was similar to that reported in Studies 1, 2, and 3 with the exception of a low 
357 
incidence of CHF in the TCH arm. 
358 
Metastatic Breast Cancer Studies 
359 
 The data below reflect exposure to Herceptin in one randomized, open-label study, Study 5, of 
360 
chemotherapy with (n = 235) or without (n = 234) trastuzumab in patients with metastatic breast 
361 
cancer, and one single-arm study (Study 6; n = 222) in patients with metastatic breast cancer.  Data 
362 
in Table 4 are based on Studies 5 and 6. 
363 
 Among the 464 patients treated in Study 5, the median age was 52 years (range: 25−77 years).  
364 
Eighty-nine percent were White, 5% Black, 1% Asian, and 5% other racial/ethnic groups.  
365 
All patients received 4 mg/kg initial dose of Herceptin followed by 2 mg/kg weekly.  The 
366 
percentages of patients who received Herceptin treatment for ≥ 6 months and ≥ 12 months were 58% 
367 
and 9%, respectively. 
368 
 Among the 352 patients treated in single agent studies (213 patients from Study 6), the median 
369 
age was 50 years (range 28−86 years), 86% were White, 3% were Black, 3% were Asian, and 8% in 
370 
other racial/ethnic groups.  Most of the patients received 4 mg/kg initial dose of Herceptin followed 
371 
by 2 mg/kg weekly.  The percentages of patients who received Herceptin treatment for ≥ 6 months 
372 
and ≥ 12 months were 31% and 16%, respectively. 
373 
 
374 
Table 4 
Per-Patient Incidence of Adverse Reactions Occurring in ≥ 5% of Patients in 
Uncontrolled Studies or at Increased Incidence in the Herceptin Arm (Studies 5 and 6)  
 
Single Agenta 
n = 352 
Herceptin + 
Paclitaxel 
n = 91 
Paclitaxel 
Alone 
n = 95 
Herceptin + 
ACb 
n = 143 
ACb Alone 
n = 135 
Body as a Whole 
 
 
 
 
 
Pain 
47% 
61% 
62% 
57% 
42% 
Asthenia 
42% 
62% 
57% 
54% 
55% 
Fever 
36% 
49% 
23% 
56% 
34% 
Chills 
32% 
41% 
4% 
35% 
11% 
Headache 
26% 
36% 
28% 
44% 
31% 
Abdominal pain 
22% 
34% 
22% 
23% 
18% 
Back pain 
22% 
34% 
30% 
27% 
15% 
Infection 
20% 
47% 
27% 
47% 
31% 
Flu syndrome 
10% 
12% 
5% 
12% 
6% 
Accidental injury 
6% 
13% 
3% 
9% 
4% 
Allergic reaction 
3% 
8% 
2% 
4% 
2% 
Cardiovascular 
 
 
 
 
 
Tachycardia 
5% 
12% 
4% 
10% 
5% 
Congestive heart failure 
7% 
11% 
1% 
28% 
7% 
 
375 


 
13 
Table 4 (cont’d) 
Per-Patient Incidence of Adverse Reactions Occurring in ≥ 5% of Patients in 
Uncontrolled Studies or at Increased Incidence in the Herceptin Arm (Studies 5 and 6)  
 
Single Agenta 
n = 352 
Herceptin + 
Paclitaxel 
n = 91 
Paclitaxel 
Alone 
n = 95 
Herceptin + 
ACb 
n = 143 
ACb Alone 
n = 135 
Digestive 
 
 
 
 
 
Nausea 
33% 
51% 
9% 
76% 
77% 
Diarrhea 
25% 
45% 
29% 
45% 
26% 
Vomiting 
23% 
37% 
28% 
53% 
49% 
Nausea and vomiting 
8% 
14% 
11% 
18% 
9% 
Anorexia 
14% 
24% 
16% 
31% 
26% 
Heme & Lymphatic 
 
 
 
 
 
Anemia 
4% 
14% 
9% 
36% 
26% 
Leukopenia 
3% 
24% 
17% 
52% 
34% 
Metabolic 
 
 
 
 
 
Peripheral edema 
10% 
22% 
20% 
20% 
17% 
Edema 
8% 
10% 
8% 
11% 
5% 
Musculoskeletal 
 
 
 
 
 
Bone pain 
7% 
24% 
18% 
7% 
7% 
Arthralgia 
6% 
37% 
21% 
8% 
9% 
Nervous 
 
 
 
 
 
Insomnia 
14% 
25% 
13% 
29% 
15% 
Dizziness 
13% 
22% 
24% 
24% 
18% 
Paresthesia 
9% 
48% 
39% 
17% 
11% 
Depression 
6% 
12% 
13% 
20% 
12% 
Peripheral neuritis 
2% 
23% 
16% 
2% 
2% 
Neuropathy 
1% 
13% 
5% 
4% 
4% 
Respiratory 
 
 
 
 
 
Cough increased 
26% 
41% 
22% 
43% 
29% 
Dyspnea 
22% 
27% 
26% 
42% 
25% 
Rhinitis 
14% 
22% 
5% 
22% 
16% 
Pharyngitis 
12% 
22% 
14% 
30% 
18% 
Sinusitis 
9% 
21% 
7% 
13% 
6% 
Skin 
 
 
 
 
 
Rash 
18% 
38% 
18% 
27% 
17% 
Herpes simplex 
2% 
12% 
3% 
7% 
9% 
Acne 
2% 
11% 
3% 
3% 
< 1% 
Urogenital 
 
 
 
 
 
Urinary tract infection 
5% 
18% 
14% 
13% 
7% 
 a Data for Herceptin single agent were from 4 studies, including 213 patients from Study 6. 
 b Anthracycline (doxorubicin or epirubicin) and cyclophosphamide. 
 
376 
 Metastatic Gastric Cancer 
377 
 The data below are based on the exposure of 294 patients to Herceptin in combination with a 
378 
fluoropyrimidine (capecitabine or 5-FU) and cisplatin (Study 7).  In the Herceptin plus 
379 
chemotherapy arm, the initial dose of Herceptin 8 mg/kg was administered on Day 1 (prior to 
380 


 
14 
chemotherapy) followed by 6 mg/kg every 21 days until disease progression.  Cisplatin was 
381 
administered at 80 mg/m2 on Day 1 and the fluoropyrimidine was administered as either 
382 
capecitabine 1000 mg/m2 orally twice a day on Days 1–14 or 5-fluorouracil 800 mg/m2/day as a 
383 
continuous intravenous infusion Days 1 through 5.  Chemotherapy was administered for six 21-day 
384 
cycles.  Median duration of Herceptin treatment was 21 weeks; median number of Herceptin 
385 
infusions administered was eight. 
386 
 
387 
Table 5 
Study 7:  Per Patient Incidence of Adverse Reactions of All Grades  
(Incidence  ≥ 5% between Arms) or Grade 3/4 (Incidence > 1% between Arms)  
and Higher Incidence in Herceptin Arm 
Body System/Adverse Event 
Herceptin + FC   
(N = 294) 
N (%) 
FC  
(N = 290)  
N (%) 
All Grades 
Grades 3/4 
All Grades 
Grades 3/4 
Investigations 
Neutropenia 
230 (78) 
101 (34) 
212 (73) 
83 (29) 
Hypokalemia 
83 (28) 
28 (10) 
69 (24) 
16 (6) 
Anemia 
81 (28) 
36 (12) 
61 (21) 
30 (10) 
Thrombocytopenia 
47 (16) 
14 (5) 
33 (11) 
8 (3) 
Blood and Lymphatic System Disorders 
Febrile Neutropenia 
⎯ 
15 (5) 
⎯ 
8 (3) 
Gastrointestinal Disorders 
Diarrhea 
109 (37) 
27 (9) 
80 (28) 
11 (4) 
Stomatitis 
72 (24) 
2 (1) 
43 (15) 
6 (2) 
Dysphagia  
19 (6) 
7 (2)  
10 (3) 
1 (≤ 1) 
Body as a Whole 
Fatigue 
102 (35) 
12 (4) 
82 (28) 
7 (2) 
Fever 
54 (18) 
3 (1) 
36 (12) 
0 (0) 
Mucosal Inflammation 
37 (13) 
6 (2) 
18 (6) 
2 (1) 
Chills 
23 (8) 
1 (≤ 1) 
0 (0) 
0 (0) 
Metabolism and Nutrition Disorders 
Weight Decrease 
69 (23) 
6 (2) 
40 (14) 
7 (2) 
Infections and Infestations 
Upper Respiratory Tract Infections 
56 (19) 
0 (0) 
29 (10) 
0 (0) 
Nasopharyngitis 
37 (13) 
0 (0) 
17 (6) 
0 (0) 
Renal and Urinary Disorders 
Renal Failure and Impairment 
53 (18) 
8 (3) 
42 (15) 
5 (2) 
Nervous System Disorders 
Dysgeusia 
28 (10) 
0 (0) 
14 (5) 
0 (0) 
 
388 


 
15 
 The following subsections provide additional detail regarding adverse reactions observed in 
389 
clinical trials of adjuvant breast cancer, metastatic breast cancer, metastatic gastric cancer, or 
390 
post-marketing experience. 
391 
Cardiomyopathy 
392 
 Serial measurement of cardiac function (LVEF) was obtained in clinical trials in the adjuvant 
393 
treatment of breast cancer.  In Study 3, the median duration of follow-up was 12.6 months 
394 
(12.4 months in the observation arm; 12.6 months in the 1-year Herceptin arm); and in Studies 1 and 
395 
2, 7.9 years in the AC-T arm, 8.3 years in the AC-TH arm.  In Studies 1 and 2, 6% of all randomized 
396 
patients with post-AC LVEF evaluation were not permitted to initiate Herceptin following 
397 
completion of AC chemotherapy due to cardiac dysfunction (LVEF < LLN or ≥ 16 point decline in 
398 
LVEF from baseline to end of AC).  Following initiation of Herceptin therapy, the incidence of 
399 
new-onset dose-limiting myocardial dysfunction was higher among patients receiving Herceptin and 
400 
paclitaxel as compared to those receiving paclitaxel alone in Studies 1 and 2, and in patients 
401 
receiving one-year Herceptin monotherapy compared to observation in Study 3 (see Table 6, 
402 
Figures 1 and 2).  The per-patient incidence of new-onset cardiac dysfunction, as measured by 
403 
LVEF, remained similar when compared to the analysis performed at a median follow-up of 2.0 
404 
years in the AC-TH arm.  This analysis also showed evidence of reversibility of left ventricular 
405 
dysfunction, with 64.5% of patients who experienced symptomatic CHF in the AC-TH group being 
406 
asymptomatic at latest follow-up, and 90.3% having full or partial LVEF recovery. 
407 
 
408 


 
16 
Table 6a  
Per-patient Incidence of New Onset  
Myocardial Dysfunction (by LVEF) Studies 1, 2, 3 and 4 
 
LVEF < 50%  
and Absolute Decrease from Baseline  
Absolute LVEF Decrease 
 
LVEF 
< 50% 
≥ 10% 
decrease 
≥ 16% 
decrease 
< 20% and ≥ 10% 
≥ 20% 
Studies 1 & 2b,c  
AC→TH 
(n = 1856) 
23.1% 
(428) 
18.5% 
(344) 
11.2% 
(208) 
37.9% 
(703) 
8.9% 
(166) 
AC→T 
(n = 1170) 
11.7% 
(137) 
7.0% 
(82) 
3.0% 
(35) 
22.1% 
(259) 
3.4% 
(40) 
Study 3d 
Herceptin 
(n = 1678) 
8.6% 
(144) 
7.0% 
(118) 
3.8% 
(64) 
22.4% 
(376) 
3.5% 
(59) 
Observation 
(n = 1708) 
2.7% 
(46) 
2.0% 
(35) 
1.2% 
(20) 
11.9% 
(204) 
1.2% 
(21) 
Study 4e 
TCH 
(n = 1056) 
8.5% 
(90) 
5.9% 
(62) 
3.3% 
(35) 
34.5% 
(364) 
6.3% 
(67) 
AC→TH 
(n = 1068) 
17% 
(182) 
13.3% 
(142) 
9.8% 
(105) 
44.3% 
(473) 
13.2% 
(141) 
AC→T 
(n = 1050) 
9.5% 
(100) 
6.6% 
(69) 
3.3% 
(35) 
34% 
(357) 
5.5% 
(58) 
 a For Studies 1, 2 and 3, events are counted from the beginning of Herceptin treatment.  For 
Study 4, events are counted from the date of randomization.  
 b Studies 1 and 2 regimens: doxorubicin and cyclophosphamide followed by paclitaxel 
(AC→T) or paclitaxel plus Herceptin (AC→TH). 
   c Median duration of follow-up for Studies 1 and 2 combined was 8.3 years in the AC→TH 
arm. 
  d  Median follow-up duration of 12.6 months in the one-year Herceptin treatment arm. 
  e Study 4 regimens: doxorubicin and cyclophosphamide followed by docetaxel (AC→T) or 
docetaxel plus Herceptin (AC→TH); docetaxel and carboplatin plus Herceptin (TCH). 
 
 
409 


 
17 
Figure 1  
410 
Studies 1 and 2:  Cumulative Incidence of Time to First LVEF  
411 
Decline of ≥ 10 Percentage Points from Baseline and to  
412 
Below 50% with Death as a Competing Risk Event 
413 
 
414 
 
415 
Time 0 is initiation of paclitaxel or Herceptin + paclitaxel therapy. 
416 
 
417 


 
18 
Figure 2  
418 
Study 3:  Cumulative Incidence of Time to First LVEF  
419 
Decline of ≥ 10 Percentage Points from Baseline and to  
420 
Below 50% with Death as a Competing Risk Event 
421 
 
422 
Time 0 is the date of randomization. 
423 
 
424 
Figure 3 
425 
Study 4:  Cumulative Incidence of Time to First LVEF  
426 
Decline of ≥ 10 Percentage Points from Baseline and to  
427 
Below 50% with Death as a Competing Risk Event 
428 
 
429 
Time 0 is the date of randomization. 
430 
 
431 


 
19 
 The incidence of treatment emergent congestive heart failure among patients in the metastatic 
432 
breast cancer trials was classified for severity using the New York Heart Association classification 
433 
system (I−IV, where IV is the most severe level of cardiac failure) (see Table 2).  In the metastatic 
434 
breast cancer trials, the probability of cardiac dysfunction was highest in patients who received 
435 
Herceptin concurrently with anthracyclines. 
436 
 In Study 7, 5.0% of patients in the Herceptin plus chemotherapy arm compared to 1.1% of 
437 
patients in the chemotherapy alone arm had LVEF value below 50% with a  ≥ 10% absolute decrease 
438 
in LVEF from pretreatment values. 
439 
Infusion Reactions 
440 
 During the first infusion with Herceptin, the symptoms most commonly reported were chills and 
441 
fever, occurring in approximately 40% of patients in clinical trials.  Symptoms were treated with 
442 
acetaminophen, diphenhydramine, and meperidine (with or without reduction in the rate of 
443 
Herceptin infusion); permanent discontinuation of Herceptin for infusion reactions was required in 
444 
< 1% of patients.  Other signs and/or symptoms may include nausea, vomiting, pain (in some cases 
445 
at tumor sites), rigors, headache, dizziness, dyspnea, hypotension, elevated blood pressure, rash, and 
446 
asthenia.  Infusion reactions occurred in 21% and 35% of patients, and were severe in 1.4% and 9% 
447 
of patients, on second or subsequent Herceptin infusions administered as monotherapy or in 
448 
combination with chemotherapy, respectively.  In the post-marketing setting, severe infusion 
449 
reactions, including hypersensitivity, anaphylaxis, and angioedema have been reported.   
450 
Anemia 
451 
 In randomized controlled clinical trials, the overall incidence of anemia (30% vs. 21% [Study 5]), 
452 
of selected NCI-CTC Grade 2–5 anemia (12.3% vs. 6.7% [Study 1]), and of anemia requiring 
453 
transfusions (0.1% vs. 0 patients [Study 2]) were increased in patients receiving Herceptin and 
454 
chemotherapy compared with those receiving chemotherapy alone.  Following the administration of 
455 
Herceptin as a single agent (Study 6), the incidence of NCI-CTC Grade 3 anemia was < 1%.  In 
456 
Study 7 (metastatic gastric cancer), on the Herceptin containing arm as compared to the 
457 
chemotherapy alone arm, the overall incidence of anemia was 28% compared to 21% and of NCI- 
458 
CTC Grade 3/4 anemia was 12.2% compared to 10.3%. 
459 
Neutropenia 
460 
 
In randomized controlled clinical trials in the adjuvant setting, the incidence of selected 
461 
NCI-CTC Grade 4−5 neutropenia (1.7% vs. 0.8% [Study 2]) and of selected Grade 2−5 neutropenia 
462 
(6.4% vs. 4.3% [Study 1]) were increased in patients receiving Herceptin and chemotherapy 
463 
compared with those receiving chemotherapy alone.  In a randomized, controlled trial in patients 
464 
with metastatic breast cancer, the incidences of NCI-CTC Grade 3/4 neutropenia (32% vs. 22%) and 
465 
of febrile neutropenia (23% vs. 17%) were also increased in patients randomized to Herceptin in 
466 
combination with myelosuppressive chemotherapy as compared to chemotherapy alone.  In Study 7 
467 
(metastatic gastric cancer) on the Herceptin containing arm as compared to the chemotherapy alone 
468 
arm, the incidence of NCI-CTC Grade 3/4 neutropenia was 36.8% compared to 28.9%; febrile 
469 
neutropenia 5.1% compared to 2.8%. 
470 
Infection 
471 
 The overall incidences of infection (46% vs. 30% [Study 5]), of selected NCI-CTC Grade 2−5 
472 
infection/febrile neutropenia (24.3% vs. 13.4% [Study 1]) and of selected Grade 3−5 
473 
infection/febrile neutropenia (2.9% vs. 1.4%) [Study 2]) were higher in patients receiving Herceptin 
474 
and chemotherapy compared with those receiving chemotherapy alone.  The most common site of 
475 
infections in the adjuvant setting involved the upper respiratory tract, skin, and urinary tract. 
476 
 In Study 4, the overall incidence of infection was higher with the addition of Herceptin to AC-T 
477 
but not to TCH [44% (AC-TH), 37% (TCH), 38% (AC-T)].  The incidences of NCI-CTC Grade 3−4 
478 
infection were similar [25% (AC-TH), 21% (TCH), 23% (AC-T)] across the three arms. 
479 


 
20 
 In a randomized, controlled trial in treatment of metastatic breast cancer, the reported incidence of 
480 
febrile neutropenia was higher (23% vs. 17%) in patients receiving Herceptin in combination with 
481 
myelosuppressive chemotherapy as compared to chemotherapy alone. 
482 
Pulmonary Toxicity 
483 
Adjuvant Breast Cancer 
484 
 Among women receiving adjuvant therapy for breast cancer, the incidence of selected NCI-CTC 
485 
Grade 2−5 pulmonary toxicity (14.3% vs. 5.4% [Study 1]) and of selected NCI-CTC Grade 3−5 
486 
pulmonary toxicity and spontaneous reported Grade 2 dyspnea (3.4% vs. 0.9% [Study 2]) was higher 
487 
in patients receiving Herceptin and chemotherapy compared with chemotherapy alone.  The most 
488 
common pulmonary toxicity was dyspnea (NCI-CTC Grade 2−5:  11.8% vs. 4.6% [Study 1]; 
489 
NCI-CTC Grade 2−5:  2.4% vs. 0.2% [Study 2]). 
490 
 Pneumonitis/pulmonary infiltrates occurred in 0.7% of patients receiving Herceptin compared 
491 
with 0.3% of those receiving chemotherapy alone.  Fatal respiratory failure occurred in 3 patients 
492 
receiving Herceptin, one as a component of multi-organ system failure, as compared to 1 patient 
493 
receiving chemotherapy alone. 
494 
 In Study 3, there were 4 cases of interstitial pneumonitis in the one-year Herceptin treatment arm 
495 
compared to none in the observation arm at a median follow-up duration of 12.6 months. 
496 
Metastatic Breast Cancer 
497 
 Among women receiving Herceptin for treatment of metastatic breast cancer, the incidence of 
498 
pulmonary toxicity was also increased.  Pulmonary adverse events have been reported in the 
499 
post-marketing experience as part of the symptom complex of infusion reactions.  Pulmonary events 
500 
include bronchospasm, hypoxia, dyspnea, pulmonary infiltrates, pleural effusions, non-cardiogenic 
501 
pulmonary edema, and acute respiratory distress syndrome.  For a detailed description, see Warnings 
502 
and Precautions (5.4). 
503 
Thrombosis/Embolism 
504 
 In 4 randomized, controlled clinical trials, the incidence of thrombotic adverse events was higher 
505 
in patients receiving Herceptin and chemotherapy compared to chemotherapy alone in three studies 
506 
(2.6% vs. 1.5% [Study 1], 2.5% and 3.7% vs. 2.2% [Study 4] and 2.1% vs. 0% [Study 5]). 
507 
Diarrhea 
508 
 Among women receiving adjuvant therapy for breast cancer, the incidence of NCI-CTC 
509 
Grade 2−5 diarrhea (6.7% vs. 5.4% [Study 1]) and of NCI-CTC Grade 3−5 diarrhea (2.2% vs. 0% 
510 
[Study 2]), and of Grade 1−4 diarrhea (7% vs. 1% [Study 3; one-year Herceptin treatment at 
511 
12.6 months median duration of follow-up]) were higher in patients receiving Herceptin as compared 
512 
to controls.  In Study 4, the incidence of Grade 3−4 diarrhea was higher [5.7% AC-TH, 5.5% TCH 
513 
vs. 3.0% AC-T] and of Grade 1−4 was higher [51% AC-TH, 63% TCH vs. 43% AC-T] among 
514 
women receiving Herceptin.  Of patients receiving Herceptin as a single agent for the treatment of 
515 
metastatic breast cancer, 25% experienced diarrhea.  An increased incidence of diarrhea was 
516 
observed in patients receiving Herceptin in combination with chemotherapy for treatment of 
517 
metastatic breast cancer. 
518 
Renal Toxicity 
519 
 In Study 7 (metastatic gastric cancer) on the Herceptin-containing arm as compared to the 
520 
chemotherapy alone arm the incidence of renal impairment was 18% compared to 14.5%.  Severe 
521 
(Grade 3/4) renal failure was 2.7% on the Herceptin-containing arm compared to 1.7% on the 
522 
chemotherapy only arm.  Treatment discontinuation for renal insufficiency/failure was 2% on the 
523 
Herceptin-containing arm and 0.3% on the chemotherapy only arm.  
524 
 In the post-marketing setting, rare cases of nephrotic syndrome with pathologic evidence of 
525 
glomerulopathy have been reported.  The time to onset ranged from 4 months to approximately 
526 
18 months from initiation of Herceptin therapy.  Pathologic findings included membranous 
527 


 
21 
glomerulonephritis, focal glomerulosclerosis, and fibrillary glomerulonephritis.  Complications 
528 
included volume overload and congestive heart failure. 
529 
6.2 Immunogenicity 
530 
 As with all therapeutic proteins, there is a potential for immunogenicity.  Among 903 women with 
531 
metastatic breast cancer, human anti-human antibody (HAHA) to Herceptin was detected in one 
532 
patient using an enzyme-linked immunosorbent assay (ELISA).  This patient did not experience an 
533 
allergic reaction.  Samples for assessment of HAHA were not collected in studies of adjuvant breast 
534 
cancer. 
535 
 The incidence of antibody formation is highly dependent on the sensitivity and the specificity of 
536 
the assay.  Additionally, the observed incidence of antibody (including neutralizing antibody) 
537 
positivity in an assay may be influenced by several factors including assay methodology, sample 
538 
handling, timing of sample collection, concomitant medications, and underlying disease.  For these 
539 
reasons, comparison of the incidence of antibodies to Herceptin with the incidence of antibodies to 
540 
other products may be misleading. 
541 
6.3 Post-Marketing Experience 
542 
 The following adverse reactions have been identified during post-approval use of Herceptin.  
543 
Because these reactions are reported voluntarily from a population of uncertain size, it is not always 
544 
possible to reliably estimate their frequency or establish a causal relationship to drug exposure. 
545 
• 
Infusion reaction [see Warnings and Precautions (5.2)] 
546 
• 
Oligohydramnios or oligohydramnios sequence, including pulmonary hypoplasia, skeletal 
547 
abnormalities, and neonatal death [see Warnings and Precautions (5.3)] 
548 
• 
Glomerulopathy [see Adverse Reactions (6.1)] 
549 
• 
Immune thrombocytopenia 
550 
 
551 
7 DRUG INTERACTIONS 
552 
  Patients who receive anthracycline after stopping Herceptin may be at increased risk of cardiac 
553 
dysfunction because of trastuzumab’s long washout period based on population PK analysis [see 
554 
Clinical Pharmacology (12.3)].  If possible, physicians should avoid anthracycline-based therapy for 
555 
up to 7 months after stopping Herceptin.  If anthracyclines are used, the patient’s cardiac function 
556 
should be monitored carefully. 
557 
 
558 
8 USE IN SPECIFIC POPULATIONS 
559 
8.1  Pregnancy  
560 
Pregnancy Exposure Registry and Pharmacovigilance Program 
561 
 There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to 
562 
Herceptin during pregnancy.  Encourage women who receive Herceptin during pregnancy or within 
563 
7 months prior to conception to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-
564 
6720 or visiting http://www.motherpregnancyregistry.com/.   
565 
In addition, there is a pregnancy pharmacovigilance program for Herceptin.  If Herceptin is 
566 
administered during pregnancy, or if a patient becomes pregnant while receiving Herceptin or within 
567 
7 months following the last dose of Herceptin, health care providers and patients should immediately 
568 
report Herceptin exposure to Genentech at 1-888-835-2555. 
569 
Risk Summary 
570 
  Herceptin can cause fetal harm when administered to a pregnant woman.  In post-marketing 
571 
reports, use of Herceptin during pregnancy resulted in cases of oligohydramnios and of 
572 
oligohydramnios sequence, manifesting as pulmonary hypoplasia, skeletal abnormalities, and 
573 
neonatal death [see Data].  Apprise the patient of the potential risks to a fetus.  There are clinical 
574 


 
22 
considerations if Herceptin is used in a pregnant woman or if a patient becomes pregnant within 7 
575 
months following the last dose of Herceptin [see Clinical Considerations]. 
576 
 
 The estimated background risk of major birth defects and miscarriage for the indicated population 
577 
is unknown.  In the U.S. general population, the estimated background risk of major birth defects 
578 
and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.   
579 
Clinical Considerations 
580 
Fetal/Neonatal Adverse Reactions 
581 
 Monitor women who received Herceptin during pregnancy or within 7 months prior to conception 
582 
for oligohydramnios.  If oligohydramnios occurs, perform fetal testing that is appropriate for 
583 
gestational age and consistent with community standards of care.   
584 
Data 
585 
Human Data 
586 
 In post-marketing reports, use of Herceptin during pregnancy resulted in cases of oligohydramnios 
587 
and of oligohydramnios sequence, manifesting in the fetus as pulmonary hypoplasia, skeletal 
588 
abnormalities, and neonatal death.  These case reports described oligohydramnios in pregnant 
589 
women who received Herceptin either alone or in combination with chemotherapy.  In some case 
590 
reports, amniotic fluid index increased after Herceptin was stopped.  In one case, Herceptin therapy 
591 
resumed after amniotic index improved and oligohydramnios recurred. 
592 
Animal Data 
593 
 
In studies where trastuzumab was administered to pregnant Cynomolgus monkeys during the 
594 
period of organogenesis at doses up to 25 mg/kg given twice weekly (up to 25 times the 
595 
recommended weekly human dose of 2 mg/kg), trastuzumab crossed the placental barrier during the 
596 
early (Gestation Days 20 to 50) and late (Gestation Days 120 to 150) phases of gestation.  The 
597 
resulting concentrations of trastuzumab in fetal serum and amniotic fluid were approximately 33% 
598 
and 25%, respectively, of those present in the maternal serum but were not associated with adverse 
599 
developmental effects.  
600 
8.2 Lactation 
601 
Risk Summary    
602 
 There is no information regarding the presence of trastuzumab in human milk, the effects on the 
603 
breastfed infant, or the effects on milk production.  Published data suggest human IgG is present in 
604 
human milk but does not enter the neonatal and infant circulation in substantial amounts.  
605 
Trastuzumab was present in the milk of lactating Cynomolgus monkeys but not associated with 
606 
neonatal toxicity [see Data].  Consider the developmental and health benefits of breastfeeding along 
607 
with the mother’s clinical need for Herceptin treatment and any potential adverse effects on the 
608 
breastfed child from Herceptin or from the underlying maternal condition. This consideration should 
609 
also take into account the trastuzumab wash out period of 7 months [see Clinical Pharmacology 
610 
(12.3)].  
611 
Data 
612 
 In lactating Cynomolgus monkeys, trastuzumab was present in breast milk at about 0.3% of 
613 
maternal serum concentrations after pre- (beginning Gestation Day 120) and post-partum (through 
614 
Post-partum Day 28) doses of 25 mg/kg administered twice weekly (25 times the recommended 
615 
weekly human dose of 2 mg/kg of Herceptin).  Infant monkeys with detectable serum levels of 
616 
trastuzumab did not exhibit any adverse effects on growth or development from birth to 1 month of 
617 
age.  
618 
 
 
619 


 
23 
8.3 Females and Males of Reproductive Potential 
620 
Pregnancy Testing 
621 
 Verify the pregnancy status of females of reproductive potential prior to the initiation of 
622 
Herceptin.   
623 
Contraception 
624 
Females 
625 
 Herceptin can cause embryo-fetal harm when administered during pregnancy. Advise females of 
626 
reproductive potential to use effective contraception during treatment with Herceptin and for 7 
627 
months following the last dose of Herceptin [see Use in Specific Populations (8.1) and Clinical 
628 
Pharmacology (12.3)].   
629 
8.4 Pediatric Use 
630 
 The safety and effectiveness of Herceptin in pediatric patients have not been established. 
631 
8.5 Geriatric Use 
632 
 Herceptin has been administered to 386 patients who were 65 years of age or over (253 in the 
633 
adjuvant treatment and 133 in metastatic breast cancer treatment settings).  The risk of cardiac 
634 
dysfunction was increased in geriatric patients as compared to younger patients in both those 
635 
receiving treatment for metastatic disease in Studies 5 and 6, or adjuvant therapy in Studies 1 and 2.  
636 
Limitations in data collection and differences in study design of the 4 studies of Herceptin in 
637 
adjuvant treatment of breast cancer preclude a determination of whether the toxicity profile of 
638 
Herceptin in older patients is different from younger patients.  The reported clinical experience is not 
639 
adequate to determine whether the efficacy improvements (ORR, TTP, OS, DFS) of Herceptin 
640 
treatment in older patients is different from that observed in patients < 65 years of age for metastatic 
641 
disease and adjuvant treatment. 
642 
 In Study 7 (metastatic gastric cancer), of the 294 patients treated with Herceptin, 108 (37%) were 
643 
65 years of age or older, while 13 (4.4%) were 75 and over.  No overall differences in safety or 
644 
effectiveness were observed. 
645 
 
646 
10 OVERDOSAGE 
647 
 There is no experience with overdosage in human clinical trials.  Single doses higher than 8 mg/kg 
648 
have not been tested. 
649 
 
650 
11 DESCRIPTION 
651 
 Herceptin (trastuzumab) is a humanized IgG1 kappa monoclonal antibody that selectively binds 
652 
with high affinity to the extracellular domain of the human epidermal growth factor receptor 2 
653 
protein, HER2.  Trastuzumab is produced by recombinant DNA technology in a mammalian cell 
654 
(Chinese Hamster Ovary) culture containing the antibiotic gentamicin.  Gentamicin is not detectable 
655 
in the final product. 
656 
 Herceptin (trastuzumab) is a sterile, white to pale yellow, preservative-free lyophilized powder for 
657 
Injection, for intravenous administration.   
658 
 Each multiple-dose vial of Herceptin delivers 420 mg trastuzumab, 381.8 mg α,α-trehalose 
659 
dihydrate, 9.5 mg L-histidine HCl monohydrate, 6.1 mg L-histidine, and 1.7 mg polysorbate 20.  
660 
Reconstitution with 20 mL of the appropriate diluent (BWFI or SWFI) yields a solution containing 
661 
21 mg/mL trastuzumab at a pH of approximately 6.  If Herceptin is reconstituted with SWFI without 
662 
preservative, the reconstituted solution is considered single-dose. 
663 
 Each single-dose vial of Herceptin delivers 150 mg trastuzumab, 136.2 mg α,α-trehalose 
664 
dihydrate, 3.4 mg L-histidine HCl monohydrate, 2.2 mg L-histidine, and 0.6 mg polysorbate 20. 
665 
Reconstitution with 7.4 mL of sterile water for injection (SWFI) yields a solution containing 21 
666 
mg/mL trastuzumab that delivers 7.15 mL (150 mg trastuzumab), at a pH of approximately 6. 
667 


 
24 
 
668 
12 CLINICAL PHARMACOLOGY 
669 
12.1 Mechanism of Action 
670 
 The HER2 (or c-erbB2) proto-oncogene encodes a transmembrane receptor protein of 185 kDa, 
671 
which is structurally related to the epidermal growth factor receptor.  Herceptin has been shown, in 
672 
both in vitro assays and in animals, to inhibit the proliferation of human tumor cells that overexpress 
673 
HER2. 
674 
 Herceptin is a mediator of antibody-dependent cellular cytotoxicity (ADCC).  In vitro, 
675 
Herceptin-mediated ADCC has been shown to be preferentially exerted on HER2 overexpressing 
676 
cancer cells compared with cancer cells that do not overexpress HER2. 
677 
12.2 Pharmacodynamics 
678 
Cardiac Electrophysiology 
679 
 
The effects of trastuzumab on electrocardiographic (ECG) endpoints, including QTc interval 
680 
duration, were evaluated in patients with HER2 positive solid tumors. Trastuzumab had no clinically 
681 
relevant effect on the QTc interval duration and there was no apparent relationship between serum 
682 
trastuzumab concentrations and change in QTcF interval duration in patients with HER2 positive 
683 
solid tumors. 
684 
12.3 Pharmacokinetics 
685 
 The pharmacokinetics of trastuzumab was evaluated in a pooled population pharmacokinetic (PK) 
686 
model analysis of 1,582 subjects with primarily breast cancer and metastatic gastric cancer (MGC) 
687 
receiving intravenous Herceptin.  Total trastuzumab clearance increases with decreasing 
688 
concentrations due to parallel linear and non-linear elimination pathways.  
689 
 Although the average trastuzumab exposure was higher following the first cycle in breast cancer 
690 
patients receiving the three-weekly schedule compared to the weekly schedule of Herceptin, the 
691 
average steady-state exposure was essentially the same at both dosages. The average trastuzumab 
692 
exposure following the first cycle and at steady state as well as the time to steady state was higher in 
693 
breast cancer patients compared to MGC patients at the same dosage; however, the reason for this 
694 
exposure difference is unknown. Additional predicted trastuzumab exposure and PK parameters 
695 
following the first Herceptin cycle and at steady state exposure are described in Tables 7 and 8, 
696 
respectively. 
697 
 Population PK based simulations indicate that following discontinuation of Herceptin, 
698 
concentrations in at least 95% of breast cancer and MGC patients will decrease to approximately 3% 
699 
of the population predicted steady-state trough serum concentration (approximately 97% washout) 
700 
by 7 months [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1, 8.3)]. 
701 
 
702 
Table 7 
703 
Population Predicted Cycle 1 PK Exposures (Median with 5th – 95th Percentiles) in Breast Cancer 
704 
and MGC Patients  
705 
Schedule 
Primary tumor 
type 
N 
Cmin 
(µg/mL) 
Cmax 
(µg/mL) 
AUC0-21days 
(µg.day/mL) 
8 mg/kg + 
6 mg/kg q3w 
Breast cancer 
1195 
 
29.4 
(5.8 - 59.5) 
178 
(117 - 291) 
1373 
(736 - 2245)  
MGC 
274 
 
23.1 
(6.1 - 50.3) 
132 
(84.2 - 225) 
1109 
(588 - 1938) 
4 mg/kg + 
2 mg/kg qw 
Breast cancer 
1195 
 
37.7 
(12.3 - 70.9) 
88.3 
(58 - 144) 
1066 
(586 - 1754) 
 
706 


 
25 
Table 8 
707 
Population Predicted Steady State PK Exposures (Median with 5th - 95th Percentiles) in Breast 
708 
Cancer and MGC Patients  
709 
Schedule 
Primary 
tumor type 
N 
Cmin,ss
a
 
(µg/mL) 
Cmax,ss
b
 
(µg/mL) 
AUCss, 0-21 days 
(µg.day/mL) 
Time to 
steady-
state 
(week) 
Total CL 
range at 
steady-state  
(L/day) 
8 mg/kg + 
6 mg/kg 
q3w 
 
Breast 
cancer 
1195 
 
47.4 
(5 - 115) 
179 
(107 - 309) 
1794 
(673 - 3618) 
12 
 
0.173 - 0.283 
 
MGC 
274 
 
32.9 
(6.1 - 88.9) 
131 
(72.5 - 251) 
1338 
(557 - 2875) 
9 
 
0.189 - 0.337 
 
4 mg/kg + 
2 mg/kg qw 
Breast 
cancer 
1195 
 
66.1 
(14.9 - 142) 
109 
(51.0 - 209) 
1765 
(647 - 3578) 
12 
 
0.201 - 0.244 
 
 
  
a Steady-state trough serum concentration of trastuzumab 
710 
 
  
b Maximum steady-state serum concentration of trastuzumab 
711 
 
712 
Specific Populations 
713 
Based on a population pharmacokinetic analysis, no clinically significant differences were observed 
714 
in the pharmacokinetics of trastuzumab based on age (< 65 (n = 1294); ≥ 65 (n = 288)), race (Asian 
715 
(n = 264); non-Asian (n = 1324)) and renal impairment (mild (creatinine clearance [CLcr] 60 to 
716 
90 mL/min) (n = 636) or moderate (CLcr 30 to 60 mL/min) (n = 133)). The pharmacokinetics of 
717 
trastuzumab in patients with severe renal impairment, end-stage renal disease with or without 
718 
hemodialysis, or hepatic impairment is unknown. 
719 
Drug Interaction Studies  
720 
There have been no formal drug interaction studies performed with Herceptin in humans. Clinically 
721 
significant interactions between Herceptin and concomitant medications used in clinical trials have 
722 
not been observed. 
723 
Paclitaxel and doxorubicin: Concentrations of paclitaxel and doxorubicin and their major 
724 
metabolites (i.e., 6-α hydroxyl-paclitaxel [POH], and doxorubicinol [DOL], respectively) were not 
725 
altered in the presence of trastuzumab when used as combination therapy in clinical trials. 
726 
Trastuzumab concentrations were not altered as part of this combination therapy. 
727 
Docetaxel and carboplatin: When Herceptin was administered in combination with docetaxel or 
728 
carboplatin, neither the plasma concentrations of docetaxel or carboplatin nor the plasma 
729 
concentrations of trastuzumab were altered.   
730 
Cisplatin and capecitabine: In a drug interaction substudy conducted in patients in Study 7, the 
731 
pharmacokinetics of cisplatin, capecitabine and their metabolites were not altered when administered 
732 
in combination with Herceptin. 
733 
 
734 
13 NONCLINICAL TOXICOLOGY 
735 
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 
736 
 Herceptin has not been tested for carcinogenic potential. 
737 
 No evidence of mutagenic activity was observed when trastuzumab was tested in the standard 
738 
Ames bacterial and human peripheral blood lymphocyte mutagenicity assays at concentrations of up 
739 
to 5000 mcg/mL.  In an in vivo micronucleus assay, no evidence of chromosomal damage to mouse 
740 
bone marrow cells was observed following bolus intravenous doses of up to 118 mg/kg of 
741 
trastuzumab. 
742 


 
26 
 A fertility study was conducted in female Cynomolgus monkeys at doses up to 25 times the 
743 
weekly recommended human dose of 2 mg/kg of trastuzumab and has revealed no evidence of 
744 
impaired fertility, as measured by menstrual cycle duration and female sex hormone levels. 
745 
 
746 
14 CLINICAL STUDIES 
747 
14.1 Adjuvant Breast Cancer 
748 
 The safety and efficacy of Herceptin in women receiving adjuvant chemotherapy for HER2 
749 
overexpressing breast cancer were evaluated in an integrated analysis of two randomized, 
750 
open-label, clinical trials (Studies 1 and 2) with a total of 4063 women at the protocol-specified final 
751 
overall survival analysis, a third randomized, open-label, clinical trial (Study 3) with a total of 
752 
3386 women at definitive Disease-Free Survival analysis for one-year Herceptin treatment versus 
753 
observation, and a fourth randomized, open-label clinical trial with a total of 3222 patients (Study 4). 
754 
Studies 1 and 2 
755 
 In Studies 1 and 2, breast tumor specimens were required to show HER2 overexpression (3+ by 
756 
IHC) or gene amplification (by FISH).  HER2 testing was verified by a central laboratory prior to 
757 
randomization (Study 2) or was required to be performed at a reference laboratory (Study 1).  
758 
Patients with a history of active cardiac disease based on symptoms, abnormal electrocardiographic, 
759 
radiologic, or left ventricular ejection fraction findings or uncontrolled hypertension 
760 
(diastolic > 100 mm Hg or systolic > 200 mm Hg) were not eligible. 
761 
 Patients were randomized (1:1) to receive doxorubicin and cyclophosphamide followed by 
762 
paclitaxel (AC→paclitaxel) alone or paclitaxel plus Herceptin (AC→paclitaxel + Herceptin).  
763 
In both trials, patients received four 21-day cycles of doxorubicin 60 mg/m2 and cyclophosphamide 
764 
600 mg/m2.  Paclitaxel was administered either weekly (80 mg/m2) or every 3 weeks (175 mg/m2) 
765 
for a total of 12 weeks in Study 1; paclitaxel was administered only by the weekly schedule in 
766 
Study 2.  Herceptin was administered at 4 mg/kg on the day of initiation of paclitaxel and then at a 
767 
dose of 2 mg/kg weekly for a total of 52 weeks.  Herceptin treatment was permanently discontinued 
768 
in patients who developed congestive heart failure, or persistent/recurrent LVEF decline [see 
769 
Dosage and Administration (2.3)].  Radiation therapy, if administered, was initiated after the 
770 
completion of chemotherapy.  Patients with ER+ and/or PR+ tumors received hormonal therapy.  
771 
The primary endpoint of the combined efficacy analysis was Disease-Free Survival (DFS), defined 
772 
as the time from randomization to recurrence, occurrence of contralateral breast cancer, other second 
773 
primary cancer, or death.  The secondary endpoint was overall survival (OS). 
774 
 A total of 3752 patients were included in the joint efficacy analysis of the primary endpoint of 
775 
DFS following a median follow-up of 2.0 years in the AC→paclitaxel + Herceptin arm.  The 
776 
pre-planned final OS analysis from the joint analysis included 4063 patients and was performed 
777 
when 707 deaths had occurred after a median follow-up of 8.3 years in the AC→paclitaxel + 
778 
Herceptin arm.  The data from both arms in Study 1 and two of the three study arms in Study 2 were 
779 
pooled for efficacy analyses.  The patients included in the primary DFS analysis had a median age of 
780 
49 years (range, 22−80 years; 6% > 65 years), 84% were white, 7% black, 4% Hispanic, and 4% 
781 
Asian/Pacific Islander.  Disease characteristics included 90% infiltrating ductal histology, 38% T1, 
782 
91% nodal involvement, 27% intermediate and 66% high grade pathology, and 53% ER+ and/or 
783 
PR+ tumors.  Similar demographic and baseline characteristics were reported for the efficacy 
784 
evaluable population, after 8.3 years of median follow-up in the AC→paclitaxel + Herceptin arm.  
785 
Study 3 
786 
 In Study 3, breast tumor specimens were required to show HER2 overexpression (3+ by IHC) or 
787 
gene amplification (by FISH) as determined at a central laboratory.  Patients with node-negative 
788 
disease were required to have ≥ T1c primary tumor.  Patients with a history of congestive heart 
789 
failure or LVEF < 55%, uncontrolled arrhythmias, angina requiring medication, clinically significant 
790 


 
27 
valvular heart disease, evidence of transmural infarction on ECG, poorly controlled hypertension 
791 
(systolic > 180 mm Hg or diastolic > 100 mm Hg) were not eligible. 
792 
 Study 3 was designed to compare one and two years of three-weekly Herceptin treatment versus 
793 
observation in patients with HER2 positive EBC following surgery, established chemotherapy and 
794 
radiotherapy (if applicable).  Patients were randomized (1:1:1) upon completion of definitive 
795 
surgery, and at least four cycles of chemotherapy to receive no additional treatment, or one year of 
796 
Herceptin treatment or two years of Herceptin treatment.  Patients undergoing a lumpectomy had 
797 
also completed standard radiotherapy.  Patients with ER+ and/or PgR+ disease received systemic 
798 
adjuvant hormonal therapy at investigator discretion.  Herceptin was administered with an initial 
799 
dose of 8 mg/kg followed by subsequent doses of 6 mg/kg once every three weeks.  The main 
800 
outcome measure was Disease-Free Survival (DFS), defined as in Studies 1 and 2. 
801 
 A protocol specified interim efficacy analysis comparing one-year Herceptin treatment to 
802 
observation was performed at a median follow-up duration of 12.6 months in the Herceptin arm and 
803 
formed the basis for the definitive DFS results from this study.  Among the 3386 patients 
804 
randomized to the observation (n = 1693) and Herceptin one-year (n = 1693) treatment arms, the 
805 
median age was 49 years (range 21−80), 83% were Caucasian, and 13% were Asian.  Disease 
806 
characteristics:  94% infiltrating ductal carcinoma, 50% ER+ and/or PgR+, 57% node positive, 32% 
807 
node negative, and in 11% of patients, nodal status was not assessable due to prior neo-adjuvant 
808 
chemotherapy.  Ninety-six percent (1055/1098) of patients with node-negative disease had high-risk 
809 
features: among the 1098 patients with node-negative disease, 49% (543) were ER− and PgR−, and 
810 
47% (512) were ER and/or PgR+ and had at least one of the following high-risk features:  
811 
pathological tumor size greater than 2 cm, Grade 2−3, or age < 35 years.  Prior to randomization, 
812 
94% of patients had received anthracycline-based chemotherapy regimens. 
813 
 After the definitive DFS results comparing observation to one-year Herceptin treatment were 
814 
disclosed, a prospectively planned analysis that included comparison of one year versus two years of 
815 
Herceptin treatment at a median follow-up duration of 8 years was performed. Based on this 
816 
analysis, extending Herceptin treatment for a duration of two years did not show additional benefit 
817 
over treatment for one year [Hazard Ratios of two-years Herceptin versus one-year Herceptin 
818 
treatment in the intent to treat (ITT) population for Disease-Free Survival (DFS) = 0.99 (95% CI: 
819 
0.87, 1.13), p-value = 0.90 and Overall Survival (OS)  = 0.98 (0.83, 1.15); p-value = 0.78].   
820 
Study 4 
821 
 In Study 4, breast tumor specimens were required to show HER2 gene amplification (FISH+ only) 
822 
as determined at a central laboratory.  Patients were required to have either node-positive disease, or 
823 
node-negative disease with at least one of the following high-risk features:  ER/PR-negative, tumor 
824 
size > 2 cm, age < 35 years, or histologic and/or nuclear Grade 2 or 3.  Patients with a history of 
825 
CHF, myocardial infarction, Grade 3 or 4 cardiac arrhythmia, angina requiring medication, clinically 
826 
significant valvular heart disease, poorly controlled hypertension (diastolic > 100 mm Hg), any T4 or 
827 
N2, or known N3 or M1 breast cancer were not eligible. 
828 
 Patients were randomized (1:1:1) to receive doxorubicin and cyclophosphamide followed by 
829 
docetaxel (AC-T), doxorubicin and cyclophosphamide followed by docetaxel plus Herceptin 
830 
(AC-TH), or docetaxel and carboplatin plus Herceptin (TCH).  In both the AC-T and AC-TH arms, 
831 
doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 were administered every 3 weeks for 
832 
four cycles; docetaxel 100 mg/m2 was administered every 3 weeks for four cycles.  In the TCH arm, 
833 
docetaxel 75 mg/m2 and carboplatin (at a target AUC of 6 mg/mL/min as a 30- to 60-minute 
834 
infusion) were administered every 3 weeks for six cycles.  Herceptin was administered weekly 
835 
(initial dose of 4 mg/kg followed by weekly dose of 2 mg/kg) concurrently with either T or TC, and 
836 
then every 3 weeks (6 mg/kg) as monotherapy for a total of 52 weeks.  Radiation therapy, if 
837 
administered, was initiated after completion of chemotherapy.  Patients with ER+ and/or PR+ tumors 
838 
received hormonal therapy.  Disease-Free Survival (DFS) was the main outcome measure. 
839 


 
28 
 Among the 3222 patients randomized, the median age was 49 (range 22 to 74 years; 6% 
840 
≥ 65 years).  Disease characteristics included 54% ER+ and/or PR+ and 71% node positive.  Prior to 
841 
randomization, all patients underwent primary surgery for breast cancer. 
842 
 The results for DFS for the integrated analysis of Studies 1 and 2, Study 3, and Study 4 and OS 
843 
results for the integrated analysis of Studies 1 and 2, and Study 3 are presented in Table 9.  For 
844 
Studies 1 and 2, the duration of DFS following a median follow-up of 2.0 years in the AC→TH arm 
845 
is presented in Figure 4, and the duration of OS after a median follow-up of 8.3 years in the 
846 
AC→TH arm is presented in Figure 5.  The duration of DFS for Study 4 is presented in Figure 6.  
847 
Across all four studies, at the time of definitive DFS analysis, there were insufficient numbers of 
848 
patients within each of the following subgroups to determine if the treatment effect was different 
849 
from that of the overall patient population: patients with low tumor grade, patients within specific 
850 
ethnic/racial subgroups (Black, Hispanic, Asian/Pacific Islander patients), and patients > 65 years of 
851 
age.  For Studies 1 and 2, the OS hazard ratio was 0.64 (95% CI: 0.55, 0.74).  At 8.3 years of median 
852 
follow-up [AC→TH], the survival rate was estimated to be 86.9% in the AC→TH arm and 79.4% in 
853 
the AC→T arm.  The final OS analysis results from Studies 1 and 2 indicate that OS benefit by age, 
854 
hormone receptor status, number of positive lymph nodes, tumor size and grade, and 
855 
surgery/radiation therapy was consistent with the treatment effect in the overall population. In 
856 
patients ≤ 50 years of age (n = 2197), the OS hazard ratio was 0.65 (95% CI: 0.52, 0.81) and in 
857 
patients > 50 years of age (n = 1866), the OS hazard ratio was 0.63 (95% CI: 0.51, 0.78). In the 
858 
subgroup of patients with hormone receptor-positive disease (ER-positive and/or PR-positive) 
859 
(n = 2223), the hazard ratio for OS was 0.63 (95% CI: 0.51, 0.78). In the subgroup of patients with 
860 
hormone receptor-negative disease (ER-negative and PR-negative) (n = 1830), the hazard ratio for 
861 
OS was 0.64 (95% CI: 0.52, 0.80). In the subgroup of patients with tumor size ≤ 2 cm (n = 1604), the 
862 
hazard ratio for OS was 0.52 (95% CI: 0.39, 0.71). In the subgroup of patients with tumor size > 2 
863 
cm (n = 2448), the hazard ratio for OS was 0.67 (95% CI: 0.56, 0.80).  
864 


 
29 
Table 9 
Efficacy Results from Adjuvant Treatment of  
Breast Cancer (Studies 1 + 2, Study 3, and Study 4) 
 
DFS 
events  
DFS Hazard 
ratio  
(95% CI) 
p-value 
Deaths 
(OS events) 
OS Hazard ratio 
p-value 
Studies 1 + 2a 
AC→TH 
(n = 1872)b  
(n = 2031)c 
133b 
0.48b,d 
(0.39, 0.59) 
p< 0.0001e 
289c 
 
0.64c,d 
(0.55, 0.74) 
p< 0.0001e 
AC→T  
(n = 1880)b 
(n = 2032)c 
261b 
 
418c 
 
 
Study 3f 
Chemo→ 
Herceptin 
(n = 1693 ) 
127 
0.54 
(0.44, 0.67) 
p< 0.0001g 
31 
0.75 
p = NSh 
Chemo→ 
Observation 
(n = 1693) 
219 
 
40 
 
Study 4i 
TCH 
(n = 1075) 
134 
0.67 
 (0.54 – 0.84) 
p=0.0006e,j 
56 
 
AC→TH 
(n = 1074) 
121 
0.60 
(0.48 – 0.76) 
p< 0.0001e,i 
49 
 
AC→T 
(n = 1073) 
180  
 
80 
 
CI = confidence interval. 
 a Studies 1 and 2 regimens: doxorubicin and cyclophosphamide followed by paclitaxel 
(AC→T) or paclitaxel plus Herceptin (AC→TH). 
b Efficacy evaluable population, for the primary DFS analysis, following a median follow-up 
of 2.0 years in the AC→TH arm. 
c Efficacy evaluable population, for the final OS analysis, following 707 deaths (8.3 years of 
median follow-up in the AC→TH arm). 
d Hazard ratio estimated by Cox regression stratified by clinical trial, intended paclitaxel 
schedule, number of positive nodes, and hormone receptor status. 
 e stratified log-rank test. 
 f  At definitive DFS analysis with median duration of follow-up of 12.6 months in the one-
year Herceptin treatment arm. 
 g log-rank test. 
 h NS =  non-significant. 
 i Study 4 regimens: doxorubicin and cyclophosphamide followed by docetaxel (AC→T) or 
docetaxel plus Herceptin (AC→TH); docetaxel and carboplatin plus Herceptin (TCH). 
 j A two-sided alpha level of 0.025 for each comparison. 
   
 
865 


 
30 
Figure 4  
866 
Duration of Disease-Free Survival in  
867 
Patients with Adjuvant Treatment of Breast Cancer (Studies 1 and 2) 
868 
 
869 
 
870 


 
31 
Figure 5 
871 
Duration of Overall Survival in Patients with  
872 
Adjuvant Treatment of Breast Cancer (Studies 1 and 2) 
873 
 
874 
Figure 6 
875 
Duration of Disease-Free Survival in Patients with  
876 
Adjuvant Treatment of Breast Cancer (Study 4) 
877 
 
878 
 Exploratory analyses of DFS as a function of HER2 overexpression or gene amplification were 
879 
conducted for patients in Studies 2 and 3, where central laboratory testing data were available.  
880 
The results are shown in Table 10.  The number of events in Study 2 was small with the exception of 
881 


 
32 
the IHC 3+/FISH+ subgroup, which constituted 81% of those with data.  Definitive conclusions 
882 
cannot be drawn regarding efficacy within other subgroups due to the small number of events.  
883 
The number of events in Study 3 was adequate to demonstrate significant effects on DFS in the 
884 
IHC 3+/FISH unknown and the FISH +/IHC unknown subgroups. 
885 
 
886 
Table 10 
Treatment Outcomes in Studies 2 and 3 as a Function of  
HER2 Overexpression or Amplification 
 
Study 2 
Study 3c 
HER2 Assay 
Resulta 
Number of 
Patients 
Hazard Ratio DFS  
(95% CI) 
Number of 
Patients 
Hazard Ratio DFS  
(95% CI) 
IHC 3+ 
 FISH (+) 
1170 
0.42 
(0.27, 0.64) 
91 
0.56 
(0.13, 2.50) 
 FISH (−) 
51 
0.71 
(0.04, 11.79) 
8 
⎯ 
 FISH Unknown 
51 
0.69 
(0.09, 5.14) 
2258 
0.53 
(0.41, 0.69) 
IHC < 3+ /  
FISH (+) 
174 
1.01 
(0.18, 5.65) 
299b 
0.53 
(0.20, 1.42) 
IHC unknown / 
FISH (+) 
⎯ 
⎯ 
724 
0.59 
(0.38, 0.93) 
 a IHC by HercepTest, FISH by PathVysion (HER2/CEP17 ratio ≥ 2.0) as performed 
at a central laboratory. 
 b All cases in this category in Study 3 were IHC 2+. 
 c Median follow-up duration of 12.6 months in the one-year Herceptin treatment 
arm. 
 
887 
14.2 Metastatic Breast Cancer 
888 
 The safety and efficacy of Herceptin in treatment of women with metastatic breast cancer were 
889 
studied in a randomized, controlled clinical trial in combination with chemotherapy (Study 5, 
890 
n = 469 patients) and an open-label single agent clinical trial (Study 6, n = 222 patients).  Both trials 
891 
studied patients with metastatic breast cancer whose tumors overexpress the HER2 protein.  Patients 
892 
were eligible if they had 2 or 3 levels of overexpression (based on a 0 to 3 scale) by 
893 
immunohistochemical assessment of tumor tissue performed by a central testing lab. 
894 
Previously Untreated Metastatic Breast Cancer (Study 5) 
895 
 Study 5 was a multicenter, randomized, open-label clinical trial conducted in 469 women with 
896 
metastatic breast cancer who had not been previously treated with chemotherapy for metastatic 
897 
disease.  Tumor specimens were tested by IHC (Clinical Trial Assay, CTA) and scored as 0, 1+, 2+, 
898 
or 3+, with 3+ indicating the strongest positivity.  Only patients with 2+ or 3+ positive tumors were 
899 
eligible (about 33% of those screened).  Patients were randomized to receive chemotherapy alone or 
900 
in combination with Herceptin given intravenously as a 4 mg/kg loading dose followed by weekly 
901 
doses of Herceptin at 2 mg/kg.  For those who had received prior anthracycline therapy in the 
902 
adjuvant setting, chemotherapy consisted of paclitaxel (175 mg/m2 over 3 hours every 21 days for at 
903 
least six cycles); for all other patients, chemotherapy consisted of anthracycline plus 
904 
cyclophosphamide (AC:  doxorubicin 60 mg/m2 or epirubicin 75 mg/m2 plus 600 mg/m2 
905 
cyclophosphamide every 21 days for six cycles).  Sixty-five percent of patients randomized to 
906 


 
33 
receive chemotherapy alone in this study received Herceptin at the time of disease progression as 
907 
part of a separate extension study. 
908 
 Based upon the determination by an independent response evaluation committee, the patients 
909 
randomized to Herceptin and chemotherapy experienced a significantly longer median time to 
910 
disease progression, a higher overall response rate (ORR), and a longer median duration of response 
911 
as compared with patients randomized to chemotherapy alone.  Patients randomized to Herceptin 
912 
and chemotherapy also had a longer median survival (see Table 11).  These treatment effects were 
913 
observed both in patients who received Herceptin plus paclitaxel and in those who received 
914 
Herceptin plus AC; however the magnitude of the effects was greater in the paclitaxel subgroup. 
915 
 
916 
Table 11 
Study 5:  Efficacy Results in  
First-Line Treatment for Metastatic Breast Cancer 
 
Combined Results 
Paclitaxel Subgroup 
AC Subgroup 
Herceptin + 
All Chemo-
therapy 
(n = 235) 
All Chemo-
therapy 
(n = 234) 
Herceptin + 
Paclitaxel 
(n = 92) 
Paclitaxel 
(n = 96) 
Herceptin + 
ACa 
(n = 143) 
AC 
(n = 138) 
Primary Endpoint 
Median 
TTP(mos)b,c 
7.2 
4.5 
6.7 
2.5 
7.6 
5.7 
95% CI 
7, 8 
4, 5 
5, 10 
2, 4 
7, 9 
5, 7 
p-valued  
< 0.0001 
< 0.0001 
0.002 
Secondary Endpoints 
Overall 
Response 
Rateb 
45 
29 
38 
15 
50 
38 
95% CI 
39, 51 
23, 35 
28, 48 
8, 22 
42, 58 
30, 46 
p-valuee 
 < 0.001 
 < 0.001 
0.10 
Median Resp 
Duration 
(mos)b,c 
8.3 
5.8 
8.3 
4.3 
8.4 
6.4 
25%, 75% 
Quartile 
6, 15 
4, 8 
5, 11 
4, 7 
6, 15 
4, 8 
Med Survival 
(mos)c 
25.1 
20.3 
22.1 
18.4 
26.8 
21.4 
95% CI 
22, 30 
17, 24 
17, 29 
13, 24 
23, 33 
18, 27 
p-valued  
0.05 
0.17 
0.16 
 a AC = Anthracycline (doxorubicin or epirubicin) and cyclophosphamide. 
 b Assessed by an independent Response Evaluation Committee. 
 c Kaplan-Meier Estimate. 
 d log-rank test. 
 e χ2-test. 
 
917 
 Data from Study 5 suggest that the beneficial treatment effects were largely limited to patients 
918 
with the highest level of HER2 protein overexpression (3+) (see Table 12). 
919 


 
34 
Table 12 
Treatment Effects in Study 5 as a  
Function of HER2 Overexpression or Amplification 
HER2 Assay 
Result 
Number of 
Patients 
(N) 
Relative Riskb for Time to 
Disease Progression 
(95% CI) 
Relative Riskb for Mortality 
(95% CI) 
CTA 2+ or 3+ 
469 
0.49 (0.40, 0.61) 
0.80 (0.64, 1.00) 
FISH (+)a 
325 
0.44 (0.34, 0.57) 
0.70 (0.53, 0.91) 
FISH (−)a 
126 
0.62 (0.42, 0.94) 
1.06 (0.70, 1.63) 
CTA 2+ 
120 
0.76 (0.50, 1.15) 
1.26 (0.82, 1.94) 
FISH (+) 
32 
0.54 (0.21, 1.35) 
1.31 (0.53, 3.27) 
FISH (−) 
83 
0.77 (0.48, 1.25) 
1.11 (0.68, 1.82) 
CTA 3+ 
349 
0.42 (0.33, 0.54) 
0.70 (0.51, 0.90) 
FISH (+) 
293 
0.42 (0.32, 0.55) 
0.67 (0.51, 0.89) 
FISH (−) 
43 
0.43 (0.20, 0.94) 
0.88 (0.39, 1.98) 
 a FISH testing results were available for 451 of the 469 patients enrolled on study. 
 b The relative risk represents the risk of progression or death in the Herceptin plus 
chemotherapy arm versus the chemotherapy arm. 
 
920 
Previously Treated Metastatic Breast Cancer (Study 6) 
921 
 Herceptin was studied as a single agent in a multicenter, open-label, single-arm clinical trial 
922 
(Study 6) in patients with HER2 overexpressing metastatic breast cancer who had relapsed following 
923 
one or two prior chemotherapy regimens for metastatic disease.  Of 222 patients enrolled, 66% had 
924 
received prior adjuvant chemotherapy, 68% had received two prior chemotherapy regimens for 
925 
metastatic disease, and 25% had received prior myeloablative treatment with hematopoietic rescue.  
926 
Patients were treated with a loading dose of 4 mg/kg IV followed by weekly doses of Herceptin at 
927 
2 mg/kg IV. 
928 
 The ORR (complete response + partial response), as determined by an independent Response 
929 
Evaluation Committee, was 14%, with a 2% complete response rate and a 12% partial response rate.  
930 
Complete responses were observed only in patients with disease limited to skin and lymph nodes.  
931 
The overall response rate in patients whose tumors tested as CTA 3+ was 18% while in those that 
932 
tested as CTA 2+, it was 6%. 
933 
14.3  Metastatic Gastric Cancer 
934 
 The safety and efficacy of Herceptin in combination with cisplatin and a fluoropyrimidine 
935 
(capecitabine or 5-fluorouracil) were studied in patients previously untreated for metastatic gastric or 
936 
gastroesophageal junction adenocarcinoma (Study 7).  In this open-label, multi-center trial, 
937 
594 patients were randomized 1:1 to Herceptin in combination with cisplatin and a fluoropyrimidine 
938 
(FC+H) or chemotherapy alone (FC).  Randomization was stratified by extent of disease (metastatic 
939 
vs. locally advanced), primary site (gastric vs. gastroesophageal junction), tumor measurability (yes 
940 
vs. no), ECOG performance status (0,1 vs. 2), and fluoropyrimidine (capecitabine vs. 5-fluorouracil).  
941 
All patients were either HER2 gene amplified (FISH+) or HER2 overexpressing (IHC 3+).  Patients 
942 
were also required to have adequate cardiac function (e.g., LVEF > 50%). 
943 
 On the Herceptin-containing arm, Herceptin was administered as an IV infusion at an initial dose 
944 
of 8 mg/kg followed by 6 mg/kg every 3 weeks until disease progression.  On both study arms 
945 
cisplatin was administered at a dose of 80 mg/m2 Day 1 every 3 weeks for 6 cycles as a 2 hour IV 
946 


 
35 
infusion.  On both study arms, capecitabine was administered at 1000 mg/m2 dose orally twice daily 
947 
(total daily dose 2000 mg/m2) for 14 days of each 21 day cycle for 6 cycles. Alternatively, 
948 
continuous intravenous infusion (CIV) 5-fluorouracil was administered at a dose of 800 mg/m2/day 
949 
from Day 1 through Day 5 every three weeks for 6 cycles.   
950 
 The median age of the study population was 60 years (range: 21−83); 76% were male; 53% were 
951 
Asian, 38% Caucasian, 5% Hispanic, 5% other racial/ethnic groups; 91% had ECOG PS of 0 or 1; 
952 
82% had primary gastric cancer and 18% had primary gastroesophageal adenocarcinoma.  Of these 
953 
patients, 23% had undergone prior gastrectomy, 7% had received prior neoadjuvant and/or adjuvant 
954 
therapy, and 2% had received prior radiotherapy. 
955 
 The main outcome measure of Study 7 was overall survival (OS), analyzed by the unstratified log-
956 
rank test. The final OS analysis based on 351 deaths was statistically significant (nominal 
957 
significance level of 0.0193).  An updated OS analysis was conducted at one year after the final 
958 
analysis. The efficacy results of both the final and the updated analyses are summarized in Table 13 
959 
and Figure 7.   
960 
 
961 
Table 13 
Study 7: Overall Survival in ITT Population 
 
FC Arm 
N = 296 
FC + H Arm 
N = 298 
Definitive (Second Interim) Overall Survival  
 
 
     No. Deaths (%) 
     Median  
     95% CI (mos.) 
184 (62.2%) 
11.0 
(9.4, 12.5) 
167 (56.0%) 
13.5 
(11.7, 15.7) 
     Hazard Ratio 
     95% CI 
     p-value*, two-sided 
0.73 
(0.60, 0.91) 
0.0038 
Updated Overall Survival 
 
 
     No. Deaths (%) 
     Median  
     95% CI (mos.) 
227 (76.7%) 
11.7 
(10.3, 13.0) 
221 (74.2%) 
13.1 
(11.9, 15.1) 
     Hazard Ratio  
     95% CI 
0.80 
(0.67, 0.97) 
 * Comparing with the nominal significance level of 0.0193. 
 
962 


 
36 
Figure 7 
963 
Updated Overall Survival in Patients with Metastatic Gastric Cancer (Study 7) 
964 
 
965 
 
966 
An exploratory analysis of OS in patients based on HER2 gene amplification (FISH) and protein 
967 
overexpression (IHC) testing is summarized in Table 14.  
968 
 
969 


 
37 
Table 14  
Exploratory Analyses by HER2 Status  Using Updated Overall Survival Results 
 
FC 
(N = 296)a 
FC+H 
(N = 298)b 
FISH+ / IHC 0, 1+ subgroup (N=133) 
 
 
   No. Deaths / n (%) 
   Median OS Duration (mos.) 
   95% CI (mos.) 
57/71 (80%) 
8.8 
(6.4, 11.7) 
56/62 (90%) 
8.3 
(6.2, 10.7)  
   Hazard ratio (95% CI) 
1.33 (0.92, 1.92) 
FISH+ / IHC2+ subgroup (N=160) 
 
 
   No. Deaths / n (%) 
   Median OS Duration (mos.) 
   95% CI (mos.) 
65/80 (81%) 
10.8 
(6.8, 12.8) 
64/80 (80%) 
12.3 
(9.5, 15.7) 
   Hazard ratio (95% CI) 
0.78 (0.55, 1.10) 
FISH+ or FISH- / IHC3+c subgroup (N=294) 
 
 
   No. Deaths / n (%) 
   Median OS Duration (mos.) 
   95% CI (mos.) 
104/143 (73%) 
13.2 
(11.5, 15.2) 
96/151 (64%) 
18.0 
(15.5, 21.2) 
   Hazard ratio (95% CI) 
0.66 (0.50, 0.87) 
 a Two patients on the FC arm who were FISH+ but IHC status unknown were excluded from the exploratory 
subgroup analyses. 
 b Five patients on the Herceptin-containing arm who were FISH+, but IHC status unknown were excluded from the 
exploratory subgroup analyses. 
 c Includes 6 patients on chemotherapy arm, 10 patients on Herceptin arm with FISH–, IHC3+ and 8 patients on 
chemotherapy arm, 8 patients on Herceptin arm with FISH status unknown, IHC 3+. 
 
970 
16 HOW SUPPLIED/STORAGE AND HANDLING 
971 
16.1 How Supplied 
972 
420 mg Multiple-dose vial  
973 
 Herceptin (trastuzumab) for Injection 420 mg/vial is supplied in a multiple-dose vial as a 
974 
lyophilized sterile powder, under vacuum.  Each carton contains one multiple-dose vial of Herceptin 
975 
and one vial (20 mL) of Bacteriostatic Water for Injection (BWFI), USP, containing 1.1% benzyl 
976 
alcohol as a preservative.   
977 
NDC 50242-333-01. 
978 
150 mg Single-dose vial  
979 
 Herceptin (trastuzumab) for Injection 150 mg/vial is supplied in a single-dose vial as a lyophilized 
980 
sterile powder, under vacuum.  Each carton contains one single-dose vial of Herceptin.  
981 
NDC 50242-132-01. 
982 
16.2 Storage 
983 
 Store Herceptin vials in the refrigerator at 2°C to 8°C (36°F to 46°F) until time of reconstitution.   
984 
 
985 
17 PATIENT COUNSELING INFORMATION 
986 
Cardiomyopathy 
987 
• Advise patients to contact a health care professional immediately for any of the following: new 
988 
onset or worsening shortness of breath, cough, swelling of the ankles/legs, swelling of the face, 
989 


 
38 
palpitations, weight gain of more than 5 pounds in 24 hours, dizziness or loss of consciousness 
990 
[see Boxed Warning: Cardiomyopathy]. 
991 
 
992 
Embryo-Fetal Toxicity 
993 
• Advise pregnant women and females of reproductive potential that Herceptin exposure during 
994 
pregnancy or within 7 months prior to conception can result in fetal harm.  Advise female 
995 
patients to contact their healthcare provider with a known or suspected pregnancy [see Use in 
996 
Specific Populations (8.1)]. 
997 
• Advise women who are exposed to Herceptin during pregnancy or who become pregnant within 
998 
7 months following the last dose of Herceptin that there is a pregnancy exposure registry and a 
999 
pregnancy pharmacovigilance program that monitor pregnancy outcomes.  Encourage these 
1000 
patients to enroll in the MotHER Pregnancy Registry and report their pregnancy to Genentech 
1001 
[see Use in Specific Populations (8.1)]. 
1002 
• Advise females of reproductive potential to use effective contraception during treatment and for 
1003 
7 months following the last dose of Herceptin [see Use in Specific Populations (8.3)]. 
1004 
 
1005 
HERCEPTIN® [trastuzumab] 
Manufactured by: 
Genentech, Inc. 
A Member of the Roche Group 
1 DNA Way 
South San Francisco, CA  94080-4990 
US License No.1048 
Herceptin® is a registered trademark of Genentech, Inc.
©2017 Genentech, Inc.
 



 
May 2017 
 
ANNOUNCEMENT – HERCEPTIN® VIAL CHANGE  
 
Dear Pharmacist: 
 
We want to make you aware of an upcoming change to Herceptin (trastuzumab).  Recently, the FDA 
approved a revised USPI for Herceptin (dated 04/2017) that lists a new 150mg singe-dose configuration 
along with additional label changes to meet current FDA guidance.  The new 150mg single-dose vial 
configuration for Herceptin will be introduced on May 30, 2017.   
 
Important information for you to know:  
 
● 
All customers will be asked to transition to the 150mg single-dose vial once available for order on 
May 30th.  After July 7, 2017, Genentech will only ship 150mg vials to distributors and will 
discontinue shipping the 440mg multiple-dose vial to distributors.  
● 
The National Drug Code (NDC) for the Herceptin 150mg vial is: 50242-132-01. 
● 
After July 7th, you may continue using any 440mg vials in your inventory until the expiration date 
noted on the vial when stored in conditions recommended in the USPI.  
● 
All payers, pharmacies and distributors should confirm that the current NDC for the 440mg 
multiple-use vial [NDC 50242-134-68] remains active within all systems, through product 
expiration date, in order to ensure this medicine remains available to providers and patients. 
● 
The Herceptin Wholesale Acquisition Cost (WAC) per milligram does not change with the new 
150mg vial introduction. 
● 
Authorized Herceptin distributors do not change.  A complete listing of distributors can be found 
on https://www.genentech-access.com/hcp/brands/herceptin/learn-about-our-services/product-
distribution.html 
Decisions on how we manufacture and package our medicines are taken very seriously and all of our 
medicines, including all configurations of Herceptin, are packaged to meet FDA regulations and 
specifications.  If you have any questions, please contact your Genentech Clinical Oncology Specialist or 
call the Genentech Customer Service Department at 1-800-551-2231, Monday through Friday, 6:00AM to 
5:00PM PST. 
  
Sincerely, 
 
 
Cindy Perettie 
Vice President, HER2 Franchise 
Genentech USA, Inc. 
 
HPK/102416/0066 


	  
	  
2	
Indications 
 
Adjuvant Breast Cancer 
Herceptin is indicated for adjuvant treatment of HER2-overexpressing node-positive or node-negative 
(ER/PR-negative or with one high-risk feature*) breast cancer: 
• As part of a treatment regimen containing doxorubicin, cyclophosphamide, and either paclitaxel or 
docetaxel 
• With docetaxel and carboplatin 
• As a single agent following multi-modality anthracycline-based therapy 
• Select patients for therapy based on an FDA-approved companion diagnostic for Herceptin 
*High-risk is defined as ER/PR positive with one of the following features: tumor size >2 cm, age <35 years, or tumor 
grade 2 or 3. 
 
Metastatic Breast Cancer 
Herceptin is indicated: 
• In combination with paclitaxel for the first line treatment of HER2-overexpressing metastatic breast 
cancer 
• As a single agent for treatment of HER2-overexpressing breast cancer in patients who have received 
one or more chemotherapy regimens for metastatic disease 
• Select patients for therapy based on an FDA-approved companion diagnostic for Herceptin 
 
Metastatic Gastric Cancer 
Herceptin is indicated, in combination with cisplatin and capecitabine or 5-fluorouracil, for the treatment of 
patients with HER2 overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma, 
who have not received prior treatment for metastatic disease.  
Select patients for therapy based on an FDA-approved companion diagnostic for Herceptin 
 
Boxed WARNINGS and Additional Important Safety Information 
 
• Herceptin administration can result in sub-clinical and clinical cardiac failure. The incidence and 
severity was highest in patients receiving Herceptin with anthracycline-containing 
chemotherapy regimens. In a pivotal adjuvant trial, one patient who developed CHF died of 
cardiomyopathy 
• Evaluate left ventricular function in all patients prior to and during treatment with Herceptin. 
Discontinue Herceptin treatment in patients receiving adjuvant therapy and withhold Herceptin 
in patients with metastatic disease for clinically significant decrease in left ventricular function 
• Herceptin administration can result in serious and fatal infusion reactions and pulmonary 
toxicity. Symptoms usually occur during or within 24 hours of Herceptin administration.  
Interrupt Herceptin infusion for dyspnea or clinically significant hypotension. Monitor patients 
until symptoms completely resolve. Discontinue Herceptin for anaphylaxis, angioedema, 
interstitial pneumonitis, or acute respiratory distress syndrome 
• Exposure to Herceptin during pregnancy can result in oligohydramnios and oligohydramnios 
sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. 
Advise patients of these risks and the need for effective contraception 
• Exacerbation of chemotherapy-induced neutropenia has also occurred 
• The most common adverse reactions associated with Herceptin in breast cancer were fever, nausea, 
vomiting, infusion reactions, diarrhea, infections, increased cough, headache, fatigue, dyspnea, rash, 
neutropenia, anemia, and myalgia 
• The most common adverse reactions associated with Herceptin in metastatic gastric cancer were 
neutropenia, diarrhea, fatigue, anemia, stomatitis, weight loss, upper respiratory tract infections, fever, 
thrombocytopenia, mucosal inflammation, nasopharyngitis, and dysgeusia 
 
You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also 
report side effects to Genentech at (888) 835-2555. 
 
Please see the accompanying full Prescribing Information, including Boxed WARNINGS. 


XL184-IST Pharmacy Manual Version 3.0 
 
CONFIDENTIAL  
 
 
        Page 1 of 10 
 
 
 
 
STUDY PHARMACY MANUAL 
 
PROTOCOL NUMBER: IST-______ 
 
XL184-Investigator Sponsored Trial (IST) 
   
 
 
 
    
 
Investigational Product Main 
Distributor: 
Exelixis, Inc. 
210 East Grand Avenue 
South San Francisco, CA 94080 
 
Study Drug:   
 
Cabozantinib (XL184) Tablets 
 
 
IND Number: 
 
 
                  72,596 
 
Date:                                                               21-Nov-2017 
 
Version Number:                                           3.0 
 
 
 
             
 
 
 
 
 
 
 
 
 
 
 
 
 
 
            
 
 
 
 
 
 
 
 
 
 
 
All queries regarding investigational product (IP) shipments should be directed to 
Exelixis Clinical Supplies at Clinical_Supplies@Exelixis.com 
 


XL184-IST Pharmacy Manual Version 3.0 
 
CONFIDENTIAL  
 
 
        Page 2 of 10 
 
 
This Pharmacy Manual provides instructions to help you understand the management of 
the investigational product (IP), Cabozantinib. This manual should be stored in the 
Pharmacy Binder at the same location where IP is stored. 
Detailed instructions on the management of IP are also included in the protocol. You are 
encouraged to read both this manual and the protocol closely before the study 
commences at your site and refer to them whenever a new study subject is enrolled.  
An initial supply of IP will be shipped to your site upon request following regulatory 
approval and site activation by Exelixis. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


XL184-IST Pharmacy Manual Version 3.0 
 
CONFIDENTIAL  
 
 
        Page 3 of 10 
XL184-IST PHARMACY MANUAL 
Table of Contents 
1 
SITE PERSONNEL RESPONSIBILITIES .....................................................4 
2 
STUDY DESCRIPTION .................................................................................4 
3 
INVESTIGATIONAL PRODUCT DESCRIPTION AND PACKAGING ...........4 
3.1 
Cabozantinib (XL184) Description .........................................................4 
     3.2      Cabozantinib (XL184) Packaging ..........................................................5 
4 
STORAGE AND HANDLING ..........................................................................5 
5 
DRUG SHIPMENTS ......................................................................................5 
5.1 
Initial and Resupply Shipments .............................................................5 
5.2 
Shipment Requests and Timelines ........................................................5 
5.3 
Drug Expiry Date and Notification .........................................................6 
5.4 
Drug Receipt and Confirmation .............................................................6 
6 
INVESTIGATIONAL PRODUCT ADMINISTRATION ....................................7 
6.1 
Dispensation and Administration ...........................................................7 
6.1.1 
Cabozantinib Dispensation .........................................................7 
6.1.2 
Cabozantinib Administration .......................................................7 
6.2 
Instructions on Dose Reduction and/or Hold .........................................7 
6.3 
Subject Dosing Instructions ...................................................................7 
7 
RECORD KEEPING………………………………………………………………7 
8       INVESTIGATIONAL PRODUCT ACCOUNTABILITY PROCEDURES ........8 
9 
INVESTIGATIONAL PRODUCT DISPOSITION .......................................... .8 
10 
PHARMACY MANUAL HISTORY ................................................... ……......8 
ATTACHMENT 1.0 SAMPLE OF DRUG REQUEST FORM………….…………...10 
ATTACHMENT 2.0 INSTRUCTIONS FOR WRITING IN STUDY IDENTIFIER…11 


XL184-IST Pharmacy Manual Version 3.0 
 
CONFIDENTIAL  
 
 
        Page 4 of 10 
 
1 
SITE PERSONNEL RESPONSIBILITIES 
The Principal Investigator (PI) should assign responsibility for the investigational product 
(IP) management to one primary study staff member. This person must be a licensed 
healthcare professional, preferably a pharmacist or a nurse. This manual will refer to 
this person as the Investigational Product Manager (IPM). It is recommended that a 
back-up person also be identified to cover in the absence of the primary IPM.  
2 
STUDY DESCRIPTION 
Please refer to the study protocol for a detailed description of the study. 
3 
INVESTIGATIONAL PRODUCT DESCRIPTION AND PACKAGING 
Exelixis will provide approved investigative sites with adequate supplies of labeled IP 
(refer to Attachment 2.0 for example label).   
3.1   Cabozantinib (XL184) Description 
Cabozantinib is supplied as 60 mg and 20 mg yellow film-coated tablets. The 60 mg 
tablets are oval shaped and the 20 mg tablets are round. The components of the tablets 
are listed in the following table:  
Ingredient  
Function 
% w/w 
Cabozantinib Drug Substance (25% drug load as free base) 
Active Ingredient 
31.7 
Microcrystalline Cellulose (Avicel PH-102) 
Filler 
38.9 
Lactose Anhydrous (60M) 
Filler 
19.4 
Hydroxypropyl Cellulose (EXF) 
Binder 
3.0 
Croscarmellose Sodium (Ac-Di-Sol) 
Disintegrant 
6.0 
Colloidal Silicon Dioxide, 
Glidant 
0.3 
Magnesium Stearate 
Lubricant 
0.75 
Opadry Yellow Film Coating which includes: 
HPMC 2910 / Hypromellose 6 cp  
Titanium dioxide  
Triacetin  
Iron Oxide Yellow 
Film Coating 
4.00 
Refer to the Investigator Brochure for additional information on Cabozantinib. 


XL184-IST Pharmacy Manual Version 3.0 
 
CONFIDENTIAL  
 
 
        Page 5 of 10 
3.2  Cabozantinib (XL184) Packaging 
IP will be provided in 60cc HDPE white bottles containing 30 tablets each. Each bottle 
will be printed with a unique 7-digit bottle number and a lot number for tracking 
purposes. The IP label will have a blank line under the drug type and drug name where 
the site staff will need to write in the specific IST Study Identifier (see Attachment 2.0).    
4 
STORAGE AND HANDLING 
All IP must be stored in a secure location with access available only to authorized 
personnel. The IP must be stored at controlled room temperature (20-25 degrees 
Centigrade, or 68-77 degrees Fahrenheit); allowing for excursions between 15 and 30 
degrees Centigrade (59 and 86 degrees Fahrenheit) and inventoried according to 
applicable state and federal regulations. Please contact Exelixis Clinical Supplies at 
Clinical_Supplies@exelixis.com immediately in case of any temperature excursions 
outside the accepted range. All affected IP will need to be quarantined until further 
notification. 
Refer to the Cabozantinib Material Safety Data Sheet (MSDS) for additional handling 
information if required.  
Subjects need to be instructed to: 
 Store the IP at controlled room temperature, away from direct sunlight or 
appliances/items that give off heat, and out of reach of children and/or pets.  
 Not store the study drug in a hot, unventilated car for a long period of time. 
5 
DRUG SHIPMENTS 
5.1 Initial and Re-supply Shipments 
After IST site activation, the site is required to submit the completed Initial Exelixis 
Study 
Drug 
Shipment 
Request 
Form 
(see 
Attachment 
1.0) 
by 
email 
to 
Clinical_Supplies@Exelixis.com. Subsequent re-supply shipments of IP will be made by 
following the same process outlined above. 
All Exelixis Study Drug Shipment Request Forms must be fully completed (see below) 
to avoid any delays: 
- 
Complete Section 1.0: Site Information 
o Investigator Name  


XL184-IST Pharmacy Manual Version 3.0 
 
CONFIDENTIAL  
 
 
        Page 6 of 10 
o Contact Name 
o Site Name and Address 
o Phone/Fax 
o Date Requested/Required  
o Requested By 
 
- 
Complete Section 2.0: Drug Request 
o Check the appropriate box for “Initial” or “Resupply” 
o Requested Quantity and Current Inventory 
o Current # of active patients and their current dose 
 
Note:  Allow 3-5 business days for processing and delivery of shipments. 
 
5.2 Shipment Requests and Timelines 
General drug shipments will take place Monday through Thursday only. In case of 
emergency, a special request will need to be authorized by Exelixis Clinical Supplies in 
order to ship on Friday. If a special drug shipment request is needed, please contact 
Exelixis Clinical Supplies immediately.  The Exelixis Clinical Supplies team can be 
reached directly at the following email address: Clinical_Supplies@Exelixis.com 
5.3 Drug Expiry Date Notification 
Exelixis maintains an on-going stability program for all lots of cabozantinib being used in 
study trials and is responsible for the management of the expiry dates for the 
cabozantinib supplied. In addition, Exelixis provides notification letters to sites before 
the expiry date of the affected IP. All expiry date notification letters should be filed in the 
site study pharmacy binder. 
5.4 Drug Receipt and Confirmation 
The Study Pharmacist or assigned designee is responsible for proper inspection of each 
shipment of IP received.  At the time of receipt, the Study Pharmacist or assigned 
designee must provide confirmation that all supplies are intact and in good condition. 
Once IP is received and confirmed in good condition, write in the IST Study Identifier on 
the designated blank line available on the label of the IP bottle(s) (see Attachment 2.0).   
If the shipment is damaged, missing, shows signs of tampering, etc., quarantine the 
shipment in a secure location and contact Exelixis Clinical Supplies immediately. Once 


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a final decision is made regarding the disposition of any IP placed on quarantine status, 
you will receive further information regarding the availability or unavailability of the IP. 
All IP shipment/receipt documentation must be filed in site study pharmacy binder. 
6 
INVESTIGATIONAL PRODUCT DISPENSATION/ADMINISTRATION 
6.1 Dispensation and Administration 
6.1.1   Cabozantinib Dispensation 
All cabozantinib should be dispensed in the original container supplied by Exelixis and 
should not be repackaged at any time. 
6.1.2   Cabozantinib Administration 
For the doses of cabozantinib taken outside the clinic, subjects should fast (with the 
exception of water) for at least 2 hours after eating an evening meal before taking their 
dose. After the 2-hour fast and before going to bed, subjects are to take cabozantinib 
with a full glass of water (minimum of 8 ounces or 240 milliliters) with no more food 
intake for a minimum of one hour post-dose. If the subject’s schedule requires taking 
cabozantinib during the day, the subject is to be instructed to follow the same fasting 
recommendations. The subject should take cabozantinib at approximately the same 
time every day and the subject is to adhere to the fasting requirements described in this 
section. 
6.2 Instructions on Dose Reduction and/or Hold 
Refer to the IST protocol for further details on dose reduction and dose holds.   
6.3 Subject Dosing Instructions 
Refer to Section 6.1.2 of this document for out-patient dosing instructions. Subject 
compliance with out-patient study treatment regimens will be assessed by the site using 
standard operating procedures.  
7 
RECORD KEEPING  
All records must be retained and available per site procedures. At the end of the study, 
the IP records will be incorporated into the clinical study file for long-term storage. The 
site is responsible for maintaining the study documents for at least 2 years after 
cabozantinib receives marketing approval for the indication being investigated, or 2 
years after formal discontinuation of clinical development of cabozantinib and FDA 
notification of such (i.e., the IND is closed), or until further notification from Exelixis. 


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8 
INVESTIGATIONAL PRODUCT ACCOUNTABILITY PROCEDURES 
The study investigator or assigned designee is required to maintain accurate IP 
accountability records per the site Standard Operating Procedures (SOP).   
9 
INVESTIGATIONAL PRODUCT DISPOSITION  
At no time during the study should IP be returned to Exelixis. Please follow your site’s 
Standard Operating Procedure for destruction of IP. If site is unable to destroy IP on site, 
the IP will need to be returned to the depot for destruction. Please contact Exelixis 
Clinical Supplies at Clinical_Supplies@exelixis.com for instructions on returning IP to 
the depot. 
10 
PHARMACY MANUAL HISTORY 
Pharmacy 
Manual 
Version 
Effective Date 
Change Summary 
V3 
24-Oct-2017 
Revised Version 
 
 
 
 
 
 
 
 
 
 
 


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ATTACHMENT 1.0: SAMPLE OF DRUG REQUEST FORM     
 
 
SECTION 1: SITE INFORMATION 
 
 
STUDY DRUG ORDER FORM 
 
Investigator Name:  
Contact Person:  
Site Name &Address: 
 
 
Phone/Fax: 
Date Requested: 
Date Required at Site: 
                            
Requested By: 
SECTION 2: DRUG REQUEST: 
For Clinical Site Use Only: 
For Exelixis Clinical Supplies Use Only: 
 Initial Supply          
 Resupply 
Exelixis Order # _____ 
PRODUCT 
DESCRIPTION 
(30 Tablets per 
bottle) 
REQUESTED 
QUANTITY 
CURRENT 
INVENTORY 
APPROVED 
QUANTITY 
LOT 
NUMBER 
PART NUMBER 
XL184 20 mg Tab 
 
 
 
 
 
XL184 60 mg Tab 
 
 
 
 
 
Total # of Active Subjects 
20mg 
 
 
 
 
 
40mg 
 
 
 
 
60mg 
 
 
 
 
 
To avoid any delays on shipment order processing, the “Requester” must complete all 
information requested on the form. 
 
For Exelixis Clinical Supplies Use Only 
Shipment Request Approved By: 
 
 
 
PROTOCOL: 
 
  XL184 – IST______  
 
Print Name / 
Signature 
 
Date: 
 
 
 


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Attachment 2.0: INSTRUCTIONS FOR WRITING IN STUDY 
IDENTIFIER ON STUDY DRUG BOTTLE  
 
1. Remove the drug bottle(s) from your drug shipment. 
 
2. On the label of the bottle, you will find an empty space under “XL184 
(Cabozantinib) 20mg Tablets” or “XL184 (Cabozantinib) 60mg Tablets”. (See 
below for sample label text) 
 
3. Fill in the space by writing in your IST Study Number.   
 
Note:  The IST Study number is on your Exelixis Study Drug Shipment Request 
Form. 
 
Sample Labels: