Clinical trial NCT03501979
Conditions: Metastatic Breast Cancer Leptomeningeal Disease
Keywords: HER2+ metastatic breast cancer leptomeningeal disease tucatinib trastuzumab capecitabine
Sponsor: University of Alabama at Birmingham
Start date: 2019-02-20; Completion date: 2021-06-22
Enrollment: 17 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
A phase 2 non-randomized study to assess the safety and efficacy of the combination of tucatinib and trastuzumab with capecitabine for the treatment of leptomeningeal metastases in HER2-neu positive breast cancer.

Detailed description:
The purpose of this study is to evaluate a new treatment for patients with HER2+ metastatic breast cancer (MBC) with leptomeningeal disease (LMD). This is a rare and fast-growing form of cancer. Leptomeningeal disease refers to the seeding of tumor cells to the leptomeninges and dissemination in the cerebrospinal fluid.

Currently, there are is no standard of care treatment for LMD. However, we think the combination therapy will be safe and well-tolerated and may also improve survival. Blood and spinal fluid samples will be collected to evaluate the effects on the body and the cancer, which will help provide greater understanding to therapy response in patients.

The study has a two-stage design with the first stage including 15 subjects from up to ten institutions nationwide. If it advances to the second stage based on the number of successes, another 15 subjects will be enrolled.

Arms: arm 1: Tucatinib will be taken orally at 300 mg twice a day starting with Cycle 1, Day 1. A cycle consists of 21 days. Capecitabine will be taken orally at 1000 mg/m2 twice a day on Days 1-14 starting with cycle 1. Trastuzumab is given intravenously as a loading dose of 8 mg/kg on Cycle 1, Day 1 and then at 6 mg/kg for all subsequent cycles.
Interventions: intervention 1: Tucatinib intervention 2: Trastuzumab intervention 3: Capecitabine
Intervention descriptions: intervention 1: Tucatinib study drug is given in tablet form and taken daily. intervention 2: Trastuzumab is approved by the FDA and is available commercially. Trastuzumab must be prepared and is administered intravenously. intervention 3: Capecitabine is approved by the FDA and is available commercially as an oral drug.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
A Phase II Non-randomized Study to Assess the Safety and 
Efficacy of the Combination of Tucatinib and Trastuzumab and 
Capecitabine for Treatment of Leptomeningeal Metastases in 
HER2 Positive Breast Cancer 
 
 
NCT#: 03501979 
 
Date: 7/28/2022 
 
 


 
 
 
 
A Phase II Non-randomized Study to Assess the Safety and Efficacy of the Combination of 
Tucatinib and Trastuzumab and Capecitabine for Treatment of Leptomeningeal Metastases 
in HER2 Positive Breast Cancer 
 
 
Protocol Number 
TBCRC049/MDACC 2017-0615 
 
Protocol Chairs 
Rashmi K. Murthy, MD, MBE 
                                                  Assistant Professor, Department of Breast Medical Oncology  
                                                  University of Texas MD Anderson Cancer Center 
                                                  1155 Pressler Street, CPB 5.3450, Unit 1354 
                                                  Houston, TX 77030 
                                                  Email: rmurthy1@mdanderson.org 
 
                                                  Barbara J. O’Brien, MD 
                                                  Assistant Professor, Department of Neuro-oncology  
                                                  University of Texas MD Anderson Cancer Center  
                                                  1515 Holcombe Blvd,   
                                                  Unit 431 
                                                  Houston, TX 77030 
                                                  Email: bjobrien@mdanderson.org 
 
                                                  Erica Stringer-Reasor, MD 
                                                  The University of Alabama at Birmingham  
                                                  Assistant Professor, Department of Medicine  
                                                  Section Hematology/Oncology 
                                                  Email: esreasor@uabmc.edu 
 
Collaborators 
Maria Gule-Monroe, MD            
                                                  Jason Johnson, MD                  
                                                  Nicholas Navin, PHD  
                                                  John DeGroot, MD, PHD  
                                                   Ben Park, MD, PHD 
 
Statistician 
Donald A. Berry, PHD 
                                                  University of Texas MD Anderson Cancer Center 
 
Supporters 
Seattle Genetics, Inc. 
 
Lead Site 
University of Texas MD Anderson Cancer Center 
 
Coordinating/IND Site 
University of Alabama at Birmingham 
 
Protocol Version: 
October 10, 2018 (Version 1); April 25, 2019 (Version 2); 
                                                 November 19, 2019 (Version 3); February 28, 2020 (Version 4) 
                                                 March 18, 2020 (Version 5); April 07, 2020 (Version 6),   
                                                 November 20,2020 (Version 7)  


Tucatinib and Trastuzumab with Capecitabine for HER2+ LMD 
Protocol Chairs:  Rashmi Murthy, MD, Barbara O’Brien, MD (MDACC), and  Erica Stringer-Reasor, MD (UAB) 
Protocol Version 7:  November 2 0, 2020 
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Table of Contents 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .............................................................................. 5 
     SCHEMA ............................................................................................................................................................... 7 
     STUDY DESIGN/SUMMARY ............................................................................................................................ 8 
     OBJECTIVES ....................................................................................................................................................... 8 
3.1 
PRIMARY OBJECTIVE .................................................................................................................................... 8 
3.2 
SECONDARY OBJECTIVES .............................................................................................................................. 8 
3.3 
EXPLORATORY OBJECTIVES .......................................................................................................................... 8 
     BACKGROUND AND RATIONALE ................................................................................................................. 9 
4.1 
STUDY DISEASE ............................................................................................................................................ 9 
4.2 
STUDY DRUGS ............................................................................................................................................ 11 
4.3 
STANDARD OF CARE AGENTS ............................................................................................................ 13 
4.4 
RATIONALE FOR THE COMBINATION ........................................................................................................... 15 
4.5 
SYMPTOM BURDEN AND QUALITY OF LIFE ASSESSMENT ........................................................................... 15 
4.6 
CORRELATIVE SCIENCE BACKGROUND ....................................................................................................... 15 
4.7 
SUMMARY ................................................................................................................................................... 16 
     PARTICIPANT SELECTION ........................................................................................................................... 16 
5.1 
INCLUSION CRITERIA .................................................................................................................................. 16 
5.2 
EXCLUSION CRITERIA ................................................................................................................................. 18 
5.3 
INCLUSION OF UNDERREPRESENTED POPULATIONS .................................................................................... 19 
     REGISTRATION PROCEDURES ................................................................................................................... 19 
6.1 
OVERSIGHT ................................................................................................................................................. 19 
6.2 
GUIDELINES FOR COORDINATING INSTITUTION .......................................................................................... 20 
6.3 
GUIDELINES FOR OTHER TBCRC INSTITUTIONS ........................................................................................ 20 
     AGENT ADMINISTRATION AND EXPECTED TOXICITY ...................................................................... 21 
7.1 
OVERVIEW .................................................................................................................................................. 21 
7.2 
SEQUENCE OF ADMINISTRATION ................................................................................................................. 21 
7.3 
HANDLING OF MISSED DOSES ..................................................................................................................... 22 
7.4 
STUDY DRUG ACCOUNTABILITY ................................................................................................................. 22 
7.5 
STUDY AGENTS ........................................................................................................................................... 22 
     DOSE MODIFICATIONS ................................................................................................................................. 25 
8.1 
TUCATINIB .................................................................................................................................................. 25 
8.2 
TRASTUZUMAB ........................................................................................................................................... 26 
8.3 
CAPECTABINE ............................................................................................................................................. 26 
8.4 
COMBINATION THERAPY – SPECIFIC ADVERSE EVENTS ............................................................................. 27 
8.5 
SPECIAL CONSIDERATIONS .......................................................................................................................... 28 
     CONCOMITANT THERAPY AND SUPPORTIVE CARE GUIDELINES ................................................. 28 
9.1 
ALLOWED THERAPY ................................................................................................................................... 29 
9.2 
PROHIBITED THERAPY ................................................................................................................................. 29 
       DURATION OF PARTICIPATION ............................................................................................................. 30 
10.1 
DURATION OF THERAPY .............................................................................................................................. 31 
10.2 
DURATION OF FOLLOW-UP ......................................................................................................................... 31 
10.3 
CRITERIA FOR REMOVAL FROM STUDY ....................................................................................................... 31 


Tucatinib and Trastuzumab with Capecitabine for HER2+ LMD 
Protocol Chairs:  Rashmi Murthy, MD, Barbara O’Brien, MD (MDACC), and  Erica Stringer-Reasor, MD (UAB) 
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10.4 
DISCONTINUATION OF TREATMENT ........................................................................................................................................ 31  
10.5 
WITHDRAWAL FROM STUDY ....................................................................................................................... 32 
10.6 
ADDITIONAL INFORMATION ........................................................................................................................ 32 
       CORRELATIVE/SPECIAL STUDIES .......................................................................................................... 32 
11.1 
BLOOD SAMPLES......................................................................................................................................... 32 
11.2 
CSF SAMPLES ............................................................................................................................................. 32 
11.3 
SPECIMEN COLLECTION ............................................................................................................................... 33 
11.4 
GENETIC TESTING ....................................................................................................................................... 33 
       SPECIMEN BANKING ................................................................................................................................... 33 
       STUDY CALENDAR ....................................................................................................................................... 34 
       MEASUREMENT OF EFFECT ..................................................................................................................... 36 
14.1 
DEFINITIONS ........................................................................................................................................... 36 
14.2 
RESPONSE CATEGORIES .............................................................................................................................. 36 
14.3 
NEUROLOGIC CLINICAL EVALUATION ........................................................................................... 38 
14.4 
LMD RESPONSE CRITERIA ......................................................................................................................... 39 
14.5 
RESPONSE REVIEW ..................................................................................................................................... 40 
       ADVERSE EVENT REPORTING REQUIREMENTS ............................................................................... 41 
15.1 
GENERAL .................................................................................................................................................... 41 
15.2 
DEFINITIONS ............................................................................................................................................... 41 
15.3 
REPORTING PROCEDURES ........................................................................................................................... 42 
       DATA AND SAFETY MONITORING .......................................................................................................... 44 
16.1 
DATA MANAGEMENT AND REPORTING ....................................................................................................... 45 
16.2 
MEETINGS/TELECONFERENCES ................................................................................................................... 45 
16.3 
DATA AND SAFETY MONITORING ............................................................................................................... 45 
       REGULATORY CONSIDERATIONS .......................................................................................................... 46 
17.1 
PROTOCOL REVIEW AND AMENDMENTS ..................................................................................................... 46 
17.2 
INFORMED CONSENT ................................................................................................................................... 46 
17.3 
ETHICS AND GCP ........................................................................................................................................ 46 
       MULTI-CENTER GUIDELINES .................................................................................................................. 47 
18.1 
STUDY DOCUMENTATION ........................................................................................................................... 47 
18.2 
RECORDS RETENTION ................................................................................................................................. 47 
18.3 
PUBLICATION .............................................................................................................................................. 47 
       STATISTICAL CONSIDERATIONS ............................................................................................................ 48 
19.1 
STUDY DESIGN/ ENDPOINTS ....................................................................................................................... 48 
19.2 
SAMPLE SIZE, STUDY DURATION, AND EVALUABLE SUBJECTS.................................................................. 48 
19.3 
ANALYSIS OF ENDPOINTS ........................................................................................................................... 48 
APPENDICES .............................................................................................................................................................. 49 
APPENDIX A: PHASE I FORMULATION STUDIES IN HEALTHY SUBJECTS ....................................................................... 50 
APPENDIX B: COMPLETED OR ONGOING CLINICAL STUDIES ........................................................................................ 51 
APPENDIX C: PERFORMANCE STATUS CRITERIA ......................................................................................................... 52 
APPENDIX D: CYP3A4, CYP2C8, AND CYP3A4 INDUCERS AND INHIBITORS ........................................................... 53 
APPENDIX E: MD ANDERSON SYMPTOM INVENTORY – BRAIN TUMOR (MDASI-BT) ............................................... 55 
APPENDIX F: LINEAR ANALOG SELF ASSESSMENT (LASA) ....................................................................................... 57 
APPENDIX G: NANO (NEUROLOGIC ASSESSMENT IN NEURO-ONCOLOGY) ............................................................... 58 
. 


Tucatinib and Trastuzumab with Capecitabine for HER2+ LMD 
Protocol Chairs:  Rashmi Murthy, MD, Barbara O’Brien, MD (MDACC), and  Erica Stringer-Reasor, MD (UAB) 
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APPENDIX H: STUDY DRUG DIARY ............................................................................................................................. 60 
APPENDIX I: RECIST CRITERIA V 1.1 .........................................................................................................................65                             
REFERENCES  ..........................................................................................................................................................  67 


Tucatinib and Trastuzumab with Capecitabine for HER2+ LMD 
Protocol Chairs:  Rashmi Murthy, MD, Barbara O’Brien, MD (MDACC), and  Erica Stringer-Reasor, MD (UAB) 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
Activated partial thromboplastin time (aPTT) 
Ado-Trastuzumab Emtansine  (Kadcyla) (TDM-1) 
Adverse Event (AE) 
American Society of Clinical Oncology – College of American Pathologists (ASCO-CAP) 
Breast Cancer (BC) 
Capecitabine (C) 
Comprehensive Cancer Center (CCC) 
Congestive Heart Failure (CHF) 
Central Nervous System (CNS) 
Case Report Form (CRF) 
Cerebrospinal fluid (CSF) 
Circulating tumor DNA (ctDNA) 
Clinical Trials Network Monitoring Office (CTNMO) 
Clinical Benefit Rate (CBR) 
Computed Tomography (CT) 
Creatnine (Cr) 
Creatinine Clearance (CrCL) 
Digital imaging and communications in medicine (DICOM) 
Disease-free survival (DFS) 
Electrocardiogram (ECG) 
Epidermal Growth Factor Receptor (EGFR) 
Extra – central nervous system (Extra – CNS) 
Fluorescence in situ hybridization (FISH) 
Food and Drug Administration (FDA) 
Gastrointestinal (GI) 
Hand foot syndrome (PPE) 
Human Epidermal Growth Factor Receptor 2 (HER2) 
Herceptin (Trastuzumab) (T) 
Her2-neu positive breast cancer (HER2+ BC) 
Hormone receptor positive (HR+) 
Immunohistochemistry (IHC) 
Infusion associated reaction (IAR) 
Institutional Review Board (IRB) 
International normalized ratio (INR) 
Intrathecal (IT) 
Intravenous (IV) 
Karnofsky performance status (KPS) 
Linear Analog Symptom Assessment – Quality of Life (LASA-QOL) 
Leptomeningeal Disease (LMD) 
Left Ventricular Ejection Fraction (LVEF) 


Tucatinib and Trastuzumab with Capecitabine for HER2+ LMD 
Protocol Chairs:  Rashmi Murthy, MD, Barbara O’Brien, MD (MDACC), and  Erica Stringer-Reasor, MD (UAB) 
Protocol Version 7:  November 2 0, 2020 
CONFIDENTIAL 
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Lumbar puncture (LP) 
Maximum concentration observed (Cmax) 
Maximum tolerated dose (MTD) 
Magnetic Resonance Imaging (MRI) 
Metastatic Breast Cancer (MBC) 
MD Anderson Cancer Center (MDACC) 
MD Anderson Assessment Symptom Inventory – Brain Tumor (MDASI- BT) 
Multigated acquisition scan (MUGA) 
NCI Common Terminology Criteria for Adverse Event (CTCAE) 
Neurologic Assessment in Neuro-oncology (NANO) 
Objective Response Rate (ORR) 
Ommaya Reservoir (OR) 
Oral route (PO) 
Overall survival (OS) 
Perjeta (Pertuzumab) 
Pharmacokinetic (PK) 
Positron emission tomography-computed tomography (PET/CT) 
Progression-free survival (PFS) 
Progressive Disease (PD) 
Quality of Life (QOL) 
Response assessment for neuro-oncology – leptomeningeal disease (RANO-LMD) 
Response evaluation criteria in solid tumors (RECIST) 
Response Rate (RR) 
Recommended phase 2 dose (RP2D) 
Serious Adverse Event (SAE) 
Stable Disease (SD) 
Stereotactic radiosurgery (SRS) 
Transaminases (AST/ALT) 
Translational breast cancer research consortium (TBCRC) 
Tucatinib (ONT-380) 
Twice daily (BID) 
Tykerb (Lapatinib) 
Tyrosine Kinase Inhibitor (TKI) 
University of Alabama at Birmingham (UAB) 
Upper limit of normal (ULN) 
Vascular Endothelial Growth Factor Receptor (VEGF) 
Ventricular Access Device (VAD) 
Whole Brain Radiation (WBRT) 


Tucatinib and Trastuzumab with Capecitabine for HER2+ LMD 
Protocol Chairs:  Rashmi Murthy, MD, Barbara O’Brien, MD (MDACC), and  Erica Stringer-Reasor, MD (UAB) 
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    SCHEMA 
 
 
 
 
 
 
 
 
 
Eligible: 
• Advanced, 
HER2+ BC 
• Untreated 
LMD 
• No prior 
capecitabine 
w/i 12 
months 
Tucatinib + Capecitabine + 
Trastuzumab* 
Off Treatment 
 
 
 
 
 
N=30 
Imaging and Questionnaires:  Neuroaxis imaging every 2 cycles and extra-CNS imaging every 
4 cycles (or sooner if clinically indicated); MDASI-BT will be performed Day 1 of each cycle 
(within 72 hours prior) and LASA QOL will be performed at every  2 cycles CNS restaging visit 
(within 72 hours prior) 
Biospecimen (blood and CSF): Please see study calendar for details 
*Drug Dosing: 
Tucatinib:  300 mg PO BID, Days 1-21 
Capecitabine: 1000 mg/m2 PO BID, Days 1-14 
Trastuzumab: 6mg/kg IV, every 3 weeks (NOTE:If maintenance Trustuzumab not  
                       received within the prior 30days, a loading dose of 8 mg/kg should be                 
                       given on C1D1  


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Tucatinib and Trastuzumab with Capecitabine for HER2+ LMD 
Protocol Chairs:  Rashmi Murthy, MD, Barbara O’Brien, MD (MDACC), and  Erica Stringer-Reasor, MD (UAB) 
 
 
 
 
    STUDY DESIGN/SUMMARY 
Treatment strategies for patients with leptomeningeal disease (LMD) are an area of unmet clinical 
need in advanced HER2- positive breast cancer (HER2+ BC). The incidence of LMD is increasing, 
current treatments are not adequate, and prognosis is very poor. Further study is warranted and thus 
we propose a phase II trial to determine the efficacy of combining tucatinib (ONT-380) plus 
trastuzumab (T) plus capecitabine (C) in patients with metastatic HER2+ BC and LMD. The results 
would contribute to the field in an area of unmet clinical need. The ease of use and tolerability of 
tucatinib will be unparalleled and this HER2 specific inhibitor has the potential to become the first 
oral drug to be studied in a prospective fashion in patients with HER2+ BC and LMD. We 
hypothesize that combination therapy with tucatinib + T + C will improve OS in patients with 
metastatic HER2+ BC and LMD, for which no effective systemic therapy exists. Further, we 
hypothesize that this therapy will be safe and well-tolerated, will control extra-central nervous 
system (extra-CNS) disease, and will improve quality of life (QOL). Importantly, we will also 
collect and bank blood and CSF samples to assess drug bioavailability and identify candidate 
biomarkers which may predict response to therapy and provide better understanding of underlying 
mechanisms of metastasis to the leptomeninges. 
 
 
    OBJECTIVES 
 
3.1 Primary Objective 
To determine the efficacy in terms of overall survival (OS) for the combination of tucatinib plus T 
plus C in HER2+ BC with LMD 
 
3.2 Secondary Objectives 
 
3.2.1 To assess safety of the combination of tucatinib plus T plus C in HER2+ BC with 
LMD 
 
3.2.2 To assess CNS progression free survival at 12 weeks. 
 
3.2.3 To assess response rate (RR) and clinical benefit rate (CBR) (response or stable 
disease) in the CNS. 
 
3.2.4 To evaluate RR and CBR of extra-CNS disease 
 
3.2.5 To assess the impact on symptom burden and quality of life 
 
3.3 Exploratory Objectives 
 
3.3.1 To obtain and bank samples of blood and CSF from patients with HER2+ LMD 
 
3.3.2 To determine bioavailability of tucatinib in the cerebrospinal fluid (CSF) 
 
3.3.3 To assess levels of circulating tumor DNA (ctDNA) in the CSF and blood; and to 
correlate with response 
 
3.3.4 To characterize the genomic profile from CSF ctDNA and to correlate with blood  
 


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Tucatinib and Trastuzumab with Capecitabine for HER2+ LMD 
Protocol Chairs:  Rashmi Murthy, MD, Barbara O’Brien, MD (MDACC), and  Erica Stringer-Reasor, MD (UAB) 
 
 
ctDNA 
 
Note: In cases where genomic information from primary and/or metastatic tissue is available, 
further correlations may be considered. 
 
 
    BACKGROUND AND RATIONALE 
 
4.1 Study Disease 
 
4.1.1 HER2-positive Breast Cancer (HER2+) 
Approximately 20% of breast cancer (BC) overexpresses the human epidermal growth factor 
receptor 2 (HER2) indicating a more aggressive subtype. 1 HER2 is a trans-membrane tyrosine 
kinase receptor that mediates cell growth, differentiation, and survival. Prior to the development 
of HER2-targeted therapies, the prognosis of HER2-positive patients was among the worse for all 
breast cancer patients. This has changed with the approval of trastuzumab(Herceptin®) in 1998 
and more recently with lapatinib, pertuzumab, and ado-trastuzumab emtansine (T-DM1). 
 
HER2 targeted therapy using either antibody-based therapy or a small molecule tyrosine kinase 
inhibitor (TKI) has led to significant and ongoing improvements in disease-free survival (DFS), 
progression-free survival (PFS), and OS in both the adjuvant and metastatic settings.2-6 
Trastuzumab (T), a humanized anti-HER2 antibody that binds to the HER2 extracellular domain, 
was the first anti-HER2 agent approved by the United States Food and Drug Administration (FDA) 
for use in the treatment of HER2+ breast cancer, and remains the backbone of treatment in the 
adjuvant and first-line metastatic settings, usually in combination with a taxane. 
 
The approval of trastuzumab was followed by the approval of lapatinib (TYKERB®), a small 
molecule tyrosine kinase inhibitor (TKI) that targets both HER2 and epidermal growth factor 
receptor (EGFR).7-9 In addition, pertuzumab (PERJETA®), another antibody-based therapy which 
binds to HER2 at a site different than trastuzumab and inhibits HER2 dimerization, has also been 
approved for use in combination with trastuzumab and docetaxel as first-line therapy for patients 
with HER2+ metastatic disease.10,11 Finally, ado-trastuzumab emtansine (T-DM1; Kadcyla®), an 
antibody-drug conjugate, was approved by the FDA in February 2013, for patients who progress 
following prior therapy with trastuzumab and a taxane.12 
 
Current standard of care for metastatic HER2+ BC is evolving, and depends in part upon which 
treatment patients received previously. The current standard of care for patients with HER2+ 
metastatic breast cancer (MBC) consists of treatment with pertuzumab plus trastuzumab and a 
taxane as first-line treatment, followed by T-DM1 in the secondline.13,14  Treatment options for 
patients who progress after treatment with both pertuzumab and T-DM1 remain relatively limited. 
There is no standard sequencing in later lines, with better treatment options needed and clinical 
trials often being preferred. 
 
4.1.2 Ongoing Medical Need in HER2+ Breast Cancer 
Despite the improvements in outcomes for HER2+ BC, up to a quarter of all  
patients treated with anti-HER2 therapy in the adjuvant setting relapse, and essentially all 
patients in the metastatic setting ultimately progress, including those treated with the newest  
agents such as pertuzumab and T-DM1.Treatment failures may result from primary or acquired 
resistance to HER2 blockade.15-18 There is increasing evidence that dual targeting of HER2,  


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Tucatinib and Trastuzumab with Capecitabine for HER2+ LMD 
Protocol Chairs:  Rashmi Murthy, MD, Barbara O’Brien, MD (MDACC), and  Erica Stringer-Reasor, MD (UAB) 
 
 
 
either through combination of two different HER2 targeted antibodies such as trastuzumab and 
pertuzumab, or through use of an antibody-based therapy such as trastuzumab and a TKI, can 
lead to further improvements in efficacy in metastatic disease.7,19 In particular, the combination 
of a small molecule TKI with an antibody-based therapy may help overcome resistance to 
antibody-mediated inhibition. Lapatinib, a dual epidermal growth factor receptor (EGFR)/HER2 
oral TKI, is approved for use in combination with capecitabine in patients with metastatic disease 
who have progressed following prior trastuzumab and taxane therapy, or in combination with 
letrozole in patients with hormone receptor positive (HR+), HER2+ metastatic disease.9,20,21 
Lapatinib is also approved in combination with trastuzumab alone with efficacy noted in heavily 
pretreated patients.7,22 Use of lapatinib, however, has been limited by the anti-EGFR/human 
epidermal growth factor receptor 1 (HER1) activity of the drug, which results in toxicities such 
as rash, diarrhea, and fatigue. Therefore, there is a need and enthusiasm for a more selective 
molecule inhibitor of HER2, such as tucatinib that could be combined with other anti-HER2 
therapies to improve clinical outcomes and limit toxicities. 
 
Recent data suggest that the incidence of first relapse occurring in the central nervous system (CNS) 
is increasing in patients who have received trastuzumab-based adjuvant therapy. 23 Approximately 
30% of HER2+ patients with metastatic disease will develop CNS metastases.23-27  The increasing 
prevalence of CNS metastases in HER2+ BC patients may be due to several factors. First, HER2+ 
BC appears to display tropism for the CNS. Second, with better control of non-CNS disease, patients 
may be living longer; subsequently CNS metastases become more of a critical clinical issue. Finally, 
and perhaps most importantly, the CNS may represent a sanctuary site for HER2+ disease as large 
molecules such as trastuzumab do not penetrate the blood-brain barrier. 
 
Treatment options for CNS metastases are limited. Treatment of parenchymal CNS metastases 
currently consists of use of whole brain or stereotactic radiation, or surgical resection. Patients may 
also receive chemotherapy alone, or capecitabine and lapatinib, although response rates are 
generally modest.28 The development of HER2 targeted therapies with clinical benefits in both CNS 
and extra-CNS sites could lead to improved clinical outcomes as well as quality of life by avoiding 
or delaying the use of local therapies, such as surgery or radiation that may cause neurocognitive 
impairment. 
 
4.1.3 Leptomeningeal Disease 
Leptomeningeal disease (LMD) refers to the seeding of tumor cells to the leptomeninges and 
dissemination in the cerebrospinal fluid (CSF), which is located  
between the pia and arachnoid and within the ventricular system, by metastatic tumor cells.29 The 
mechanism of this seeding is not well understood. Synchronous or pre- existing parenchymal CNS 
metastases are common in patients with LMD. Classically, LMD presents with multifocal 
neurological deficits and progressive neurologic decline. LMD is diagnosed based on clinical 
findings, brain and spine imaging findings, and/or CSF cytology. As newer therapies increase the 
life span of cancer patients, and as the sensitivity of imaging studies improves, more patients with 
solid tumors are being diagnosed with this generally late complication of cancer. As more targeted 
therapies are developed for metastatic HER2+ breast cancer, the incidence of LMD may increase  
with better treatments and overall longer survival of these patients. In patients with a diagnosis of 
LMD and HER2+ BC, the median OS from time of LMD diagnosis to death is 4.4 months.30,31 
Recent data from a retrospective study from a second large institution showed a survival time of  
 


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Tucatinib and Trastuzumab with Capecitabine for HER2+ LMD 
Protocol Chairs:  Rashmi Murthy, MD, Barbara O’Brien, MD (MDACC), and  Erica Stringer-Reasor, MD (UAB) 
 
 
 
5.2 months from the time of LMD diagnosis.32 Despite the poor prognosis, there is no standard of 
care treatment for LMD. The current management of LMD utilizes a multidisciplinary approach to 
try to penetrate the blood brain barrier and in an attempt to thoroughly treat the entire neuroaxis. 
Treatments may include external beam radiotherapy, and systemic and/or intrathecal (IT) 
chemotherapy. There have been few clinical trials directly addressing LMD and data with regard 
to PFS and RR is limited, as there are no standardized parameters for determining response to 
treatment in LMD.33-38 There is an ongoing clinical trial that is evaluating IT trastuzumab for LMD 
in HER2+ Breast Cancer (NCT01325207) and has recently completed accrual (results are pending). 
Continued investigations are required to improve the long-term outcome of patients with LMD and 
to minimize the potential toxicities of treatment. Future advances in the development of systemic 
therapies that penetrate the CNS and recognition of molecular changes that allow or cause CNS 
seeding may result in improvement in outcomes. Additionally, the identification of subgroups of 
patients who may be predicted to develop LMD will be useful for the implementation of potential 
preventative measures 
 
4.2 Study Drugs 
 
4.2.1 Tucatinib (formerly Array-380, ONT-380) 
 
4.2.1.1 
Overview : Product Description and Mechanism of Action 
Tucatinib is an oral, potent, HER2-specific TKI that is being developed by Seattle Genetics, as a 
novel treatment for HER2+ BC. Unlike other small molecule inhibitors of HER2 that are currently 
either approved or in development for treatment of HER2+ BC, all of which are dual inhibitors of 
both EGFR and HER2, tucatinib selectively inhibits HER2. This enables tucatinib to provide potent 
inhibition of HER2 while minimizing many of the side effects associated with dual inhibitors, 
including skin and gastrointestinal (GI) toxicity. 
 
4.2.1.2 
Tucatinib: Preclinical 
Tucatinib has nanomolar activity against purified HER2 enzyme and was approximately 500-fold 
selective for HER2 versus EGFR in cell-based assays,39 properties that could potentially translate 
clinically into a favorable toxicity profile in comparison to less specific HER2 TKIs that also inhibit 
EGFR.40-42 tucatinib also significantly inhibited phosphorylation of truncated HER2 (p110/p95), 
which is thought to be associated with trastuzumab resistance in HER2+ breast cancer. Nonclinical 
in vivo pharmacology studies of tucatinib as a single agent, as well as in combination with standard-
of-care therapies, demonstrated significant tumor growth inhibition in HER2-dependent tumor 
xenograft models, including models of breast cancer.39,43 tucatinib treatment also significantly 
enhanced survival in HER2-driven intracranial tumor xenograft models.44 Combined, these 
preclinical data supported the rationale for the first- in-human Phase 1 study of tucatinib. 
 
4.2.1.3 
Tucatinib Clinical Trial Summary 
 
The first in human phase I trial of tucatinib demonstrated an acceptable safety profile and 
established the maximum tolerated dose.45 As of June 14 2016, tucatinib has been investigated in  
six clinical studies. Three studies have been completed, including two completed Phase 1 
formulation studies in healthy subjects (Appendix A). The initial phase I single-agent study showed  
objective responses with no treatment-related grade 3 diarrhea (Appendix A). Three other clinical 
trials are active to examine the safety and efficacy of tucatinib when combined with other anti- 


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HER2 therapies (Appendix B). Currently, an international Phase 2 randomized, double-blinded, 
placebo-controlled study of tucatinib in combination with trastuzumab and capecitabine in patients 
with pretreated, unresectable locally advanced or metastatic HER2+ MBC (NCT02614794), 
recently named HER2CLIMB is actively recruiting patients.46 Patients with or without brain 
metastases are eligible and the primary endpoint is bi-compartmental progression free survival 
(PFS) based on assessment of both CNS and extra-CNS disease.47 
 
4.2.1.4 
Phase I Single-Agent Tucatinib Study (ARRAY-380-101) 
In a phase I, open-label study, tucatinib was studied to determine the maximum tolerated dose (MTD) 
and to assess safety, pharmacokinetics, and preliminary antitumor activity with HER2- positive 
advanced solid tumors, and with an expansion cohort of patients with HER2+ MBC. Fifty patients 
received tucatinib, 33 in the dose-escalation and 17 in the expansion; 43 patients had HER2+MBC. 
Patients were heavily pre-treated, with a median number of five prior treatment regimens. All of the 
patients with a diagnosis of breast cancer had received prior trastuzumab, and 88% of these patients 
had received prior lapatinib. 
Dose-limiting toxicities of increased transaminases occurred at 800 mg BID, thus 600 mg oral 
route(PO), twice daily(BID) was established as the MTD. Thirty- one patients received doses at or 
above the MTD of 600 mg BID. Common adverse events (AEs) were usually Grade 1/2 in severity 
and included nausea (56%), diarrhea (52%), fatigue (50%), vomiting (40%) and constipation, pain 
in extremity and cough (20% each). The half-life of tucatinib was 5.38 hours and increases in 
exposure were approximately dose proportional. Among the 35 patients evaluable for efficacy at 
any dose level (defined as having measurable disease and at least one follow-up scan), best response 
was partial response (PR) in 5 patients (14%), stable disease (SD) in 18 patients (51%), and 
progressive disease (PD) in 12 patients (34%). Tumor shrinkage was seen in both skin and visceral 
lesions, including liver metastases. The manuscript has been accepted and is pending publication.48 
 
4.2.1.5 
Phase IB, Combination Tucatinib with and without capecitabine and trastuzumab 
(ONT380-005) 
In a phase IB study, with 3+3 dose escalation study design, tucatinib combined with 1) C alone, 2) 
T alone, 3) C and T was evaluated to assess safety, tolerability and maximum tolerated dose 
(MTD)/recommended phase 2 dose (RP2D). The study was initiated in December 2013 and 
enrollment completed (n=60) in December 2015, with patients (n=15) still active on study. As of 
June 14, 2016, the combination of tucatinib with C + T shows anti-tumor activity in patients treated 
with a median of three prior HER2 agents including pertuzumab with an objective response rate 
(ORR) of 58% (14/24) with responses seen in patients with and without brain metastases. Also, an 
encouraging duration of treatment was noted in the high risk population with a median of 6.3 
months. 
Additionally, the combination was well tolerated with majority of AEs being grade 1 without need 
for dose reductions of the study drug. There was also encouraging data in the tucatinib doublet arms 
with an ORR of 40% in the tucatinib + Trastuzumab arm. Updated efficacy results from the phase 
IB trial were recently published and further study of the triplet combination is ongoing in the  
randomized phase 2 study (HER2CLIMB; NCT02614794). 46,49 
 
 


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4.3 Standard of Care Agents 
 
4.3.1 Trastuzumab (T) 
 
4.3.1.1 
Summary 
T or its biosimilar: Ogivri, Herzuma ,Ontruzant ,Trazimera  Kanjinti )is a humanized anti-HER2 
antibody that binds to 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. 50 
 
4.3.1.2 
Efficacy 
The clinical benefit of T in women with MBC has been demonstrated in multiple clinical studies. 
One large open label randomized Phase 3 study showed that, compared to chemotherapy alone, the 
addition of T significantly increased PFS, ORR, median duration of response, and OS.2 Based on 
these data, trastuzumab was approved by the FDA for use in HER2+ metastatic BC in combination 
with paclitaxel for first-line treatment and as a single agent for patients whose cancers progressed 
after prior chemotherapy for metastatic disease. Since this initial pivotal clinical trial, data have 
emerged demonstrating efficacy of trastuzumab in the metastatic setting combined with a variety 
of chemotherapeutic agents, as well as other HER2 targeted agents, including capecitabine.13 Data 
support the use of trastuzumab in multiple lines of treatment in the setting of metastatic disease, 
even after failure of first line regimens that included trastuzumab and a taxane.51 
 
4.3.1.3 
Safety 
The most common adverse reactions in patients receiving trastuzumab in the adjuvant and 
metastatic BC setting are fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased 
cough, headache, fatigue, dyspnea, rash, neutropenia, anemia, and myalgia. Adverse reactions 
requiring interruption or discontinuation of trastuzumab treatment include congestive heart failure 
(CHF), significant decline in left ventricular ejection fraction (LVEF), severe infusion reactions, 
and pulmonary toxicity. Trastuzumab can cause left ventricular cardiac dysfunction, arrhythmias, 
hypertension, disabling cardiac failure, cardiomyopathy, and cardiac death. T can also cause 
asymptomatic decline in LVEF. There is a 4- to 6-fold increase in the incidence of symptomatic 
myocardial dysfunction among patients receiving T as a single agent or in combination therapy 
compared with those not receiving T. The highest absolute incidence occurs when T is administered 
with an anthracycline. 
 
4.3.2 Capecitabine (C) 
 
4.3.2.1 
Summary 
C is a prodrug of fluorouracil. It undergoes hydrolysis in the liver and tissues to form fluorouracil 
which is the active moiety. Fluorouracil is a fluorinated pyrimidine antimetabolite that inhibits 
thymidylate synthetase, blocking the methylation of deoxyuridylic acid to thymidylic acid, 
interfering with DNA, and to a lesser degree, RNA synthesis. 
 
4.3.2.2 
Efficacy 
The clinical benefit of C in women with MBC has been demonstrated in multiple clinical studies.  
 


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Tucatinib and Trastuzumab with Capecitabine for HER2+ LMD 
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Use of capecitabine as monotherapy was evaluated in patients with metastatic breast cancer at a 
dose of 1000mg/m2 PO BID with demonstrated efficacy and safety.52 C has also been approved to 
be used in combination with the oral HER2/EGFR inhibitor lapatinib at a dose of 1000 mg/m2 PO 
BID based on the results of studies showing an increase in PFS by adding lapatinib to capecitabine 
when compared to C alone.21 Also, the addition of capecitabine to trastuzumab in patients who had 
previously progressed on trastuzumab showed an improvement in efficacy when compared to 
capecitabine alone.7 C has also been used in combination with the oral HER2/EGFR inhibitor 
lapatinib in the treatment of brain metastasis, with response rates noted in small single-arm 
studies.53 
 
4.3.2.3 
Safety 
The most common adverse reactions in patients receiving capecitabine in the MBC setting include 
palmar-plantar erythrodysethesia, diarrhea, nausea, stomatitis, vomiting, fatigue, abdominal pain, 
and constipation. Diarrhea with C may sometimes be severe, and patients with diarrhea must be 
closely monitored, and given fluid and electrolyte replacement if they become dehydrated. In 
addition, less commonly, cardiotoxicity may occur with capecitabine, including myocardial 
infarction/ischemia, angina, dysrhythmia, cardiac failure, sudden death, electrocardiogram(ECG) 
changes, and cardiomyopathy. These adverse reactions may be more common in patients with a 
prior history of coronary artery disease. 
 
4.4 Rationale for the Combination 
 
4.4.1.1 
Tucatinib and CNS Activity 
As previously discussed, one of the key challenges in HER2 MBC is development of effective 
tolerable therapies that treat CNS disease. In support of this concept, data was presented from 
patients in the two ongoing phase Ib combination studies (+TDM1 and +/- C +/-T) 
(NCT02025192; NCT01983501) with response-evaluable CNS metastases treated with tucatinib 
300mg PO BID demonstrating good overall tolerability and evidence of CNS activity. 54,55 
 
This early clinical activity of tucatinib against HER2 positive disease with brain metastases will be 
further studied and confirmed in the ongoing randomized phase 2 study ((HER2CLIMB; 
NCT02614794).46 In addition, there is an ongoing clinical trial evaluating different doses of 
tucatinib in combination with trastuzumab (NCT01921335); results were recently reported showing 
early signs of clinical benefit in the CNS.56 
 
4.5 Symptom Burden and Quality of Life Assessment 
Symptom burden and quality of life (QOL) assessments will be conducted throughout the study. 
Symptom burden will be assessed using the MD Anderson Symptom Inventory – Brain Tumor 
(MDASI-BT), a validated patient questionnaire at study initiation and at each cycle visit (Q21 days) 
(Appendix E). The 22 item MDASI-BT demonstrated validity and reliability in patients with 
primary brain tumors and has also be utilized in the LMD patient population.57 The questions 
address the severity of symptoms caused by disease or by treatment and how they affect normal 
function and interfere with a patient’s life. This is a self-reporting instrument that can be used to 
identify symptom occurrence throughout the disease trajectory and to evaluate interventions 
designed for symptom management; the questionnaire takes approximately 10-15 minutes to 
complete. Quality of life will be assessed using the Linear Analog Scale Assessment Quality of Life  


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(LASA QOL) (Appendix F) and will be completed at study initiation and at each restaging visit 
(Q42 days). 
 
4.6 Correlative Science Background 
Integration of CSF and blood sample collection into this phase II clinical trial will help us to 
potentially achieve multiple translational advances. Almost no information exists about the 
underlying biology and molecular characteristics of tumor cells in CSF in patients with LMD.58 The 
gold standard test for diagnosis and response assessment in LMD, the identification of malignant 
cells on CSF cytology, is less than ideal with several key limitations, including poor sensitivity, 
which makes diagnosis and response assessment difficult.29 A more uniform and precise method for 
assessment of disease status, and response to therapy in LMD is needed. New technology and 
techniques allow for isolating and characterizing blood circulating tumor DNA (ctDNA) and early 
studies indicate the potential for identifying ctDNA in the CSF.59-61 This has potential for 
characterizing LMD and providing insights into molecular features that promote CSF metastasis 
and survival in the leptomeninges. 
 
We will obtain and bank samples from the blood and CSF from each patient enrolled on the study. 
 
To determine the CSF bioavailability of tucatinib in patients with LMD, we will conduct 
pharmacokinetic (PK) studies in the CSF, with parallel assessments in the blood, on day 1 & 2 of 
cycles 1 and 2. These collections will occur in the first 15 patients enrolled. We intend to collect 
parallel samples at time 0 (baseline), 2-3h(T-max), and 5-7h (T ½) following administration of 
tucatinib on Day 1. In addition, collection is recommended on Day 2, 24h (trough)(day 2) following 
administration of the dose of tucatinib. 
 
We will attempt to identify and evaluate ctDNA levels in the banked CSF and correlate to ctDNA 
levels in the blood. This would explore whether we can use CSF and/or blood monitoring to follow 
tumor burden and identify response to treatment. Of note, a pilot study is currently underway at the 
University of Texas MD Anderson Cancer Center to attempt to assess levels of ctDNA in CSF and 
blood samples of patients with metastatic breast cancer and LMD. 
 
Additionally, we aim to collect genomic information from the primary and/or metastatic disease sites 
as available. Correlation of these genomic profiles with the genomic profile obtained from the CSF 
and blood ctDNA may enable better understanding of the molecular mechanisms behind LMD 
metastasis. 
In subsequent studies, we will propose to evaluate potential biomarkers for response: HER2 
mutation, vascular endothelial growth factor (VEGF) levels, cytokines, chemokines, IL-6, IL-8, 
IMP-9, and other proteins. 
 
4.7 Summary 
Treatment strategies for patients with LMD are an area of unmet clinical need in advanced HER2+ 
BC. As more targeted therapies are developed for metastatic HER2+ BC, the incidence of LMD 
may continue to increase as a late complication. Prognosis is poor and there are no standard 
therapeutic options. Future advances in the development of systemic targeted therapies that are 
well- tolerated and penetrate the CNS may result in improvement in outcomes. 
 
 


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Tucatinib and Trastuzumab with Capecitabine for HER2+ LMD 
Protocol Chairs:  Rashmi Murthy, MD, Barbara O’Brien, MD (MDACC), and  Erica Stringer-Reasor, MD (UAB) 
 
 
 
 
Tucatinib has been well-tolerated and has demonstrated single-agent and combinatory anti-tumor 
activity, including partial responses in heavily treated patients and those with CNS metastases. 
Notably, toxicities associated with dual EGFR/HER2 inhibitors have been uncommon. Based upon 
the preclinical and clinical profile observed to date, tucatinib may address unmet needs in the 
treatment of patients with HER2+ BC and LMD, and can be combined with other HER2-directed 
therapies and cytotoxic chemotherapies. 
 
We propose a phase II trial to determine the safety, tolerability, and efficacy of combining tucatinib 
plus T plus C in patients with metastatic HER2+ BC and LMD. 
 
The results would contribute to the field in an area of unmet clinical need. The ease of use and 
tolerability of tucatinib will be unparalleled and this HER2 specific inhibitor has the potential to 
become the first oral drug to be effective and studied in a prospective fashion in patients with 
metastatic HER2+ BC and LMD.  The frequent collection of CSF samples (as part of typical clinical 
practice) in a study such as this provides translational scope to characterize potential biomarkers 
for diagnosis and response assessment and for recognition of molecular changes that cause CNS 
seeding. 
 
    PARTICIPANT SELECTION 
 
5.1 Inclusion Criteria 
5.1.1 Men and women, age ≥ 18 years at time of consent 
5.1.2 Histologically proven metastatic infiltrating carcinoma of the breast that is HER2 
positive – Immunohistochemistry (IHC) 3+ and/or Fluorescence in situ hybridization 
(FISH) ratio > 2.0, or average HER2 copy number > 6.0 signals per cell or per current 
ASCO-CAP (American Society of Clinical Oncology – College of American 
Pathologists) or NCCN (National Comprehensive Cancer Network) guidelines. 
(NOTE: HER2 testing may be performed on primary and/or metastatic site; Any 
estrogen and progesterone [ER/PR] status is allowed.) 
5.1.3 Evidence of leptomeningeal disease (LMD) as diagnosed by a) presence of malignant 
cells in CSF (+CSF cytology) and/or b) Magnetic Resonance Imaging (MRI) evidence 
of LMD, plus clinical signs and/or symptoms. NOTE: Measurable extra- CNS disease 
is not required (Appendix K). Note: Patients who have MRI evidence of focal LMD 
with negative cytology and no symptoms are not eligible for enrollment. 
5.1.4 Performance status: Karnofsky Performance Status >50 or Eastern Cooperative 
Oncology Group (ECOG) < 3 (see Appendix C) 
 
5.1.5 Patient is able and willing to undergo study-required testing, including: 
• Contrast-enhanced MRI (See MRI brain and spine acquisition manual). Note: If 
patient’s have implants in place that are MRI incompatible, these must be 
removed prior to enrollment. 
• Placement of an Ommaya reservoir (or other ventricular access device (VAD)). 
Note: This is mandatory for the first 15 patients enrolled onto the protocol.In the 
second stage, this is strongly recommended per protocol. If a patient cannot or  


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chooses not to undergo Ommaya placement or other VAD in the second stage, the 
patient will be allowed to enroll. 
• Evaluation by medical oncologist at baseline and at every cycle (required) 
• Evaluation by neurologist/neuro-oncologist at baseline and at every cycle  
(strongly recommended); if this is not possible at a site, a medical oncologist may 
per perform the protocol specified evaluations at each visit. 
5.1.6 Patients who are on steroids due to CNS disease or LMD diagnosis, should be on a 
stable dose for at least 5 days prior to registration. 
5.1.7 Prior treatment allowances are as follows: 
• >14 days since last dose of any previous endocrine therapy, chemotherapy, 
trastuzumab or other antibody-based therapy. 
NOTE: If patients have been previously receiving trastuzumab on a weekly basis (at a dose of 
2mg/kg), only a 7 day washout will be required. 
 
• > 14 days or five half-lives since previous treatment with any experimental agent, 
whichever is greater 
• Cumulative dose of doxorubicin > 360 mg/m2 or previous treatment with another 
anthracycline with cumulative dose equivalent to > 360 mg/m2 doxorubicin is not 
allowed. 
• Patients must not have received any therapy specifically directed at LMD, 
including prior radiation for bulky/diffuse LMD or intrathecal therapy for LMD. 
• Patients with hx of treated parenchymal brain metastasis or new/active concurrent 
parenchymal brain metastasis are allowed on trial. 
 Previously treated or progressive parenchymal brain metastases allowed 
• Washout from WBRT = 14 days 
• Washout from focal radiotherapy (SRS/GK) = 7 days 
 Concurrent new parenchymal brain metastasis 
• Untreated new brain metastasis not needing urgent local therapy 
may proceed on study treatment 
o It is strongly encouraged to defer WBRT where possible 
• If lesions are large and require urgent local therapy 
o Washout from WBRT = 14 days 
o Washout from focal radiotherapy (SRS/GK) = 7 days 
 It is strongly encouraged to defer WBRT where 
possible 
• Radiotherapy: 
o Patients may not receive radiotherapy concurrently with the study drug. 
o Patients must not have received whole brain radiotherapy (WBRT) for 
parenchymal metastases within the last 2 weeks (14 days) or focal CNS 
radiotherapy/stereotactic radiosurgery (SRS) within 1 week (7 days) prior to  
 


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o first dose of study drug. (See 5.1.7 regarding patients with parenchymal brain 
metastasis) 
o Radiation for the purpose of palliation in the setting of a painful bone or dural 
metastasis while on study treatment can be allowed with hold of treatment at 
the discretion of the treating physicians. 
5.1.8 All toxicity related to prior cancer therapies must have resolved to ≤ Grade 1, with the 
 following exceptions: alopecia; neuropathy, which must have resolved to ≤ Grade 2; and CHF, 
which must have been ≤ Grade 1 in severity at the time of occurrence, and must have resolved 
completely. Must be without significant systemic illness (e.g. infection unresponsive to treatment 
after 7 days) 
 
5.1.9 Adequate hematologic, liver, and renal function, as follows: 
• Hemoglobin ≥ 9 g/dL 
• ANC ≥ 1000 cells/μL 
 
• Platelets ≥ 100,000/μ 
• Total bilirubin ≤ 1.5 X ULN, unless a known history of Gilbert’s disease (≤3 X 
ULN) 
• Transaminases (AST/SGOT and ALT/SGPT) ≤ 2.5X ULN (< 5 X ULN if liver 
metastases are present) 
• International normalized ratio (INR) and activated partial thromboplastin time 
(aPTT) ≤ 1.5 X ULN 
• Creatinine clearance (CrCL) ≥ 50 mL/min 
5.1.10 Left ventricular ejection fraction (LVEF) must be within institutional limits of normal 
as assessed by ECHO or MUGA documented within 4 weeks prior to enrollment on 
the study. 
5.1.11 Able to understand the study requirements and document informed consent indicating 
his/her awareness of the investigational nature and the risks of this study. 
5.2 Exclusion Criteria 
5.2.1 Medical, social, or psychosocial factors that, in the opinion of the Investigator, could 
impact safety or compliance with study procedures. 
5.2.2 Patient is pregnant or is breastfeeding. Note: If female and of child-bearing potential 
(females who are not surgically sterile or who have had a period in the last 12 months), 
has negative pregnancy test within 7 days prior to treatment. If a sexually active male 
or a sexually active female of child-bearing potential, agrees to use dual (two 
concurrent) forms of medically accepted contraception from the time of consent until 
6 months after the last dose. 
5.2.3 History of allergic reactions to compounds of similar chemical or biological 
composition to capecitabine (Group A only), trastuzumab or tucatinib, except for a 
history of Grade 1 or Grade 2 infusion related reaction to trastuzumab, that has been  
 
 


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successfully managed. 
5.2.4 Known to be HIV positive, or a carrier for Hepatitis B and/or Hepatitis C (whether 
active disease or not) 
5.2.5 Known liver disease, autoimmune hepatitis, or sclerosing cholangitis 
5.2.6 Inability to swallow pills or any significant gastrointestinal diseases, which would 
preclude adequate absorption of oral medications 
Use of a strong CYP2C8/CYP3A4 inducer or inhibitor within three elimination half- 
lives of the inducer or inhibitor prior to the start of study treatment (Appendix D). 
Note: Concomitant use of tucatinib and sensitive CYP3A substrates should be avoided 
(see Appendix D Table 1). 
 
5.2.7 Known impaired cardiac function or clinically significant cardiac disease such as 
ventricular arrhythmia requiring therapy or congestive heart failure. Note: Patients 
with hypertension must have controlled disease defined as systolic blood pressure  
< 150 mmHg and/or diastolic blood pressure < 100 mmHg on antihypertensive 
medications. 
5.2.8 Myocardial infarction or unstable angina within 6 months prior to the first dose of 
study drug. 
5.2.9 Patient with known dihydropyrimidine dehydrogenase deficiency 
5.2.10 Previous treatment with tucatinib. 
5.2.11 Previous treatment with capecitabine within 12 months prior to study registration 
5.2.12 Prior history of other cancer (except non melanoma skin, cervical intraepithelial 
neoplasia) with evidence of disease within the last 5 years. 
 
5.3 Inclusion of Underrepresented Populations 
Individuals of all races and ethnic groups are eligible for this trial. There is no bias towards age or 
race in the clinical trial outlined. This trial is open to the accrual of men and women. 
 
 
    REGISTRATION PROCEDURES 
 
6.1 Oversight 
The University of Alabama at Birmingham (UAB) in Birmingham, AL will be the overall study 
sponsor, primary IRB of record, and coordinating center for this study. Dr. Erica Reasor at UAB 
will hold the IND for this study. Dr. Erica Reasor will serve as TBCRC Co-Chair for this study 
along with Dr. Rashmi Murthy and Dr. Barbara O’Brien from MD Anderson who have scientifically 
developed this study. All three protocol chairs will have key input on the medical decisions (i.e. 
eligibility questions, toxicity management, and response assessments) for the duration of the trial 
though may share and/or designate these responsibilities based upon type of questions (e.g., medical 
oncology vs. neurologic nature) or availability during the course of the study. 
 
 


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6.2 Guidelines for Coordinating Institution 
The Clinical Trials Network Monitoring Office (CTNMO) of the UAB Comprehensive Cancer 
Center (CCC) coordinates investigator-initiated clinical trials under good clinical practice conditions 
at participating sites to achieve timely study subject enrollment. 
Once a study subject has been screened and deemed eligible for study entry by the  
participating site, a study-specific study subject eligibility checklist, a copy of the dated and signed 
consent form, and corresponding source documentation are faxed to the participating site study 
coordinator for eligibility verification. Subsequently, a study- specific number is assigned to the 
study subject and sent to the participating site. Finally, a patient registration form is completed and 
faxed by the CTNMO site to the participating site coordinator for clarification or correction. Once 
the participating site addresses queries, any corrected data forms or copies of corrected source 
documentation are faxed to the CTNMO. 
 
Prior to accepting the registration, the registration office will verify the following: 
• Institutional review board (IRB) approval at the registering institution 
• Patient eligibility 
• Existence of a signed consent form 
• Existence of a signed authorization for use and disclosure of protected health 
information 
• Pre-treatment tests and procedures must be completed within the guidelines 
specified in the protocol including assessment of baseline symptoms 
• Study drugs availability on site 
 
6.3 Guidelines for Other TBCRC Institutions 
Eligible participants will be entered on study centrally at UAB by the Study Coordinator or 
designee. Once a patient is identified as a candidate for the trial the investigator or his/her 
designee will contact UAB CTNMO registration office (Tel: 205- 975-5387, Fax: 205-975-9875) 
prior to obtaining informed consent to verify treatment availability. 
 
Registration will be completed upon submission of documentation of eligibility to the 
registration office. 
 
The registration procedures are as follows: 
 
1) Obtain written informed consent from the participant prior to the performance 
of any study related procedures or assessments. 
2) Complete the protocol specific UAB eligibility checklist using the eligibility 
assessment documented in the participant’s medical/research record. To be 
eligible for registration to the study, the participant must meet all inclusion and 
exclusion criteria as described in the protocol and reflected on the eligibility 
checklist. 
3) Fax the eligibility checklist(s) and all pages of the consent form(s) to UAB 
CTNMO (Attn: Pam Dixon) at 205-975-9875. 
4) The registrar will validate eligibility and register the participant on the study. 
5) An email confirmation of the registration will be sent to the protocol chairs, site 
PI, site study coordinator(s), treating investigator(s) and registering person  
 
 


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6) Immediately following the registration. 
7) Patient can proceed with treatment. 
 
Please contact the lead study coordinator and/or registrar at 205-975-5387 with any questions 
regarding this process. 
 
Note: All registration materials will be provided to each site by the UAB CTNMO at the site 
initiation visit. Turnaround time on registration will be same day. 
 
 
Participants MUST be registered with the Coordinating Institution prior to the start of 
protocol treatment. 
 
Following registration, participants should begin protocol treatment within 10 days. Issues that 
would cause treatment delays should be discussed with the protocol chairs and site principal 
investigator. If a participant does not receive protocol therapy following registration within allowed 
time period, the participant may be determined by the protocol chairs or site PI to become ineligible 
and cancelled from the study. Any requests for eligibility exceptions and/or deviations must be 
approved by the protocol chairs prior to execution. All enrolled patients will need evaluation at 
study start and with each cycle by a medical oncologist and a neuro-oncologist/neurologist. If there 
is a barrier or lack of access to a neuro-oncologist/neurologist at any given site, a medical oncologist 
may perform all protocol specified evaluations. 
 
Note: The decision to enroll a patient in this study will be made following a discussion by members 
of the local multidisciplinary team and this should be documented in the medical record. 
 
    AGENT ADMINISTRATION AND EXPECTED TOXICITY 
 
7.1 Overview 
Subjects in the study will receive combination treatment with tucatinib + 
capecitabine + trastuzumab on an every 21 day cycle. 
 
Tucatinib will be taken at 300 mg PO BID, starting with cycle 1, Day 1. Capecitabine will be taken 
at 1000 mg/m2 PO BID on days 1-14 of a 21-day cycle, starting on Cycle 1, Day 1. Trastuzumab 
will be given as a loading dose of 8 mg/kg IV on Cycle 1, Day 1, and then at 6 mg/kg IV once every 
21 days, starting with Cycle 2 Day 1. 
 
For patients who are continuing trastuzumab treatment from the prior regimen, the loading dose 
will be deferred and they will receive the standard 6mg/kg dose with cycle 1 of study treatment. 
These patients will receive trastuzumab at 6 mg/kg each cycle, starting at Cycle 1 Day 1. 
Trastuzumab may alternately be given on a weekly basis at 2 mg/kg IV q 7 days. Trastuzumab 
infusion rates will be per institutional guidelines. 
 
7.2 Sequence of Administration 
Sequence of treatment for cycles 1-2 is recommended as follows to coordinate with PK assessments 
for the first 15 patients enrolled with OR or VAD in place: 
 
 


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1) CSF and blood collections for PK analysis at time 0. 
2) 1st dose of tucatinib (Recommend in the AM to allow time for subsequent PK  
                           collections throughout the day). 
3) CSF and blood PK collections at 2-3h and 5-7h, after the dose of tucatinib. If 
trastuzumab infusion is not possible to be organized on the same day after PK 
collection, then it may be deferred to Day 2 of the cycle at the discretion of the 
treating physician. Additionally, capecitabine may be administered in conjunction 
with tucatinib on day 1 or its initiation may be deferred to Day 2 at the discretion 
of the treating physician. Note: Regardless of start date of capecitabine, patients 
should intend to complete the 14 day course per cycle. 
4) 2nd dose of tucatinib (can be taken by the patient at home). 
5) On Day 2, it is strongly encouraged to obtain trough PK CSF and blood 
collections at 24H (prior to 3rd dose of tucatinib) 
 
Sequence of treatment for cycles 3 and beyond in patients with OR will be per the treating 
physician’s guidance. 
 
Sequence of treatment will be per the treating physician’s guidance for patients without an OR in 
place or those who will not have PK assessments. 
 
7.3 Handling of Missed Doses 
If doses of the oral medications (capecitabine, tucatinib) are missed or vomited, they should not be 
retaken. Patients should continue with the next scheduled dose. 
 
7.4 Study Drug Accountability 
Tucatinib used during the course of the study should be handled according to the provided 
instructions. Tucatinib is to be tracked and documented from the time of receipt at the site, through 
patient dosing, and until returned to the sponsor or designee for destruction. All supplies, 
including partially used or empty bottles, should be tracked. 
 
Each site designee will conduct drug accountability monitoring during the course of the study and 
will conduct final drug accountability monitoring at site closure. All used and unused tucatinib bottles 
should be handled according to the provided instructions. In addition, drug compliance will be 
documented in the form a drug diary by each subject (Appendix J). 
 
7.5 Study Agents 
 
7.5.1 Capecitabine 
Capecitabine is approved by the FDA and is an oral drug available via a commercial source. 
Capecitabine should be prepared and administered per instructions in the package insert. 
Capecitabine will be administered orally under the direction of the treating physician. Per package 
insert, it is recommended that capecitabine be administered with food. Capecitabine should be 
stored according to the package insert. 
 
Risks Associated with Capecitabine: 
Risks associated with Capecitabine include but are not limited to diarrhea,  
 


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coagulopathy, cardiotoxicity, hand-and-foot syndrome (PPE), and hyperbilirubinemia. Please 
see package Insert/national prescribing information for more details. 
 
Management of capecitabine toxicities may require temporary interruption, dose reduction, or 
treatment discontinuation with capecitabine as per guidelines in Section 8. 
 
7.5.2 Trastuzumab 
Trastuzumab is approved by the FDA and is available via a commercial source. 
 
Trastuzumab should be prepared and administered per instructions in the package insert. 
Trastuzumab will be administered IV under the direction of the Investigator. 
 
Trastuzumab should be stored according to the package insert. 
 
Risks Associated with Trastuzumab: 
 
Risks associated with trastuzumab include but are not limited to fever, nausea, vomiting, infusion 
reactions, diarrhea, infections, increased cough, headache, fatigue, dyspnea, rash, neutropenia, 
anemia, myalgia, and CHF. Please see the Trastuzumab® SmPC or Package Insert/national 
prescribing information for more details. Management of increased left ventricular dysfunction, 
pulmonary toxicity, or infusion reactions may require temporary interruption or treatment 
discontinuation of trastuzumab as per guidelines provided in the package insert as well as in Section 
8. 
 
7.5.3 Tucatinib (ONT-380) 
Tucatinib is a potent, selective, adenosine triphosphate (ATP)-competitive small molecule inhibitor 
of the receptor tyrosine kinase HER2. 
 
Chemical 
Name: 
(N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6- 
(4,4-
dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine Tucatinib drug product is supplied as 
both a coated yellow oval-shaped tablet in a 150 mg dosage strength for PO. The tablets are 
manufactured from a drug product intermediate amorphous dispersion of tucatinib in 
polyvinylpyrrolidine-vinyl acetate copolymer (PVP-VA), which is then combined with standard 
pharmaceutical excipients and compressed into tablets. 
 
Tucatinib tablets in a 50mg dosage strength will also be provided for any dose reductions needed. 
 
Each tucatinib tablet contains either 150mg or 50 mg of active ingredient. Complete dosing 
instructions will be provided to study patients by the pharmacist or treating physician at each study 
site. 
 
Each bottle of study drug will be labeled in compliance with applicable regulatory  
requirements. 
 
Bottles of tucatinib drug product (tablets) are to be stored under refrigeration (2 to 8°C). Drug is 
required to be maintained in cold packs (e.g., coolers) after being dispensed to the subject; the 
cold packs will be provided by each site. The subject will be instructed to place drug in the  
 


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refrigerator as soon as possible. Refer to the investigator’s brochure for additional details. 
 
 
Risks Associated with the tucatinib in combination with trastuzumab alone and with 
trastuzumab and capecitabine: 
Overall, tucatinib has been well tolerated in clinical trials to date. The most frequent AEs seen with 
tucatinib have been mild to moderate in severity, and toxicities associated with dual EGFR/HER2 
inhibitors such as Grade 3 diarrhea and rash have been uncommon. 
 
The most likely potential overlapping toxicities seen for the combination of tucatinib plus 
capecitabine and trastuzumab in this study include GI toxicity, such as nausea, constipation, and 
diarrhea, as well as elevation of liver function tests and fatigue. In 13 patients treated in study ONT-
380-005 using this three-drug combination (at a dose of tucatinib dose of 300 mg BID), the most 
common AEs (occurring in >15%  patients) were diarrhea, nausea, fatigue, PPE, vomiting, 
constipation, dizziness, and headache. The majority of these AEs have been Grade 1 or Grade 2. 
Grade ≥3 events seen with the three-drug combination and considered related to tucatinib included 
reversible Grade 3, AST/ALT elevation (n=1) and Grade 4 cerebral edema with related events of 
Grade 3 dysarthria and Grade 3 visual field deficit (n=1). Similar AE profiles have also been seen 
in patients treated with tucatinib 300 mg PO BID plus capecitabine alone (n=7) and tucatinib 300 
mg PO BID plus trastuzumab alone (n=13), although the combination of tucatinib plus trastuzumab 
was not associated with PPE. 
 
While decreased left ventricular function and interstitial lung disease (ILD) have not been reported 
with tucatinib, these events have been seen with other HER2-inhibitors, and therefore represent a 
potential risk. Other theoretical risks exist which have not yet been seen in patients treated with 
tucatinib. 
 
Patients will be closely monitored for occurrence of GI and liver toxicity, and cardiac function will 
also be monitored closely. The specific safety plans for monitoring for cardiac toxicity and 
hepatotoxicity are outlined in Section 8. 
 
In addition, patients will be closely monitored throughout the study for the occurrence of any other 
expected and/or unexpected toxicities. Patients will be allowed to use concomitant medication to 
manage GI and other symptoms, per treating physician discretion. Because metabolism studies 
have indicated that tucatinib is metabolized in human liver by CYP2C8, strong inducers or 
inhibitors of CYP2C8 will be prohibited. In addition, because tucatinib is also metabolized by 
CYP3A4 to a lesser extent, strong inhibitors and inducers of CYP3A4 will also be prohibited. Dose 
modifications and treatment interruptions of any of the study drugs will be allowed as described in 
Section 8. See Appendix D for list of CYP2C8 and CYP3A4 inducers and inhibitors of particular 
interest in this trial. 
 
Preliminary data from an ongoing drug-drug interaction (DDI) study (ONT-380-012 indicate that 
co-administration of multiple doses of tucatinib (300 mg BID) with midazolam (a sensitive CYP3A 
substrate) increased the geometric mean midazolam exposure (AUC) approximately 5.85-fold 
(90%CI 5.14 to 6.66) in healthy subjects, compared with administration of midazolam alone. The 
findings indicate a potential safety risk to humans exposed to tucatinib who are taking concomitant 
medications that are sensitive CYP3A substrates, as administration of tucatinib may potentially 
increase exposure to the concomitant medication. Therefore, concomitant use of tucatinib with  


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sensitive CYP3A substrates should be avoided (see Appendix D Table 1). 
 
 
    DOSE MODIFICATIONS 
All AEs and clinically significant laboratory abnormalities should be assessed by the Investigator for 
relationship to tucatinib, capecitabine, and trastuzumab, as applicable. In the event that the 
relationship is unclear, discussion should be held with the study PI and/or protocol chairs to discuss 
which study drug(s) should be held and/or modified. An AE may be considered related to tucatinib 
alone, capecitabine alone, trastuzumab alone, both of the drugs, or to none. Dosing should be 
modified (including holding the dose, dose reduction, or discontinuation of drug) as described below. 
Dose reductions or treatment interruption for reasons other than those described below may be made 
by the Investigator if it is deemed in the best interest of patient safety. Doses held for toxicity will 
not be replaced. 
 
8.1 Tucatinib 
Tucatinib should be discontinued if a delay greater than two weeks is required due to treatment-
related toxicity, unless a longer delay is approved by the study PI or protocol chairs. Tucatinib 
should be held for any patients who experiences a Grade 3 or greater AE considered related to 
tucatinib or to the combination of tucatinib and capecitabine or trastuzumab; except for nausea, 
vomiting, or diarrhea in the absence of use of optimal anti-emetic or anti-diarrheal medications. Up 
to 3 dose reductions of tucatinib are allowed as shown below. 
 
8.1.1 Recommended Tucatinib Dose Reduction Schedule 
 
Starting Dosea 
1st Dose Reduction 
2nd Dose Reduction 
3rd Dose Reduction 
300 mg PO BID 
250 mg PO BID 
200 mg PO BID 
150 mg PO BID 
a. Dose reductions of greater increments than those listed in this table (i.e. more than 50 mg per dose reduction) 
may be made if considered clinically appropriate by the investigator. However, tucatinib may not be dose reduced 
below 150 mg BID. 
 
8.1.2 Dose Modifications of Tucatinib and Trastuzumab for Clinical Adverse Events Other 
Than Left Ventricular Dysfunction Related to Either Tucatinib and/or Trastuzumab, 
or Hepatocellular Toxicity * 
 
 
 
 
Clinical Adverse Event 
Related to Tucatinib 
Related to Trastuzumab 
≥ Grade 3 AEs other than 
Grade 3 fatigue lasting ≤ 3 
days; alopecia; nausea; 
vomiting; diarrhea; rash; 
correctable electrolyte 
abnormalities which return to 
≤Grade 1 within 7 days. 
Hold until severity ≤ Grade 1 or 
pre-treatment level. 
Restart at next lowest dose 
level. 
Do not administer until severity 
≤ Grade 1 or pre-treatment 
level. 
Restart without dose reduction. 
Grade 3 nausea, vomiting, or 
diarrhea WITHOUT optimal 
use of anti-emetics or anti- 
diarrheals. 
Hold until severity ≤ Grade 1 or 
pre-treatment level. Initiate 
appropriate therapy. Restart 
without dose reduction. 
Do not administer until severity 
≤ Grade 1 or pre-treatment 
level. Initiate appropriate 
therapy. 
Restart without dose reduction. 


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anti-emetics or anti-diarrheals. 
next lowest dose level. 
level. 
Restart without dose reduction. 
Grade 4 nausea, vomiting, or 
diarrhea regardless of use of 
anti-emetics or anti-diarrheals. 
Do not administer until severity 
≤ Grade 1. 
Reduce to next lowest dose 
level. 
Do not administer until severity 
≤ Grade 1. Restart without dose 
reduction. 
Grade 3 rash WITHOUT 
optimal use of topical 
corticosteroids or anti- 
infectives. 
Hold until severity ≤ Grade 1 or 
pre-treatment level. Initiate 
appropriate therapy. Restart 
without dose reduction. 
Do not administer until severity 
≤ Grade 1 or pre-treatment 
level. Initiate appropriate 
therapy. 
Restart without dose reduction. 
Grade 3 rash WITH optimal use 
of topical corticosteroids or 
anti-infectives. 
Hold until severity ≤ Grade 1 or 
pre-treatment level. Restart at 
next lowest dose level. 
Do not administer until severity 
≤ Grade 1 or pre-treatment 
level. 
Restart without dose reduction. 
Grade 4 rash regardless of use 
of topical corticosteroids or 
anti-infectives. 
Hold until severity ≤ Grade 1 or 
pre-treatment level. Restart at 
next lowest dose level. 
Do not administer until severity 
≤ Grade 1 or pre-treatment 
level. 
Restart without dose reductions. 
a. No dose modifications are required for alopecia 
*Note that if the AE in question does not recover to the Grade required for restarting study medication as 
outlined in the table, the patient may need to discontinue the drug completely. Patients requiring a hold of 
tucatinib for > 6 weeks must discontinue study treatment, unless a longer delay is approved by the investigator. 
 
 
8.2 Trastuzumab 
There are no dose reductions for trastuzumab. Trastuzumab may also be given on a weekly basis 
at 2 mg/kg IV q 7 days, but only in the circumstance that trastuzumab infusion has been delayed, 
and weekly infusions are required to resynchronize the cycle length to 21 days. If trastuzumab 
cannot be restarted at the same dose after being held for an AE, it must be discontinued. As 
trastuzumab is given as an IV infusion, infusion- associated reactions (IARs) may occur. 
If a significant IAR occurs, the infusion should be interrupted and appropriate medical therapies 
should be administered (per the package insert). Permanent discontinuation should be considered 
in patients with severe IAR. This clinical assessment should be based on the severity of the 
preceding reaction and response to administered treatment for the adverse reaction. 
 
No standard premedication is required for future treatments if patients have developed an infusion 
syndrome. Patients may be given acetaminophen prior to treatments. Serious reactions have been 
treated with supportive therapy such as oxygen, beta-agonists, corticosteroids and withdrawal of 
study agent as indicated. 
 
8.3 Capecitabine 
Capecitabine doses should be modified as described below. Capecitabine should be held for any 
patient who experiences a Grade 2 or greater AE considered related to capecitabine. Capecitabine 
dose should not be re-escalated after a dose reduction is made. 
 
 
NOTE: Patients who discontinue capecitabine for any reason except disease progression, 
may continue receiving tucatinib and trastuzumab alone. 
 
8.3.1 Dose Modification of Capecitabine for Clinical Adverse Events Considered 
Related to Capecitabine 
 
 


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8.3.2  
 
CTCAE Grades During a Course of Therapy 
Dose Adjustment for 
Next Treatment 
(% of Starting Dose)a 
Grade 1 
Maintain dose level. 
Maintain dose level. 
Grade 2 
1st appearance 
Interrupt until resolved to Grade ≤ 1. 
100% 
2nd appearance 
Interrupt until resolved to Grade ≤ 1. 
75% 
3rd appearance 
Interrupt until resolved to Grade ≤ 1. 
50% 
4th appearance 
Discontinue permanently. 
NA 
Grade 3 
1st appearance 
Interrupt until resolved to Grade ≤ 1. 
75% 
2nd appearance 
Interrupt until resolved to Grade ≤ 1. 
50% 
3rd appearance 
Discontinue permanently. 
NA 
Grade 4 
1st appearance 
Discontinue permanently. 
Abbreviations: Common Terminology Criteria for Adverse Events (CTCAE); not applicable (NA). 
a. Dose modification table is based upon XELODA® package insert; dose rounding should be 
performed per institutional guidelines 
 
8.4 Combination Therapy – Specific Adverse Events 
 
8.4.1 Dose Modification for Liver Dysfunction 
Dose modification may be required in the case of liver function abnormalities. 
For dose modifications of tucatinib and capecitabine, see Table 10.4 below. Dose modification 
of trastuzumab is not required but dosing should be held at investigator discretion. 
 
8.4.2 Dose Modifications of Tucatinib and Capecitabine for Liver Function 
Abnormalities 
 
 
Liver Function Abnormalities 
Action for Tucatinib Regardless 
of Relationship to Drug 
Capecitabine 
Grade 2 elevation of ALT and/or AST (>3 - 
≤5 x ULN) 
Dose modification not required 
If abnormalities are 
considered related to 
capecitabine, please 
follow guidelines as per 
Table in section 8.3.1. 
If abnormalities are 
not considered related 
to capecitabine, 
modifications are not 
Grade 3 elevation of ALT and/or AST (>5–20 
x ULN) 
Hold until severity ≤ Grade1 
Restart at next lowest dose level 
Grade 4 elevation of ALT and/or AST (>20 x 
ULN) 
Discontinue drug 
Elevation of ALT and/or AST (>3 x ULN) 
AND Bilirubin (>2 x ULN) 
Discontinue drug 
Grade 2 elevation of bilirubin (>1.5–3 x ULN) 
AND both ALT and AST (<3 x ULN) 
Hold until severity ≤ Grade 1 
Restart at same dose level 
Grade 3 elevation of bilirubin (>3 – ≤10 x 
ULN) AND both ALT and AST (<3 x ULN) 
Hold until severity ≤ Grade 
1 Restart at next lowest dose 
mandated but may be 
made at the discretion 
of the investigator. 
Grade 4 elevation of bilirubin (>10 x ULN) 
Discontinue drug 
Abbreviations: alanine aminotransferase (ALT); aspartate aminotransferase 
(AST); upper limit of normal (ULN). 
 
 


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Dose Modifications for left ventricular dysfunction 
Tucatinib and trastuzumab dose modification guidelines for left ventricular dysfunction are 
provided below: 
 
Symptomatic 
CHF 
LVEF < 40% 
LVEF below institutional 
limits of normal and 
≥ 10% points below 
pretreatment baseline, or 
≥16% absolute decrease 
from pretreatment 
baseline 
LVEF 40% to 
≤ 45% and 
decrease is 
< 10% points 
from baseline 
LVEF > 45% 
Discontinue 
tucatinib and 
trastuzumab. 
Do not administer 
tucatinib or 
trastuzumab. Repeat 
LVEF assessment 
within 4 weeks. 
If LVEF < 40% is 
confirmed, 
discontinue 
tucatinib and 
trastuzumab. 
Do not administer 
tucatinib, or 
trastuzumab. 
Repeat LVEF assessment 
within 4 weeks. 
If the LVEF has not 
recovered to within 10% 
points from baseline, 
discontinue tucatinib and 
trastuzumab, as applicable. 
Continue treatment 
with tucatinib and 
trastuzumab. 
Repeat LVEF 
assessment within 
4 weeks. 
Continue 
treatment with 
tucatinib and 
trastuzumab. 
Abbreviations: Congestive Heart Failure (CHF); Left Ventricular Ejection Fraction (LVEF). 
 
If tucatinib and trastuzumab is held for decreased LVEF, hold for at least 4 weeks. If LVEF 
returns to normal limits and the absolute decrease from baseline is ≤ 15%, trastuzumab and 
tucatinib may be restarted. Permanently discontinue tucatinib and trastuzumab for persistent 
(i.e., > 4 weeks) LVEF decline or for suspension of dosing on > 3 occasions for 
cardiomyopathy. 
 
8.5 Special considerations 
For toxicities which are considered by the treating investigator unlikely to develop into 
serious or life–threatening events (e.g. alopecia, altered taste etc.), treatment may be 
continued at the same dose without reduction or interruption. 
 
The treating investigator may reduce a subject’s dose for a toxicity of any grade/duration where 
s/he believes it to be in the best interests of the subject. 
 
 
    CONCOMITANT THERAPY AND SUPPORTIVE CARE GUIDELINES 
In general, concomitant medications and therapies deemed necessary for the supportive care and 
safety of the subject are allowed, provided their use and rationale for use is documented in the 
medical records. The administration of any other therapies intended to treat the primary condition 
including chemotherapy and biologic agents is NOT permitted. Similarly, the use of other 
concurrent investigational drugs is not allowed. 
 
No other targeted therapy, chemotherapy, anti-estrogen therapy, radiation therapy, or 
investigational systemic therapy is allowed concomitant with study treatment. Continuation of 
bisphosophonate therapy for the treatment of bone metastases is allowed. Use of growth  
factor support neutropenia in accordance with the NCCN guidelines is allowed to address  


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neutropenia. 
 
9.1 Allowed Therapy 
Patients may continue to use any ongoing medications not prohibited by the inclusion/exclusion 
criteria. However, efforts should be made to maintain stable doses of concomitant medications 
during the course of study treatment. 
• During study treatment, patients may receive supportive care to include 
bisphosphonates, hematologic and anti-infectious support and pain management 
• Supportive care medications such as anti-diarrheals, anti-emetics, antacids, and 
laxatives are permitted. Prophylactic use of anti-diarrheals are permitted at the 
discretion of the investigator 
• Use of topical 10% urea cream or other topical emollients are permitted for 
prophylaxis and treatment of PPE related to capecitabine use 
• Prophylactic and symptomatic treatment of nausea and vomiting may be used 
per standard of care 
• Thoracentesis or paracentesis may be performed, if needed for comfort 
• Acetaminophen may be used to manage drug-related AEs such as fever, 
myalgias or arthralgias and anti-histamines may be used to manage drug-related 
AEs such pruritus 
• Systemic corticosteroids such as dexamethasone and prednisone may be used in 
certain circumstances. 
o Patients requiring systemic corticosteroids for control of LMD 
symptoms are eligible for enrollment as long as they are on a stable dose 
for at least 5 days prior to initiation of treatment. 
o Patients on a stable dose of systemic corticosteroids for indications other 
than control of LMD will be allowed to continue on corticosteroids and 
to undergo enrollment and initiation of study treatment. 
 
 
9.2 Prohibited therapy 
The following therapies are prohibited during the study (unless otherwise noted): 
• Investigational drugs and devices 
• Anti-cancer therapy, including but not limited to chemotherapy and hormonal 
therapy 
• Radiation therapy, except for palliative radiotherapy at to non-CNS sites which 
may be given upon consultation with protocol chairs. 
• Warfarin 
• Strong inhibitors or inducers of CYP2C8 – Selected listing of strong inhibitors 
and inducers may be found in Appendix D. 
• Strong inhibitors or inducers of CYP3A4 – Selected listing of strong inhibitors 
and inducers may be found in Appendix D. 


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Tucatinib and Trastuzumab with Capecitabine for HER2+ LMD 
Protocol Chairs:  Rashmi Murthy, MD, Barbara O’Brien, MD (MDACC), and  Erica Stringer-Reasor, MD (UAB) 
 
 
 
Note: Preliminary data from an ongoing drug-drug interaction (DDI) study (ONT-380- 012 indicate 
that co-administration of multiple doses of tucatinib (300 mg BID) with midazolam (a sensitive 
CYP3A substrate) increased the geometric mean midazolam exposure (AUC) approximately 5.85-
fold (90%CI 5.14 to 6.66) in healthy subjects, compared with administration of midazolam alone. 
The findings indicate a potential safety risk to humans exposed to tucatinib who are taking 
concomitant medications that are sensitive CYP3A substrates, as administration of tucatinib may 
potentially increase exposure to the concomitant medication. Therefore, concomitant use of 
tucatinib with sensitive CYP3A substrates should be avoided (see Appendix D Table 1). Consider 
using an alternate medication which is not a sensitive CYP3A substrate. If the use of sensitive 
CYP3A substrates is unavoidable, consider dose reduction of CYP3A substrates with narrow 
therapeutic indices and/or increased monitoring for potential adverse reactions as described in the 
medication’s prescribing information. 
 
  DURATION OF PARTICIPATION 
Patients may continue participation in the study until any of the criteria below are met. Long- term 
follow-up will continue every three months following the last study treatment, until loss to follow-
up, death, withdrawal of consent, or study closure. Patients will be contacted by telephone or have 
an in-person assessment of OS and/or disease recurrence, as well as information regarding any 
additional anticancer therapies administered after completion of study treatment. 
 
 


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Review of medical records may be used to obtain this information if reasonable efforts to make phone 
or personal contact are unsuccessful. 
 
All reasons for discontinuation of treatment and withdrawal must be clearly recorded in the 
patient’s medical record and case report form. 
 
10.1 Duration of Therapy 
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. Treatment may continue for an unspecified time period until one of criteria in Section 
10.4 applies.  The patient should complete the evaluations scheduled for the end of study visit, 
provided written consent has not been withdrawn. 
Upon treatment discontinuation, further management will be determined by the patient’s treating 
physicians as clinically indicated. 
 
10.2 Duration of Follow-Up 
Participants will be followed every 6 weeks via telephone call and/or chart review for 6 months after 
removal from study or until death, whichever occurs first. Participants removed from study for 
unacceptable AEs will be followed in the same method. Note: Only subjects who initiate protocol 
treatment will be followed. 
 
In the event that a subject does not continue her post-study care at the institution, every attempt will 
be made to collect this information either by direct contact or through communication with her 
outside physician(s). 
 
10.3 Criteria for Removal from Study 
Participants will be removed from study when any of the criteria listed in Section 10.5 applies. All 
patients who initiate protocol treatment will be included in the overall evaluation of survival 
(intent-to-treat analysis). Patients who sign consent but then do not initiate study treatment for 
any reason will not be included in the analysis. All reasons for discontinuation of therapy should 
be documented clearly in the medical record. 
 
If a subject discontinues or withdraws from the study, but has provided research blood and/or CSF 
samples, these may be used for planned or future correlative studies. Every attempt will be made to 
get a research blood and CSF samples if the subject is able and willing to do so. 
 
10.4 Discontinuation of Treatment 
The reasons for discontinuation of protocol treatment include: 
• Evidence of disease progression in the CNS and/or extra-CNS. 
• Non-compliance with the study protocol; including, but not limited to not 
attending the majority of scheduled visits. The Protocol Chair will determine 
when non-compliance should lead to removal from study. Note: The patients will 
still be included in the overall evaluation of survival (intent-to-treat analysis). 
• Unacceptable major toxicity (i.e., adverse event). Note: The patients will still be  
 
 


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• Included in the overall evaluation of survival (intent-to-treat analysis). 
• Intercurrent illness or condition that would, in the judgment of the treating 
investigator, affect assessment of clinical status to a significant degree or require 
discontinuation of study treatment. 
• At subject’s own request. Note: The reason for discontinuation from the study 
must be documented. The patients will be included in the overall evaluation of 
survival (intent-to-treat analysis) if any protocol therapy was administered prior to 
withdrawal. 
 
• Study is closed for any reason (e.g. new information shows that the patient’s 
welfare would be at risk if she continued study treatment). 
• General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the opinion of the treating investigator. 
 
10.5 Withdrawal from Study 
The reasons for withdrawal of a subject from the study include: 
• Withdrawal consent 
• Loss to follow-up 
• Death 
• Study is terminated for any reason 
 
10.6 Additional Information 
Any remuneration for participants in appreciation of their taking part in this study may be 
determined by the individual institution per their specific institutional and IRB standards. There 
is no subject remuneration planned. 
 
 
  CORRELATIVE/SPECIAL STUDIES 
 
11.1 Blood Samples 
 
Pharmacokinetic(PK) studies: Peripheral blood samples will be obtained per the Study Calendar. 
Blood Samples will be collected at each time point in designated tubes in a PK kit provided by the 
Seattle Genetics. 
 
Non-Pharmacokinetic (PK) studies: Approximately 30 ml total of peripheral blood will be 
obtained for research purposes from each participant per the Study Calendar: 
 
- 
Up to 20 ml will be collected for ctDNA analysis 
- 
Up to 10ml will be collected for banking (optional). 
 
11.2 CSF Samples 
PK studies: CSF samples will be obtained per the Study Calendar. CSF Samples will be 
 


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collected at each time point in a designated tubes in a PK kit provided by Seattle Genetics. 
 
Non-PK studies: Up to 20 ml total of CSF will be obtained for research purposes from each 
participant per the Study Calendar. 
 
- 
Up to 10 ml will be collected for ctDNA analysis 
- 
Up to 10 ml will be collected for banking (optional). 
 
11.3 Specimen collection 
 
Specimen collection will be standardized across all sites, as will cytopreservation and packaging. 
Samples will be collected in designated tubes and all tubes will be labeled with HIPPA compliant 
participant identifier, and sealed in plastic bags labeled as biohazard. Processing, storage, and 
shipment information will be provided in laboratory manuals. 
 
PK samples will be processed and shipped to the sponsor according to the Laboratory Manual. PK 
analyses will be conducted by Seattle Genetics and sample kits including tubes/packing materials 
will be provided to each site. All blood and CSF samples for PK studies will be stored at the site and 
shipped directly to the sponsor. Non- PK blood and CSF research specimens will be banked and 
analyzed at MD Anderson. 
 
Note: Please see supplemental lab manuals for details regarding supplies, collection, processing, and 
shipments. 
 
11.4 Genetic Testing 
Participants will be given information as part of the informed consent process that samples will be 
used for research tests that will include genetic studies and testing. The intent is not to give 
participants (or his/her medical providers) the results of any testing 
done for research purposes; however, incidental germline (heritable) mutations may be identified 
of which a participant may or may not already be aware. In the case that an incidental genetic 
finding is identified, the Protocol Chair of this project will be notified. The possible decisions for 
handling incidental findings may include notification of the participant (and provider); 
recommendation for genetic counseling, which may or may not include genetic testing (e.g., if the 
finding was not done in a 
CLIA certified laboratory); or, neither. In general, a member of the participant’s treating team will 
be given the information to help with notification. In all cases, the current policy of the coordinating 
center and local/participating site IRB, as applicable, will be followed and any additional approvals 
that may be required prior to participant notification will be secured in advance. 
 
 
  SPECIMEN BANKING 
The study PI and collaborators have approval by the TBCRC to use all research bio-specimens  
collected during the conduct of this trial to address the research questions described in the protocol 
document. All future use of residual or repository specimens collected in this trial for  
 
 


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purposes not prospectively defined will require review and approval by the TBCRC according to 
its established policies. 
 
Secondary use of bio-specimens for new endpoints must be submitted to the TBCRC Central Office 
for possible review by the TBCRC Correlative Science Review Committee. 
 
 
  STUDY CALENDAR 
 
Parameter 
Baseline1 
Treatment Cycles 
End of 
Study13 
1 
2 
3 
4 
5 
6 7 
8** 
Demographics 
X 
CLINICAL EVALUATIONS: 
History and Physical 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
Vital signs and Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Neurologic Exam2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
LABORATORY/OTHER EVALUATIONS: 
Hematology (CBC/diff, plt)3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Comprehensive Metabolic Panel3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test (serum or  urine)4 
X 
CSF Evaluation5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
LVEF (Echocardiogram or MUGA) 
X 
RADIOLOGIC EVALUATIONS: 
Extra-CNS/Systemic Staging6 
X 
X 
X 
CNS/Neuroaxis Imaging7 
X 
X 
X 
X 
X 
TREATMENT ADMINISTRATION: 8 
Tucatinib + Capecitabine + 
Trastuzumab 
X 
X 
X 
X 
X 
X 
X 
X 
CORRELATIVE STUDIES: 
PK Samples:  Blood and CSF9 
X 
X 
Non-PK Samples: CSF10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Non-PK Samples: Blood11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Symptom/QOL Questionnaires12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
NOTE: Additional tests may be performed at the discretion of the treating investigator as  clinically 
indicated.  The sample collection schedules outlined above are based on an ideal  subject. The sample 
schedule should be followed as closely as is realistically possible; 


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 however, the schedule may be modified due to problems such as scheduling delays or conflicts (e.g., 
clinic closure, poor weather conditions, vacations,  etc.). 
 
**The above study calendar reflects 8 cycles of treatment. However, responding patients may 
continue on for additional cycles and would undergo the same study assessments as noted above at 
every other cycle. 
 
1. Within 28 days prior to starting treatment, unless otherwise noted. 
2. Neurologic exam performed by neurologist or neuro-oncologist at each site. NANO 
Scoring performed at Day 1 of each cycle or within 72 hours prior. (Appendix G). 
3. Hematology and serum chemistry within 72 hours prior to Day 1 of each cycle. Serum 
chemistry includes measurement of sodium, potassium, chloride, bicarbonate, BUN, 
creatinine, glucose, total bilirubin, calcium, total protein, albumin, AST, ALT, and 
alkaline phosphatase. 
4. For women of childbearing potential only, within 7 days of initiating treatment. 
5. CSF evaluation: Obtain sample to assess standard parameters (i.e., cell count, 
differential, glucose, protein, cytolopathology) via OR or VAD (OR or VAD 
placement is mandatory for the first 15 patients) and/or LP (lumbar puncture). These 
studies will be performed at each study site on Day 1 of each cycle (within 72 hours 
prior). 
6. Systemic/Extra-CNS Staging: CT (or MRI) of the chest, abdomen, and pelvis,   and 
bone scan or PET/CT. For subjects with extra-CNS disease: Repeat assessments to 
include only the imaging required to monitor for sites of disease and are required at 
least every 4 cycles.  For subjects without extra-CNS disease:  imaging may   be 
repeated at physician discretion. In all subjects, systemic imaging is required at End of 
Study (or within the 6 weeks prior) and imaging may be performed at closer intervals 
per treating physician’s discretion. 
7. Neuro-axis Imaging: Contrast-enhanced MRI of the brain and spine with specific 
recommended neuroaxis imaging sequences (See MRI brain and spine acquisition 
manual). Repeat scans at least every 2 cycles or per treating physician discretion (e.g., 
suspicion or evidence of progression clinically). 
8. All patients will receive trastuzumab, capecitabine and tucatinib. NOTE: If 
capecitabine is discontinued by treating physician due to toxicity (not progression), 
then patients may continue treatment/assessments with tucatinib and trastuzumab 
alone. 
9. PK Studies: Cycles 1 and 2 Day 1 at time 0 (pre-treatment), and at 2-3h and 5-7h 
following administration of dose of tucatinib (within 1 hour of the parallel blood 
sample). An additional sample will be obtained 24 hs (+/- 1 hr) following administration 
of dose of tucatinib on Day 1 and before administration of dose of tucatinib on Day 2 of 
Cycles 1 and 2. (Note: PK studies will be performed in patients with OR or VAD 
(n=15). 
10. Non- PK CSF samples: Day 1 of each cycle (within 72 hours prior) 
11. Non-PK Blood Samples: Day 1 of each cycle (within 72 hours prior) 
12. MDASI-BT will be performed Day 1 of each cycle (within 72 hours prior) and LASA 
             QOL will be performed at every  2 cycles CNS restaging visit (within 72 hours prior)       
        (Appendices C & D, respectively). 
13. End of study (i.e., end of study drug treatment) procedures will be requested of all 
patients, as feasible. End of study is when patients are taken off protocol due to disease 


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progression or adverse event. 
 
 
  MEASUREMENT OF EFFECT 
CNS response will be assessed by clinical, cytological, and radiographic means as a composite. 
Systemic response will be assessed by standard clinical and radiographic parameters. Measurable 
disease is not required. 
 
Participants should be re-evaluated every cycle with neurologic exam and CSF analysis. Every 2 
cycles (every 6 weeks), patients will undergo radiographic evaluation with neuroaxis imaging, in 
addition to neurologic exam and CSF analysis, for CNS restaging purposes. Extra-CNS restaging 
will be performed every 4 cycles (every 12 weeks). More frequent CNS and extra-CNS restaging 
can be performed at the discretion of the treating physician. 
 
Response in the CNS and in extra-CNS sites will be evaluated and recorded 
separately in this trial. Extra-CNS response will be evaluated using the international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST V 1.1) Committee. 
Response of parenchymal brain metastases will be evaluated with Response Assessment in Neuro-
oncology Brain Metastases (RANO-BM) criteria.47 Response of LMD will be evaluated in this 
study using a composite criteria further defined below. 
 
14.1 Definitions 
 
Evaluable for Overall Survival. All patients who initiate protocol treatment will be considered 
evaluable for the primary endpoint, which is overall survival. 
 
Evaluable for Toxicity. All patients who receive at least one dose of tucatinib + capecitabine + 
trastuzumab will be evaluable for toxicity from the time of their first dose. Those patients who enroll 
on study but never receive study treatment will not be evaluable for toxicity analysis. 
 
Evaluable for Objective Response. Only those patients who have received at least one cycle of 
therapy, and have had their disease re-evaluated by established CNS response assessment 
parameters (CSF cytopathology, neuroaxis imaging, clinical evaluation) will be considered 
evaluable for objective response in the CNS. 
 
14.2 Response Categories 
See below for LMD response categories: Response, progressive or refractory disease, stable 
disease. Extra-CNS response will be classified per RECIST V 1.1 (Appendix K). 
 
14.2.1 Systemic Disease Parameters 
The status of extra-CNS disease will be monitored using standard staging studies. Per treating 
physician discretion, CT chest, abdomen, and pelvis plus/minus bone scan or PET/CT will be 
performed at baseline (within 28 days of enrollment) and reassessed  every 4 cycles (12 weeks), per 
protocol. 
 
Response in extra-CNS sites will be evaluated in this study using RECIST v 1.1. 
Measurable disease by RECIST  V 1.1 is not required (Appendix K). 
 
 


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Note: In cases of LMD response/stable disease, but disease progression in extra-CNS sites, patients 
may be continued or taken off protocol at the treating physician’s discretion. 
 
14.2.2 LMD Disease Parameters 
The LMD response evaluation used in this trial comprises a composite assessment derived from the 
RANO-LMD working group (per publication and direct communication).62 The composite 
assessment includes CSF cytopathology, neuroaxis imaging, and a neurologic clinical evaluation 
which includes 1) a neurologic examination utilizing the Neurological Assessment in Neuro-
Oncology Group (NANO) scoring instrument and 2) an evaluation of symptoms (MDASI-BT). 
 
Note: In patients with concurrent active parenchymal brain metastases, response will be evaluated 
using the RANO-BM Criteria. 
 
14.2.3 CSF Cytopathology Assessment 
CSF cytology slides will be interpreted by an experienced pathologist at each study site for the 
presence of malignant cells to evaluate cytologic response. CSF cytology will be assessed on day 
1 cycle 1 and CSF cytologic response will be assessed on day 1 of each subsequent cycle (every 3 
weeks +/- 3 days) while patient remains on treatment. “Positive” CSF cytology is defined as 
malignant cells identified in the CSF. Cytologic failure (indicating progressive or refractory 
disease) will be defined as persistent positive cytology (if initially positive) at 6 weeks or the 
development of positive cytology after two serial negative cytologies. Cytologic response will be 
defined as initially positive cytology that is negative on subsequent CSF evaluation, and confirmed 
negative on followup CSF evaluation 3 weeks later. 
 
Note: Standard CSF evaluation including cytology, cell count, glucose, and protein will be 
performed and processed/interpreted at each study site. 
 
14.2.4 Neuroaxis Radiographic Assessment 
Neuroaxis imaging (MRI brain and spine with and without contrast) will be performed at baseline 
(within 28 days of enrollment) and reassessed every 2 cycles (6 weeks +/- 3 days) after the first 
dose of study drug. Recommended MRI prerequisites and sequences are detailed in the MRI Brain 
and Spine Image Acquisition Manual. 
 
Radiographic findings may be interpreted by the treating physician(s) in collaboration with an 
experienced radiologist at each site to determine treatment response at each staging visit. In addition, 
the findings will be recorded on the supplemental CNS response assessment scorecard form by the 
radiologist at each site. Patients will be given an overall radiographic response assessment for LM 
as follows: complete response (CR), partial response(PR), stable disease (SD), or progressive 
disease (PD).  
 
For the composite LMD response assessment, radiographic CR or PR will be considered definitive 
improvement. In cases of definite radiographic worsening, patients will be considered to have 
disease progression based upon LMD response 
criteria, and discontinued from the protocol (however, in cases of clinical benefit, patients may be 
continued on the study drug, at the treating physician’s discretion). 
 
For patients with parenchymal brain metastases, CNS objective response will be classified as CR,  


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PR, SD, or PD based on the RANO-BM Criteria. If a patient is found to have isolated progression 
in the CNS (including either parenchymal brain or dural metastases but not skull-based or 
leptomeningeal metastases) and does not have progression of disease outside the CNS, the patient 
may be eligible to continue on study drugs after completion of focal local treatment (SRS) of the 
brain/dural metastases to allow for clinical benefit. Continuation of study treatment requires 
discussion with and documented approval from the overall study PIs and may continue until either 
systemic progression, LMD progression, or a second isolated CNS progression. The patient may 
continue on study provided the following criteria are met and the patient continues to receive 
clinical benefit: 
 
• The patient is not experiencing any worsening of cancer-related symptoms. 
Patients who are clinically deteriorating and unlikely to receive further benefit 
from continued treatment should discontinue study treatment. 
• The patient is tolerating study drug 
• Review and concurrence by the overall Study PIs 
• Patient has no evidence of unequivocal systemic progression 
• Patient has not had a previous isolated CNS progression while on study 
• Patient does not require treatment with whole brain radiation or neuro-surgery 
 
Study treatment may be held up to 3 weeks to allow local CNS therapy with SRS. Longer holds must 
be discussed and approved by the Study PIs. Oral study drugs (tucatinib/placebo and capecitabine) 
are to be held 1 week prior to planned CNS- directed therapy. The potential for radiosensitization 
with tucatinib is unknown. 
Capecitabine is a known radiation sensitizer and therefore needs to be held prior to CNS-directed 
radiotherapy. Trastuzumab has been shown not to potentiate radiation and therefore may continue 
as per protocol schedule during radiotherapy. Oral study drugs may be re-initiated 7 days or more 
after completion of SRS. Plans for holding and re-initiating study drugs before and after local 
therapy will require discussion with, and documented approval from, the Study PIs. Because the 
primary goal of the study is to assess response in LMD, every effort should be made to avoid 
radiation to LMD target lesions. 
 
Note: Neuro-axis imaging (MRI brain and spine) will be uploaded onto a DICOM formatted disc 
and sent to MD Anderson within 5 business days for central review by the collaborating neuro-
radiologist, who will evaluate the results and complete an independent CNS radiographic response 
scorecard (Appendix I) for cenral review. 
 
14.2.5 Neurologic Clinical Evaluation 
 
A neurologic clinical evaluation will be performed at day 1 (every 3 weeks, +/- 3  
days) of every cycle. The neurologic clinical evaluation will be comprised of 2 parts: 
1) neurologic examination utilizing an adaptation of the standardized NANO 
instrument (Appendix G), and 2) clinical assessment of neurologic symptoms (i.e., seizures, 
headaches). Note: The treating physicians may utilize the MDASI-BT questionnaire (Appendix E) 
for the clinical assessment. 
 
Selection of Target Deficits: (Up to 4 may be selected at baseline) 
Among the neurologic deficits (neurologic sign or symptom) noted at baseline by neurologic exam  


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and/or clinical symptom assessment, up to 4 will be selected as target deficits; if there are fewer than 
4 deficits noted, then all will be included as target deficits. These target deficits may be a combination 
of neurologic signs identified on neurologic exam and/or symptoms reported by the patient. Note:  
 
The term “deficit” is used to encompass both the terms “symptom,” which is subjective and typically 
reported by the patient (for example, headache) and “sign,” which is an objective exam finding (for 
example, facial droop). A meaningful neurologic clinical evaluation takes into account both 
symptoms and signs and this is why it is recommended to choose up to 4 target “deficits” to monitor. 
 
Neurologic clinical response will be determined as follows: In regards to target deficits identified 
in the neurologic examination (as measured using the adapted NANO instrument (Appendix G)), 
progression of disease is defined by a change of 2 or more levels in a given domain (eg, gait) or 
alternatively by a change to level 3 (or level 2 in domains defined by only 3 levels) in any one 
domain. In regards to target deficits identified in the clinical symptom assessment, progression of 
disease will be determined at the discretion of the treating physician, based upon evaluation of 
deficits, as per standard clinical practice. It is expected that best response to treatment usually will 
be stabilization of neurological function (as assessed by neurological examination and symptom 
assessment). It is acknowledged that attribution of disease progression can be challenging, as 
change in neurological function may occur due to concurrent brain metastases, extra-CNS disease 
progression, concurrent medications, or treatment-related toxicity (Chamberlain, Neuro Oncol 
2017). 
 
Note: It is strongly recommended that a neurologist or neuro-oncologist perform the neurologic 
assessments at each visit. 
 
14.3 LMD Response Criteria 
Response assessment of LMD to treatment will be determined by using an adaptation of the 
RANO-LMD criteria (Response, Progressive or refractory disease, stable disease).62 
 
The table below provides the overview for the composite response criteria based on cytology, 
neurological exam as well as imaging data. 


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Assessment 
ResponseA 
Progressive or refractory diseaseB 
Stable diseaseC 
Neurological/clinical 
defined progression# 
Radiologic defined 
progression& 
Neurological 
clinical 
evaluation1 
Improved or 
stable4 
Worse 
Stable&  or Worse 
Stable 
CSF cytology2 
Negative^ 
Negative or Positive^^ 
CNS 
Imaging3 
Definite 
improvement 
5 
Stable 
Progressive 
disease (PD)x 
Stabley 
Legend: 
1 Based on neurologic exam and symptom assessment. Target deficits will be identified and followed by the 
treating neurologist/neuro-oncologist 
2CSF cytology:  Negative = true negative or atypical; Positive = true positive or suspicious 
3CNS imaging: Hydrocephalus, LM linear enhancement, and parenchymal metastases, either brain 
or spine, are noted as present or absent but not used for LM response determination. 
4 Stable neurologic clinical evaluation in the setting of definitive improvement in CNS imaging will 
be classified as response 
5Definitive improvement on CNS imaging is defined as CR (complete response) or PR (partial 
response) 
^ Initially positive cytology that is negative on subsequent CSF evaluation, and confirmed negative on 
followup CSF evaluation 3 weeks later 
^^Cytologic failure (indicating progressive or refractory disease) will be defined as persistent positive 
cytology (if initially positive) at 6 weeks or the development of positive cytology after two serial negative 
cytologies, spaced 3 weeks apart. In cases of clinical benefit, patients may be continued on study drug despite 
cytologic progression, at treating physician’s discretion. 
#As determined by the treating investigator in consultation with the neurologist/neuro-oncologist, neurologic 
exam (neurologic signs) and/or symptoms must be worse 
&In cases of clinical benefit, patients may be continued on study drug despite radiologic progression, at 
treating physician’s discretion 
x Unequivocal progression 
y Any indeterminate or equivocal progression will be considered as stable disease 
Note: Any patient with neurologic clinical progression (as determined by the treating physician) may be removed from the 
study, regardless of the status of the other measures (CSF cytology and/or neuroaxis imaging). 
 
14.4 Response Review 
Response evaluations will be completed by the treating physician(s) at each study site based on the 
parameters noted above. Treating physician(s) will determine an overall assessment: Stable disease, 
continue on protocol; response, continue on protocol; progression, discontinue protocol; or, 
discontinue protocol for any other reason 
 
The LMD Composite response criteria - (1) Response, 2) Progression or refractory disease, 
3) Stable disease – will be assigned by the study team based on review and discussion with 
treating physicians, site PI and overall study PIs. 


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Note: Treating physicians and study teams may reference Composite CNS Response Assessment 
Manual 
 
 
  ADVERSE EVENT REPORTING REQUIREMENTS 
 
15.1 General 
AE collection and reporting is a routine part of every clinical trial. This study will use the 
descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.0 that is available at http://ctep.cancer.gov/reporting//ctc.html. 
 
Information on all adverse events, whether reported by the participant, directly observed, or detected 
by physical examination, laboratory test or other means, will be collected, recorded, followed and 
reported as described in the following sections. 
 
AEs experienced by participants will be collected and reported from initiation of study medication, 
throughout the study, and within 30 days of the last dose of study medication. Participants who 
experience an ongoing adverse event related to a study procedure and/or study medication beyond 
30 days will continue to be contacted by a member of the study team until the event is resolved, 
stabilized, or determined to be irreversible by the participating investigator. 
 
Participants should be instructed to report any serious post-study event(s) that might reasonably be 
related to participation in this study. The investigator should notify the IRB and any other applicable 
regulatory agency 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. 
 
15.2 Definitions 
 
15.2.1 Adverse Event (AE) 
An AE is any undesirable sign, symptom or medical condition or experience that develops or 
worsens in severity after starting the first dose of study treatment 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. 
 
15.2.2 Serious adverse event (SAE) 
A serious adverse event is an undesirable sign, symptom, or medical condition which: 
 
• 
is fatal or life-threatening; 
• 
requires or prolongs inpatient hospitalization; 
• 
results in persistent or significant disability/incapacity; 


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• 
constitutes a congenital anomaly or birth defect; or 
• 
jeopardizes the participant and requires medical or surgical intervention to prevent 
one of the outcomes listed above; 
• 
Important Medical Events (IME) that may not result in death, be life threatening, 
or require hospitalization may be considered serious when, based upon medical 
judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 
 
Events not considered to be SAEs 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 
 
15.2.3 Expectedness 
• 
Expected: Expected AEs 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 Brochure, the package insert or is included in the informed consent 
document as a potential risk. 
• 
Unexpected: An AE 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 
 
15.2.4 Attribution 
Attribution is the relationship between an adverse event or serious adverse event and the study 
treatment. Attribution will be assigned as follows: 
 
• 
Definite – The AE is clearly related to the study treatment. 
• 
Probable – The AE is likely related to the study treatment. 
• 
Possible – The AE may be related to the study treatment. 
• 
Unlikely - The AE is doubtfully related to the study treatment. 
• 
Unrelated - The AE is clearly NOT related to the study treatment. 
 
15.3 Reporting Procedures 
 
15.3.1 General 
All adverse events will be captured on the appropriate study-specific case report forms 
(CRFs). 
 
15.3.2 Serious Adverse Events 
All SAEs, regardless of causality to study drug, will be reported to the Principal Investigator and/or 
the Study Coordinator at each institution, and also to the 


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Coordinating Center and pharmaceutical supporter, Seattle Genetics at 
drug.safety@seattlegenetics.com. 
 
All SAEs must be reported to the Coordinating Center within 1 business day after the investigator 
becomes aware of the event. Events should be reported using a MedWatch form (3500A) as 
available on the FDA website (see link below). 
 
Follow-up information must also be reported within 1 business day of receipt of the information by 
the investigator. 
 
The Coordinating Center will disseminate information regarding serious adverse events to the 
participating sites within 5 days of review of the information by the Protocol Chair (or her designee 
in the event of extended absence) only in the case that the event(s) is believed to be related (i.e., 
possibly, probably, or definitely) to the study medication. The Coordinating Center will be 
responsible for reporting of events to the FDA and supporters, as appropriate (outlined below). 
 
15.3.3 Institutional Review Board 
All AEs and SAEs will be reported to the IRB per current institutional standards. If an adverse event 
requires modification of the informed consent, these modifications will be provided to the IRB with 
the report of the adverse event. If an adverse event requires modification to the study protocol, these 
modifications will be provided to the IRB as soon as is possible. 
 
15.3.4 Food and Drug Administration (FDA) 
In this trial, unexpected adverse events believed to be definitely, probably, or possibly related to the 
medications will be reported to the Food and Drug Administration via MedWatch (using the online 
form available at https://www.accessdata.fda.gov/scripts/medwatch/. The Coordinating Center will 
be responsible for correspondence regarding adverse events with the FDA for all participating sites. 
 
15.3.5 Other 
The coordinating center will be required to report any SAEs to the pharmaceutical supporter – 
Seattle Genetics at drug.safety@seattlegenetics.com. 


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  DATA AND SAFETY MONITORING 
 
16.1 Data Management and Reporting 
All information will be collected on study-specific electronic case report forms utilizing the 
web based REDCap database system by the study staff at each institution. Site access will be 
granted to sites specific on their study role. 
 
The data submission schedule is as follows: 
 
At the time of enrollment: 
 
- 
Registration Form 
- 
Informed Consent Form (signed by the subject) 
- 
Eligibility Checklist 
- 
Source documents related to eligibility 
 
Within 2 weeks after treatment initiation: 
 
- 
Baseline study case report forms 
- 
Pertinent source documents 
 
Within 2 weeks after each cycle is completed: 
 
- 
Per-cycle case report forms 
- 
Pertinent source documents 
 
Every 2 months during follow-up: 
 
- 
Follow-up case report forms 
- 
Pertinent source documents (if necessary) 
 
 
16.2 Meetings/Teleconferences 
All study data will be reviewed for completeness and accuracy by the protocol chairs and/or their 
designees. The principal investigator (or his/her designee) at each respective institution is responsible 
for review, and ensuring the completeness and accuracy, of the data generated by his or her 
institution. 
 
The protocol chairs or his/her designated representative will schedule teleconferences to take place 
as needed depending on the rate of accrual and will include the principal investigators from each 
site. The following study team members involved with the conduct of the trial will be included as 
appropriate: study coordinators, data managers, research nurses, sub investigators, collaborators (if 
applicable), and statistician. 
 
During these meetings, matters related to the following will be discussed: subjects with progressive 
disease in the CNS and/or systemically, enrollment rate relative to 


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expectation, characteristics of participants, retention of participants, adherence to protocol (potential 
or real protocol violations), validity and integrity of the data, safety data, analysis of biospecimen 
samples, and plans for further analyses. 
 
At these meetings, the data pertaining to overall survival, toxicity, and response will also be reviewed, 
dependent upon rate of accrual as outlined in Section 19. 
 
A summary of the items discussed at each teleconference will be prepared by the protocol chair or 
his/her representative and forwarded to each participating site. In addition, study investigators meet 
2-3 times each year in regularly scheduled TBCRC meetings. 
 
16.3 Data and Safety Monitoring 
As an IND is required for this study, it will be conducted in accordance with the data and safety 
monitoring program established by the Clinical Research Office of the University of Alabama at 
Birmingham (UAB). 
 
The UAB Comprehensive Cancer Center Data and Safety Monitoring Plan (DSMP) instituted by the 
CTNMO will monitor subjects treated at UAB and the other TBCRC institutions participating in the 
trial. The Clinical Trials Monitoring Committee (CTMC) will closely (on a weekly basis) monitor 
adverse reactions observed during treatment. 
The CTMC is responsible for data and safety monitoring of the trial and adherence to DSMP. The 
office of CTNMO will also report any SAE at participating sites outside UAB to the CTMC. The 
independent Quality Assurance Committee (QAC) is responsible for oversight of the operation of 
CTMC, including adherence to DSMP. Reports from the CTMC are reviewed monthly by the QAC. 
 
All data will be sent to the Coordinating Center for central collation and review. Subject cases from 
sites will undergo a thorough review; it is unclear how often this may occur; however, each site will 
be asked to provide copies of all source documents and to ensure that all data is current. There are 
no formal on-site evaluations planned by the Coordinating Center; however, these may occur 
depending on site accrual rate, identified problems or concerns, or other reasons, as appropriate. 
 
A medical expert committee or formal data safety monitoring board are not planned or required at 
this time. However, there will be an internal data monitoring committee comprising of the protocol 
chairs, in addition to a neuro-radiologist, and the study statistician will be constituted to review all 
enrolled patients on active treatment. In addition, a biospecimen committee will be named to review 
and advise on proper collection and handling of biospecimens for the duration of the study. 


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  REGULATORY CONSIDERATIONS 
 
17.1 Protocol Review and Amendments 
This protocol, the proposed informed consent and all forms of participant information related to 
the study and any other necessary documents must be submitted, reviewed, and approved by a 
properly constituted IRB governing each study location. 
 
Information regarding study conduct and progress will be reported to the Institutional Review 
Board (IRB) per the current institutional standards of each participating center. 
 
Any changes to the protocol will be made in the form of an amendment and must be approved by 
the IRB of each institution prior to implementation. 
 
The Protocol Chairs (or his/her designee) is responsible for the coordination and development of all 
protocol amendments, and will disseminate this information to the participating centers. 
 
17.2 Informed Consent 
All participants must be provided a consent form describing this study and the investigator (or 
his/her designee) will explain to each subject the nature of the study, its purpose, the procedures 
involved, the expected duration, the potential risks and benefits involved and any discomfort it may 
entail. Each subject will be informed that participation in the study is voluntary, that s/he may 
withdraw from the study at any time, and that withdrawal of consent will not affect her subsequent 
medical treatment or relationship with the treating physician(s) or institution. The informed consent 
will be given by means of a standard written statement, written in non-technical language, which 
will be IRB approved. The subject should read and consider the statement before signing and dating 
it, and will be given a copy of the document.  No subject will enter the study or have study-specific 
procedures done before his/her informed consent has been obtained. 
 
In accordance with the Health Information Portability and Accountability Act (HIPAA), the written 
informed consent document (or a separate document to be given in conjunction with the consent 
document) will include a subject authorization to release medical information to the study sponsor 
and supporting agencies and/or allow these bodies, a regulatory authority, or Institutional Review 
Board access to subjects’ medical information that includes all hospital records relevant to the study, 
including subjects’ medical history. 
 
17.3 Ethics and GCP 
This study will be carried out in compliance with the protocol and Good Clinical Practice, as 
described in: 
 
1. ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996. 
2. US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 
and 56 concerning informed consent and IRB regulations). 


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3. Declaration of Helsinki, concerning medical research in humans (Recommendations 
Guiding Physicians in Biomedical Research Involving Human Subjects, Helsinki 1964, 
amended Tokyo 1975, Venice 1983, Hong Kong 1989, Somerset West 1996). 
 
The investigator agrees to adhere to the instructions and procedures described in it and thereby to 
adhere to the principles of Good Clinical Practice that it conforms to. 
 
 
  MULTI-CENTER GUIDELINES 
 
18.1 Study Documentation 
Each participating site is responsible for submitting copies of all relevant regulatory documentation 
to the Coordinating Center. The required documents include, but are not limited to the following: 
local IRB approvals (i.e., protocol, consent form, amendments, patient brochures and recruitment 
material, etc.), IRB membership rosters, summary of unanticipated problems or protocol deviations, 
and documentation of expertise of the investigators. The Coordinating Center will provide each 
participating site with a comprehensive list of the necessary documents. It is the responsibility of 
the participating sites to maintain copies of all documentation submitted to the Coordinating Center. 
 
The investigator or his/her designee must prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study of 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, and imaging media. 
 
18.2 Records Retention 
All study-related documents must be retained for the maximum period required by applicable 
federal regulations and guidelines or institutional policies. Following closure of the study, each 
participating center will maintain a copy of all site study records in a safe and secure location. The 
Coordinating Center will inform the investigator at each site at such time that the records may be 
destroyed. 
 
18.3 Publication 
Upon completion of protocol accrual, the results of the primary and secondary endpoints will be 
submitted for possible presentation at the American Society of Clinical Oncology annual meeting 
or the San Antonio Breast Cancer Symposium, or other relevant meetings depending on the timing 
of result availability. Final results will be submitted for publication in a peer reviewed scientific 
journal within 2 years of the date of completion and will be available to the public at that time. There 
may be multiple publications to cover both study endpoints and exploratory endpoints. The protocol 
chairs will have access to all study data, will lead the data analysis, and will hold 


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primary responsibility for publication and poster presentation of all study results. Seattle Genetics, 
collaborators and the TBCRC investigators will be provided all manuscripts and abstracts prior to 
submission to review data and provide comments. Final approval of all submitted work will be 
made by the protocol chairs. It is understood that any manuscript or releases resulting from the 
collaborative research must be approved by the Protocol Chairs and will be circulated to applicable 
participating sites/investigators prior to submission for publication or presentation. Additionally, 
any publication of study data and results must conform to the publications policy as stated the 
Translational Breast Cancer Research Consortium’s (TBCRC) “Policies and Procedures”. 
 
 
  STATISTICAL CONSIDERATIONS 
 
19.1 Study Design/ Endpoints 
This phase II study will aim to estimate the efficacy of the combination and verify safety. Based on 
retrospective data from a single tertiary care institution, the median overall survival from the time 
of LMD diagnosis to death in 56 patients with HER2+ BC is estimated to be 4.4 months.30 This 
information was used for the development of the statistical plan after acknowledging the limitations 
and biases inherent to retrospective data as there is no prospective data in this rare patient 
population. 
 
Primary Endpoint: Overall Survival (OS) 
 
We propose a Gehan-like trial design with an interim futility analysis and overall intent to estimate 
OS.63 Enrollment is planned for 30 patients total. This design uses an early clinical benefit endpoint 
for interim analysis after the first 15 patients enrolled with the ultimate goal of estimating the overall 
survival curve if the trial goes to completion. 
 
For the interim analysis, we define success to be CNS progression-free survival for 12 weeks. An 
event will be considered to be either CNS progression before 12 weeks or death from any cause. 
We would stop enrollment with fewer than 2 successes in the first 15 patients. The probability of 
stopping after the first 15 patients enrolled is 95% if the true success rate is 2.5%, 83% for a true 
rate of 5%, 55% for a true rate of 10%, 17% for a true rate of 20%, 4% for a true rate of 30%, and 
1% for a true rate of 40%. 
 
If the trial continues to completion, we aim to estimate median overall survival and would consider 
the trial successful if the median overall survival is > 4.4 months (historical control). Computer 
simulations indicate that if the true median OS is 6.0 months, the 95% confidence interval for the 
Kaplan-Meier median OS will have width of about 6.9 months (assuming uniform accrual and 
exponential survival). The combination treatment will be declared to be worthy of further study if 
we see a median OS that matches or is higher than the historical control. Simulations indicate that 
if the true median OS is 6.0 months, we will observe a median > 4.4 with a probability of 88%. 
With regard to clinical benefit, if we see 6/30 successes (20%), the corresponding exact 95% 
confidence interval = (8%, 39%), while if we see 12/30 successes (40%), the corresponding 
interval = (23%, 59%). 


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19.2 Sample Size, Study Duration, and Evaluable Subjects 
We plan to enroll a total of 30 patients with a 6-month post-accrual additional follow-up. 
 
Study Duration: 3 years; Patients will receive treatment until disease progression or unacceptable 
toxicity or death. 
 
All patients who initiated treatment on protocol will be considered evaluable in the intent to 
treat analysis for the primary endpoint (OS). Patients who withdraw from the study after 
enrollment/registration and prior to initiation of study treatment for any reason will be replaced, 
and will not be counted towards the accrual goal of evaluable subjects. 
 
19.3 Analysis of Endpoints 
 
• Safety 
• Response in the CNS 
• Response of extra-CNS disease 
• Symptom Burden and QOL 
 
QOL assessments will be analyzed descriptively with reporting of frequencies, means, and 
correlations. We will estimate OS curves using the Kaplan-Meier method. We will tabulate 
response data. We will estimate response rates along with exact binomial 95% confidence 
intervals. We will analyze the correlation between ctDNA and response using logistic regression 
analysis and graphical analysis. 
 
MDASI-BT data will be collected on day 1 of each cycle and at end of study. We will summarize 
the MDASI-BT data at each time point using descriptive statistics and evaluate the change of 
MDASI-BT over time and its correlation with response and/or treatment tolerance using linear 
mixed models, where random effects will be used to account for within-subject correlations. 
 
 
 
APPENDICES 
(following pages) 


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APPENDIX A:  Phase I formulation studies in healthy subjects 
 
Study ID 
Design 
Treatment 
Population 
Results 
ARRAY 
380- 
102 
Phase I, open- label, 
single-dose, fixed-
sequence, 4- period 
cross over study to 
evaluate the PK, 
relative 
bioavailability, and 
safety of four 
ONT-380 
formulations in 
healthy subjects 
Single 300mg PO dose of 
ONT-380 in 4 treatment 
formulations: 
1. Capsule (control) 
2. Micronized 
3. Aqueous 
suspension 
4. Captisol/apple 
juice solution 
14 healthy subjects 
Bioavailability of 
ARRY-380 (AUC 
and Cmax) was > 
following the 
micronized and 
aqueous formulations 
and < following the 
captisol/apple juice 
solution compared to 
the control. 
ARRAY-380- 
103 
Phase I, open- 
label, single-dose, 
fixed-sequence, 4- 
period cross over 
study to evaluate 
the PK, relative 
bioavailability, 
potential food 
effect, omeprazole 
drug interaction, 
and safety of ONT-
380 PO 
capsules and 
tablets in healthy 
subjects. 
Single 300mg PO dose of 
ONT-380 in each of 4 
treatment periods: 
1. Capsules 
2. Tablets (fasted) 
3. Tablets (fed) 
4. Tablets (fasted) 
following 
omeprazole 40mg 
x 5 days 
12 healthy subjects 
ONT-380 
metabolism was not 
affected by 
formulation, food, or 
gastric pH. Tablet and 
capsule had similar 
bioavailability. 
Higher drug exposure 
was observed with 
tablet in fed state. 
Abbreviations: intravenous (IV); twice daily (BID); maximum-tolerated dose (MTD); oral (PO); 
pharmacokinetics (PK); area under the curve (AUC); Cmax (maximum concentration observed); partial 
response (PR); recommended Phase 2 dose (RP2D); stable disease (SD). 


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APPENDIX B:  Completed or ongoing clinical studies 
 
Study ID 
Design/Objective 
Treatment 
Status 
ARRAY-380-101 
Phase I, single-agent, open-label, 
dose-escalation study to identify the 
MTD/RP2D of ONT-380 capsules and 
to assess safety, PK, and preliminary 
efficacy 
Dose escalation phase: 25- 
800mg PO BID in 28-day 
cycles 
Expansion phase: 600mg 
PO BID in 28 day cycles 
Completed, 
N=50, 
including 31 at dose 
> 600. 
MTD/RP2D 600mg 
PO BID. 
Among 35 evaluable 
patients for efficacy, 5 
with PR (14%), 18 
with SD (51%). 
ONT-380-004 
(Oncothyreon) 
(NCT02025192) 
Phase Ib, open-label, dose-escalation 
trial to determine the MTD/RP2D of 
ONT-380 tablets given in combination 
with T-DM1 in patients with MBC 
previously treated with trastuzumab 
and taxane. Optional expansion cohort 
in patients with CNS metastasis at the 
MTD/RP2D. 
ONT-380, in escalating 
doses, starting at 300mg 
PO BID. T-DM1 given at 
3.6mg/kg IV q3weeks. 
N=57 
Last patient enrolled 
July 2015 
MTD = 300mg PO 
BID 
ONT-380-005 
(Oncothyreon) 
(NCT1983501) 
Phase Ib, open-label, dose-escalation 
trial to determine the MTD/RP2D of 
ONT-380 tablets given in combination 
with trastuzumab, capecitabine, and 
trastuzumab + capecitabine in patients 
with MBC previously treated with 
trastuzumab and T-DM1. Optional 
expansion cohort in patients with CNS 
metastasis at MTD/RP2D. 
ONT-380, in escalating 
doses, starting at 300mg PO 
BID. C given at 
1000mg/m2 PO BID on 
Days 1-14 of each 21-day 
cycle. H given as a loading 
dose of 8mg/kg followed by 
6mg/kg once q21 days. 
N=60 
Last patient enrolled 
December 2015 
DFCI-13-198 
(NCT01921335) 
Phase I, dose-escalation trial of 
ARRY-380 (ONT-380) tablets in 
combination with H in participants 
with brain metastases from HER2+ 
MBC to determine the MTD/RP2D of 
ONT-380 given in combination with 
trastuzumab. 
Phase Ib, CNS only. 
ONT-380, in escalating 
doses, starting at 450mg 
PO BID. Additional arm 
with once daily dosing of 
ONT-380 starting at 
750mg PO daily. 
Trastuzumab given at 
6mg/kg IV q3 weeks. 
N=40, enrollment 
complete 
ONT-380-206 
(HER2CLIMB) 
(NCT02614794 
Phase 2, randomized, blinded study of 
ONT-380 vs. Placebo in combination 
with capecitabine and trastuzumab in 
patients with metastatic HER2+ breast 
cancer. 
ONT 380 MTD/RP2D = 
300mg PO BID, 
Allows CNS metastasis 
Enrollment 
ongoing 
(n=180), first patient 
enrolled in Feb. 2016 
Abbreviations: intravenous (IV); twice daily (BID); maximum-tolerated dose (MTD); oral (PO); 
recommended Phase 2 dose (RP2D); metastatic breast cancer (MBC) 


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APPENDIX C: Performance Status Criteria 
 
 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Description 
Grade 
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 of 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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APPENDIX D:  CYP3A4, CYP2C8, and CYP3A4 inducers and inhibitors 
 
NOTE: This is a selected listing of strong and moderate CYP3A4, CYP2C8, and CYP3A4 
inducers and inhibitors for this trial. 
 
CYP3A4 Strong Inhibitors (1/2 life): Chloramphenicol (4hrs), Clarithromycin(3-7hrs), Itraconazole 
(21 hrs single dose, 64 hrs steady state), Ketoconazole (systemic) (2-8hrs), Nefazodone(2-4hrs), 
Telithromycin(10hrs), Voriconazole (dose-dependent) 
 
CYP3A4 Strong Inducers (1/2 life): Barbituates (variable), Carbamazepine (25-65 hrs), Phenytoin 
(7-42 hrs), Rifampin (3-4 hrs), St. John’s Wort (9-43 hrs) 
 
CYP2C8 Strong Inhibitors (1/2 life): Gemfibrozil (1-2 hrs), Montelukast (3-6 hrs), Quercetin (<2 
hrs), Rosiglitazone (16-24 hrs) 
 
CYP2C8 Strong Inducer: Rifampin (3-5 hrs) 
 
• FDA. “Drug Development and Drug Interactions: Table of Substrates, Inhbitors, and 
Inducers”(http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResour
ces/DrugInterac tionsLabeling/ucm093664.htm#potency). 
• EMA. “Guideline on the investigation of drug interactions” 
(http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugI
nteractionsLabeli ng/ucm093664.htm#potency). 
• Strong CYP3A inhibitors are defined as those drugs that increase the AUC of oral 
midazolam or other CYP3A substrates > 5 fold. Ritonavir, indinavir, nelfinavir, atazanivir, 
and saquinavir are also strong CYP3A3 inhibitors, but would not be used in this study as 
patients with known HIV are excluded. 


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APPENDIX E:  MD Anderson Symptom Inventory – Brain Tumor (MDASI-BT) 
 
 


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Protocol Chairs:  Rashmi Murthy, MD, Barbara O’Brien, MD (MDACC), and  Erica Stringer-Reasor, MD (UAB) 
 
 
 
 
APPENDIX F:  Linear Analog Self Assessment (LASA) 
 
Linear Analog Self Assessment (LASA): Quality of Life Assessment 
 
Subject ID:    
 
Date:    
 
 
Directions: Please circle the number (0–10) best reflecting your response to the following that 
describes your feelings during the past week, including today. 
 
1. How would you rate your physical well being over the past week? 
This question refers to such things as fatigue, activity, etc. 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
(0= As bad as it can be; 10 = As good as it can be) 
 
2. How would you rate your emotional well being over the past week? 
This question refers to such things as depression, anxiety, stress, etc. 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
(0= As bad as it can be; 10 = As good as it can be) 
 
3. How would you rate your spiritual well being over the past week? 
This question refers to such things as a sense of meaning and purpose, relationship with God, etc. 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
(0= As bad as it can be; 10 = As good as it can be) 
 
4. How would you rate your intellectual well being over the past week? 
This question refers to such things as the ability to think clearly, to concentrate, to remember, etc. 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
(0= As bad as it can be; 10 = As good as it can be) 
 
5. How would you rate your overall well being over the past week? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
(0= As bad as it can be; 10 = As good as it can be) 


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Tucatinib and Trastuzumab with Capecitabine for HER2+ LMD 
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APPENDIX G:  NANO (Neurologic Assessment in Neuro-Oncology) 
 
Domain 
Level of Function Score 
0 
1 
2 
3 
Gait 
Normal 
Abnormal but 
walks without 
assistance 
Abnormal and 
requires assistance 
(companion, cane, 
walker, etc.) 
Unable to walk 
Key Considerations:  1. Walking is ideally assessed by at least 10 steps. 
Strength 
Normal 
Movement present 
but decreased 
against resistance 
Movement present 
but none against 
resistance 
No movement 
Key Considerations: 1. Each limb should be tested separately. 2. Recommend 
assess proximal (above knee or elbow) and distal (below knee or elbow) major 
muscle groups. 3. Score should reflect worst performing area. 4. Patients with 
pre-existing level 3 function in one major muscle group/limb at baseline can be 
scored based on assessment of other major muscle groups/limb. 
Sensation 
Normal 
Decreased but 
aware of sensory 
modality 
Unaware of 
sensory modality 
--------- 
Key Considerations: 1. Recommend evaluating major body areas separately (face, 
limbs and trunk). 2. Score should reflect worst performing area. 3. Sensory 
modality includes but not limited to light touch, pinprick, temperature and 
proprioception. 4. Patients with pre-existing level 2 function in one major body 
area at baseline can be scored based on assessment of other major body areas. 
Vision 
Normal 
Partial monocular 
visual loss 
Complete 
monocular visual 
loss 
Bilateral visual 
loss 
Key Considerations: 1. Patients who require corrective lenses should be 
evaluated while wearing corrective lenses. 2. Each eye should be evaluated and 
score should reflect worst performing eye. 
Eye movements 
Normal 
Abnormality 
noted in 1 
direction of gaze 
Abnormality 
noted in more 
than 1 gaze 
direction, but not 
all 
Unable to move 
the eye in any 
gaze direction 
Key Considerations: 1. Test eye movements for each eye individually. 2. The 
score will reflect the worst performing eye (i.e. the highest score. 


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Domain 
Level of Function Score 
0 
1 
2 
3 
Facial Strength 
Normal 
Mild facial 
weakness 
(nasolabial fold 
flattening, 
asymmetric smile, 
decreased forehead 
contraction or 
partial eye closure) 
Severe facial 
weakness (severe 
NLF flattening, 
asymmetric smile 
with limited or no 
movement of face, 
incomplete eye 
closure, or labial 
incompetence 
Bilateral facial 
weakness 
Key Considerations: 1. Weakness includes nasolabial fold flattening, 
asymmetric smile and difficulty elevating eyebrow. 
Hearing 
Normal 
Impaired but 
residual 
serviceable 
hearing 
Absent unilateral 
hearing 
Bilateral hearing 
loss 
Key Considerations: 1. Each ear should be evaluated and score should reflect 
worst performing ear. 
Swallowing 
Normal 
Impaired but not 
requiring change 
in diet 
formulation, not 
aspirating by 
bedside testing 
Unable to swallow 
without risk of 
aspiration by 
bedside testing 
----------- 
Key Considerations: 1. Bedside testing comprised of a swallow test with a small 
glass of water. 
Level of 
Consciousness 
Normal 
Drowsy (easily 
arousable & 
responsive) 
Somnolent 
(difficult to arouse 
& poorly 
responsive) 
Coma 
(unarousable & 
unresponsive) 
Key Considerations: N/A 
Behavior 
Normal 
Mild/moderate 
alteration 
Severe alteration 
--------- 
Key Considerations: 1. Alteration includes but is not limited to apathy, 
disinhibition and confusion. 2. Consider subclinical seizures for significant 
alteration. 
Other* 
Normal 
Occasional or 
mild 
Persistent, 
moderate to 
severe 
------------ 
*Other neurological findings not otherwise defined in the current examination for example ataxia. 
 
 
 


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Staff initials 
Date reviewed 
 
APPENDIX H: Study Drug Diary 
 
Instructions: 
You will use this diary to record each dose of tucatinib and capecitabine that you take. You should also 
use this diary to record any side effects that you experience and medications that you take other than 
the study drugs. Please be sure to bring this diary with you to your next clinic visit. 
 
Tucatinib:  Tucatinib is taken twice a day, every day. 
Capecitabine: Capecitabine is taken twice a day for 14 days, followed by 7 days of no drug (or rest). 
The study team will tell you if you will also take capecitabine. 
 
• 
Please take both tucatinib and capecitabine at about the same times twice each day (usually 
morning and evening). 
• 
If you forget to take a dose of either study drug, you should skip that dose and take the next 
dose at the next regular time.  
• 
If you vomit after taking a dose of study drug, you should not make up the dose or take 
additional pills, you should take the next dose at the next regular time. Please, do not retake 
the pills. 
• 
Always bring your tucatinib pill bottles (including those that are empty) and your diary with 
you to each clinic visit. 
 
If you have any questions, please ask a study team member or your doctor. 
 
 
 
Subject Number: 
 
Subject Initials: 
   
 
  
Cycle Number: 
  
 
Start Date: 
 
 
Tucatinib dose/number of pills to take at each dose:    
 
 
Capecitabine dose/number of pills to take at each dose:    
 
 
 
Other information/Comments: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Subject Number/Initials:_________________           Cycle:______________ 
 
Cycle 
Day 
Due Date 
Date Taken 
Time Taken 
Tucatinib 
Capecitabine 
Comments 
(Side effects, complaints, 
medications) 
# of pills taken at each dose 
1 
                      AM 
PM 
2 
                       AM 
PM 
3 
                       AM 
PM 
4 
                       AM 
PM 
5 
                      AM 
PM 
6 
                      AM 
PM 
7 
                      AM 
PM 
8 
                      AM 
PM 
9 
                      AM 
PM 
10 
                      AM 
PM 
11 
                      AM 
PM 
12 
                      AM 
PM 
13 
                      AM 
PM 
14 
                      AM 
PM 
 
Continued on Next Page 


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Subject Number/Initials:_________________           Cycle:______________ 
 
Cycle 
Day 
Due Date 
Date Taken 
Time Taken 
Tucatinib 
Capecitabine 
Comments 
(Side effects, complaints, 
medications) 
# of pills taken at each dose 
15 
                      AM 
NO 
CAPECITABINE 
PM 
16 
                      AM 
NO 
CAPECITABINE 
PM 
17 
                       AM 
NO 
CAPECITABINE 
PM 
18 
                      AM 
NO 
CAPECITABINE 
PM 
19 
                      AM 
NO 
CAPECITABINE 
PM 
20 
                      AM 
NO 
CAPECITABINE 
PM 
21 
                      AM 
NO 
CAPECITABINE 
PM 
 
 
 
Comments:    
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX I:  RECIST Criteria V 1.1 
RECIST V1.1 is to be used to assess all extra-CNS sites of disease. Selected sections from RECIST 
V1.1 criteria are below; for detailed guidelines, see the published guideline. 64 
 
Measurability of Tumor Lesions at Baseline 
Definitions 
At baseline, tumor lesions will be categorized as follows: measurable (lesions that can be accurately 
measured in at least one dimension [longest diameter to be recorded] with a minimum size of 10 mm with 
spiral CT scan with slice thickness no greater than 5 mm or if CT scan with slice thickness > 5 mm, the 
minimum lesion size must have a longest diameter twice the actual slice thickness or nonmeasurable (all 
other lesions, including small lesions [longest diameter < 10 mm with spiral CT scan] and truly 
nonmeasurable lesions). 
 
All measurements should be recorded in metric notation by use of a ruler or calipers. All baseline 
evaluations should be performed as closely as possible to the beginning of treatment and never more than 
4 weeks (approximately 30 days) before the beginning of treatment. 
 
Lesions considered to be truly nonmeasurable include the following: blastic bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast disease, lymphangitis 
cutis/pulmonis, abdominal masses that are not confirmed and followed by imaging techniques. Lytic 
bone lesions and cystic lesions must meet criteria detailed in RECIST 1.1. 
 
Specifications by Methods of Measurements 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination when both methods have 
been used to assess the anti-tumor effect of a treatment. 
 
Clinical Examination – Clinically detected lesions will be considered measurable only when they are 
superficial (e.g., skin nodules and palpable lymph nodes). For 
the case of skin lesions, documentation by color photography—including a ruler to estimate the size of 
the lesion—is required. 
Chest X-ray – Lesions on chest X-rays may be considered measurable lesions when they are 
clearly defined and surrounded by aerated lung. 
CT and MRI – CT and MRI are the best currently available and most reproducible methods for 
measuring target lesions selected for response assessment. Conventional CT and MRI should be 
performed with contiguous cuts of 10 mm or less in slice thickness. Spiral CT should be performed by 
use of a 5-mm or less contiguous reconstruction algorithm; this specification applies to the tumors of 
the chest, abdomen, and pelvis, whereas head and neck tumors and those of the extremities usually 
require specific protocols. 
Ultrasound –It may be used as a possible alternative to clinical measurements for superficial palpable 
lymph nodes, subcutaneous lesions, and thyroid nodules. Ultrasound might also be useful to confirm 
the complete disappearance of superficial lesions usually assessed by clinical examination. 
 
 


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Tumor Response Evaluation 
Baseline Evaluation 
Assessment of Overall Tumor Burden and Measurable Disease – To assess objective response, it is 
necessary to estimate the overall tumor burden at baseline to which subsequent measurements will be 
compared. Measurable disease is defined by the presence of at least one measurable lesion, but measurable 
disease is not required for this protocol. 
 
Baseline Documentation of “Target” and “Nontarget” Lesions – All measurable lesions up to a 
maximum of 2 lesions per organ and 5 lesions in total, representative of all involved organs, may be 
identified as target lesions and recorded and measured at baseline (this means in instances where patients 
have only one or two organ sites involved a maximum of two and four lesions respectively will be 
recorded). Target lesions should be selected on the basis of their size (those with the longest diameter) 
and their suitability for accurate repeated measurements (either by imaging techniques or clinically). A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions 
will be calculated and reported as the baseline sum of diameters. The baseline sum of diameters will be 
used as the reference by which to characterize the objective tumor response. All other lesions (or sites 
of disease) should be identified as non-target lesions and should be recorded at baseline. Measurements 
of these lesions are not required, but the presence or absence of each should be noted throughout follow-
up. 
 
Equivocal New Lesions 
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-up 
evaluation will clarify if it represents truly new disease. If repeat scans confirm there is definitely a 
new lesion, then progression should be declared using the date of the initial scan. 
 
Pseudoprogression or Equivocal Progression 
For equivocal findings of progression (e.g. very small and uncertain new lesions; cystic changes or 
necrosis in existing lesions), treatment may continue until the next scheduled assessment. If at the next 
scheduled assessment, progression is confirmed, the date of progression should be the earlier date 
when progression was suspected. 
 
Response Criteria 
Evaluation of Target Lesions – This section provides the definitions of the criteria used to determine 
objective tumor response for target lesions. The criteria have been adapted from the original WHO 
Handbook, taking into account the measurement of the longest diameter only for all target lesions: CR—
the disappearance of all target lesions; PR—at least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum of diameters; PD—at least a 20% increase in the sum of 
the of diameters of target lesions, taking as reference the smallest sum of diameter recorded since the 
treatment started or the appearance of one or more new lesions; SD—neither sufficient shrinkage to 
qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameter 
since the treatment started. 
 
Evaluation of Non-target Lesions – This section provides the definitions of the criteria used to determine 
the objective tumor response for nontarget lesions: CR—the disappearance of all non- target lesions and 
normalization of tumor marker level; incomplete response/SD—the persistence of one or more non-
target lesion(s) and/or the maintenance of tumor marker level above the normal limits; and PD—the 
appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. 


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Tucatinib and Trastuzumab with Capecitabine for HER2+ LMD 
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Tucatinib and Trastuzumab with Capecitabine for HER2+ LMD 
Protocol Chairs:  Rashmi Murthy, MD, Barbara O’Brien, MD (MDACC), and  Erica Stringer-Reasor, MD (UAB) 
 
 
 
 
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Tucatinib and Trastuzumab with Capecitabine for HER2+ LMD 
Protocol Chairs:  Rashmi Murthy, MD, Barbara O’Brien, MD (MDACC), and  Erica Stringer-Reasor, MD (UAB) 
 
 
 
 
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Borges VF, Chia, S.K.L., D'Aloisio, S., Fernetich, G., Sajan, B., Mcspadden, T., 
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Lin NU, Lee EQ, Aoyama H, et al: Response assessment criteria for brain 
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Moulder SL, Borges, V.F., Baetz, T., Mcspadden, T., Fernetich, G., Murthy, R.K., 
Chavira, R., Guthrie, K., Barrett, E., Chia, S.K.: Phase I study of ONT-380, a HER2 inhibitor, in 
patients with HER2+ advanced solid tumors, with an expansion cohort in HER2+ metastatic breast 
cancer(MBC). Clinical Cancer Research (pending publication), 2017 
49. 
Murthy R, Borges VF, Conlin A, et al: Tucatinib with capecitabine and trastuzumab 
in advanced HER2-positive metastatic breast cancer with and without brain metastases: a non- 
randomised, open-label, phase 1b study. Lancet Oncol 19:880-888, 201 
 
 


Protocol Version 7:  November 2 0, 2020 
CONFIDENTIAL 
Page 68 of 68 
This document is confidential.  Do not disclose or use except as authorized. 
Tucatinib and Trastuzumab with Capecitabine for HER2+ LMD 
Protocol Chairs:  Rashmi Murthy, MD, Barbara O’Brien, MD (MDACC), and  Erica Stringer-Reasor, MD (UAB) 
 
 
 
50. 
Arteaga CL, Sliwkowski MX, Osborne CK, et al: Treatment of HER2-positive 
breast cancer: current status and future perspectives. Nat Rev Clin Oncol 9:16-32, 2012 
51. 
von Minckwitz G, du Bois A, Schmidt M, et al: Trastuzumab beyond progression 
in human epidermal growth factor receptor 2-positive advanced breast cancer: a german breast 
group 26/breast international group 03-05 study. J Clin Oncol 27:1999-2006, 2009 
52. 
Rossi D, Alessandroni P, Catalano V, et al: Safety profile and activity of lower 
capecitabine dose in patients with metastatic breast cancer. Clin Breast Cancer 7:857-60, 2007 
53. 
Bachelot T, Romieu G, Campone M, et al: Lapatinib plus capecitabine in patients 
with previously untreated brain metastases from HER2-positive metastatic breast cancer 
(LANDSCAPE): a single-group phase 2 study. Lancet Oncol 14:64-71, 2013 
54. 
Ferrario C, Welch, S., Chaves, J., Walker, L., Krop I., Hamilton, E., Borges V., 
Moulder, S.: ONT-380 in the treatment of HER2+ breast cancer central nervous system metastases 
(#612), American Society of Clinical Oncology (ASCO) Annual Meeting. Chicago, IL, 2015 
55. 
Murthy RK, Hamilton, E., Borges, V., Moulder, S., Aucoin, N., Welch, S., Chaves, 
J., Falkson, C.I., Walker, L., Ferrario, C.: ONT-380 in the treatment of HER2+ breast cancer 
central nervous system (CNS) metastases (P4-14-19), San Antonio Breast Cancer Symposium 
(SABCS) Annual Meeting San Antonio, TX, 2015 
56. 
Metzger O, Barry, W., Guo, H., Younger, J., Lawler, E., Walker, L., Freedman, R., 
Tolaney, S., Krop, I., Winer, E.P., Lin, N.: Phase I dose escalation trial of ONT-380 in combination 
with trastuzumab in patients (pts) with HER2+ breast cancer brain metastases ( P1-12-04), San 
Antonio Breast Cancer Symposium (SABCS) Annual Meeting. San Antonio, TX, 2016 
57. 
Walker J, Tremont, I., O'Brien, B., Armstrong, T. : QOL-26 Describing Symptom 
Burden in patients with leptomeningeal metastases: Selecting an instrument. , 20th Annual 
Scientific Meeting of the Society for Neuro-Oncology. San Antonio, Oxford University Press, 
2015, pp 193-194 
58. 
Boogerd W, Hart AA, van der Sande JJ, et al: Meningeal carcinomatosis in breast 
cancer. Prognostic factors and influence of treatment. Cancer 67:1685-95, 1991 
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Wang Y, Springer S, Zhang M, et al: Detection of tumor-derived DNA in 
cerebrospinal fluid of patients with primary tumors of the brain and spinal cord. Proc Natl Acad 
Sci U S A 112:9704-9, 2015 
60. 
Navin N, Kendall J, Troge J, et al: Tumour evolution inferred by single-cell 
sequencing. Nature 472:90-4, 2011 
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Pentsova EI, Shah RH, Tang J, et al: Evaluating Cancer of the Central Nervous 
System Through Next-Generation Sequencing of Cerebrospinal Fluid. J Clin Oncol 34:2404-15, 
2016 
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Chamberlain M, Junck L, Brandsma D, et al: Leptomeningeal metastases: a RANO 
proposal for response criteria. Neuro Oncol, 2016 
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and a follow-up trial of a new chemotherapeutic agent. J Chron Dis:346-353, 1961 
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Eisenhauer EA, Therasse P, Bogaerts J, et al: New response evaluation criteria in 
solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228-47, 2009 
 
 

ICF_001.pdf: 
 
 
 
 
 
A Phase II Non-randomized Study to Assess the Safety and 
Efficacy of the Combination of Tucatinib and Trastuzumab and 
Capecitabine for Treatment of Leptomeningeal Metastases in 
HER2 Positive Breast Cancer 
 
 
NCT#: 03501979 
 
Date: 7/28/2022 
 
 


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Prot Version: 20-Nov-20 
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Page 1 
 
RESEARCH PARTICIPANT INFORMATION AND CONSENT FORM 
(Part One:  Ommaya reservoir) 
 
TITLE:     A phase 2 non-randomized study to assess the safety and efficacy of the combination               
                  of tucatinib and trastuzumab with capecitabine for treatment of leptomeningeal     
                  metastases in HER2-neu positive breast cancer 
 
 
IRB PROTOCOL NO.: 
IRB-300000290 
 
SPONSOR INVESTIGATOR:  Erica M. Stringer-Reasor, M.D. 
 
SPONSOR: 
University of Alabama at Birmingham 
 
SPONSOR PROTOCOL NO.:  TBCRC 049 
 
SUPPORT PROVIDED BY:   
MD Anderson Cancer Center; Seattle Genetics, Inc.; Johns 
Hopkins University on behalf of the Translational Breast Cancer 
Research Consortium (TBCRC) 
 
SUB-INVESTIGATORS:           Ahmed M. E. Elkhanany, MD 
Gabrielle B. Rocque, MD 
Louis B. Nabors, MD 
 
 
______________________________________________________________________________ 
  
WHAT IS A CLINICAL STUDY? 
 
A clinical study is a research study that tests the effects of a new medicine or treatment in people.  
 
Your study doctor will explain the study to you. The study will only include people who understand 
the study, meet the study's entry criteria, and choose to be in it. If you choose to volunteer for this 
study, you will be asked to sign this form. This process is called informed consent.  
 
This form explains what the study is about, how it will be done, the possible risks, benefits, and side 
effects of participating in the study and your responsibilities as a participant. This form will answer 
some questions about the study, but you should speak with your study doctor if you have additional 
questions. Please take your time to review the information in this form carefully. You may take home 
an unsigned copy of this form for review before making a decision.  
 
If you have any questions about the study, or if this form has any words that you do not understand, 
ask your study doctor or the study staff. You may also want to talk to others (for example, your friends, 
family, or other doctors) about being in this study.  


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You do not have to be in this study. You are free to say ‘yes’ or ‘no’, or to drop out at any time. No 
penalty or loss of benefits will occur if you say ‘no’ or stop participating. Whatever—and whenever—
you make your decision, your regular medical care will not be affected by your decision. 
 
WHY IS THIS STUDY BEING DONE?  
 
The purpose of this study is to evaluate a new treatment for patients with HER2+ Metastatic Breast 
Cancer (MBC) with leptomeningeal disease (LMD).  
 
Currently, there is no standard of care for the treatment of metastatic HER2-neu positive (HER2+) 
metastatic breast cancer (MBC) with leptomeningeal disease (LMD). When breast cancer has spread 
to the meninges (tissues that surround the brain and/or spinal cord), LMD is diagnosed. LMD is a rare 
and fast growing form of cancer with few treatment options.  Therefore, further study in search of new 
treatments is needed.  
We want to find out what effects, good and bad, using a combination of tucatinib and trastuzumab 
with capecitabine has on patients with HER2+ MBC with LMD.  
 
We think that this combination therapy will be safe and well-tolerated with few side effects and will 
control LMD and disease in the body. We also hope that this combination of drugs will improve 
survival with few side effects in patients diagnosed with metastatic breast cancer with LMD.  As part 
of this study we will also collect samples, such as blood and spinal fluid, to assess the effects of the 
drug in the body and on the cancer, which may help us to understand why patients do and do not 
respond to therapy.  
 
HOW MANY PEOPLE WILL TAKE PART IN THE STUDY? 
 
We plan to enroll a total of 30 patients for the study across approximately 10 sites with each site 
enrolling up to 5 patients. 
 
This study is being led by investigators at the University of Alabama Birmingham (UAB) and MD 
Anderson Cancer Center (MDACC).  This study is being supported administratively and/or through 
funding by both UAB and MDACC, as well as by Seattle Genetics, Inc. and Johns Hopkins University 
on behalf of the Translational Breast Cancer Research Consortium (TBCRC).  The TBCRC is a group 
of academic medical centers across the United States that work together to conduct breast cancer 
research.   
 
HOW IS THIS STUDY DESIGNED? 
 
If you complete the consent process, then you may be eligible to participate in this study.  
Eligible participants will receive tucatinib, capecitabine, and trastuzumab. 
 
The research team wants to learn: 
• What effect tucatinib has (if any) when given with capecitabine and trastuzumab on the 
growth of tumors in the brain and meninges (tissues that surround the brain and/or spinal 
cord). 


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Page 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
WHAT DRUGS WILL BE TESTED IN THIS STUDY? 
 
The drugs involved in this study are tucatinib, capecitabine and trastuzumab (or its biosimilar: Ogivri, 
Herzuma ,Ontruzant ,Trazimera  Kanjinti in lieu of trastuzumab by the treating physician and site’s 
discretion . Tucatinib is an oral tablet, which will be taken by mouth twice each day. The doses are 
generally taken about 12 hours apart and should be taken about the same time each day. The pills may 
be taken with or without food. You will be instructed on the dose and number of pills to take by your 
treating physician. Capecitabine is also in the form of tablets which will be taken by mouth twice each 
day for the first 14 days of each 21-day treatment period (also known as a cycle). It must be taken with 
food (within 30 minutes of a meal) with water. Your doctor will determine the number of pills to take 
at each dose. Trastuzumab will be given as an infusion (through a vein in your arm) once every 21 
days.   The length of each infusion is 30-60 minutes.   For the very first dose of trastuzumab on the 
study, the length of the infusion may be longer. 
 
You will be asked to record each dose of tucatinib and capecitabine on a study drug diary.  You should 
bring your diary and all bottles of tucatinib and capecitabine with you to each clinic visit.   
 
 
STUDY DESIGN 
Eligible: 
• Advanced,  
HER2+ BC 
• Untreated 
LMD 
• No prior 
capecitabine 
w/i 12 
months 
Tucatinib + Capecitabine + 
 Trastuzumab* 
Off Treatment 
Continue until 
PD or AE, 
additional 
treatment per 
standard of care 


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Please see the study calendar below, which shows what you can expect at each of your study visits.   
 
Parameter 
Screening 
Treatment Cycles 
End of 
Study 
1 
2 
3 
4 
5 
6 
7 
8** 
Demographics 
X 
 
 
CLINICAL EVALUATIONS: 
 
 
 
 
 
 
 
 
 
 
History and Physical 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
Performance Status 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
Vital signs and Weight 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
Neurologic Exam2 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
LABORATORY/OTHER  EVALUATIONS: 
 
 
 
 
 
 
 
 
 
 Complete Blood Count 
X 
X X 
X 
X 
X 
X 
X 
X 
 
Comprehensive Metabolic Panel 
X 
X X 
X 
X 
X 
X 
X 
X 
 
Pregnancy Test (serum or urine) 
X 
 
 
 
 
 
 
 
 
 
CSF Evaluation 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
LVEF (Echocardiogram or MUGA) 
X 
 
 
 
 
 
 
 
 
 
RADIOLOGIC EVALUATIONS: 
 
 
 
 
 
 
 
 
 
 
Extra-CNS/Systemic Staging 
X 
 
 
 
X 
 
 
 
X 
CNS/Neuroaxis Imaging7 
X 
 
 
X 
 
X 
 
X 
 
X 
TREATMENT ADMINISTRATION:  
 
 
 
 
 
 
 
 
 
 
Tucatinib + Capecitabine + 
Trastuzumab   
 
X X 
X 
X 
X 
X 
X 
X 
 
CORRELATIVE STUDIES: 
 
 
 
 
 
 
 
 
 
 
PK Samples:  Blood and CSF9 
 
X X 
 
 
 
Non-PK Samples: CSF 
 
X X 
X 
X 
X 
X 
X 
X 
X 
Non-PK Samples: Blood 
 
X X 
X 
X 
X 
X 
X 
X 
X 
Symptom/QOL Questionnaires 
 
X X 
X 
X 
X 
X 
X 
X 
X 
 
**The above study calendar reflects 8 cycles of treatment. However, patients who are 
benefiting/responding to therapy may continue on for additional cycles and would undergo the same 
test as noted above at every other cycle.  
 
 


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Screening Tests and Procedures:  
As part of the study screening process, this consent form must be signed.  The following tests and 
procedures will be done during screening to determine if you are eligible to participate in the study. 
It is possible that these tests may show that you can’t take part in the study. If this happens, your 
doctor will discuss these reasons with you.  
 
At Screening/Baseline – within 28 days before enrollment/starting treatment 
After you sign this informed consent form, tests or procedures will be done to find out if you can be 
in the study.  These include the following: 
 
• 
Review of your current symptoms, medications, active medical problems, and your 
medical history 
• 
Physical examination (performed by medical oncologist) 
• 
Neurologic physical exam (performed by a neurologist/neuro-oncologist) 
• 
Vital signs (blood pressure, heart rate, temperature, and breathing rate) 
• 
ECHO (echocardiogram) or MUGA (multiple gated acquisition) scan to measure how 
much blood your heart pumps out with each heartbeat 
• 
Performance status (measurement of how well you can carry out daily activities) 
• 
Blood draws for routine laboratory tests and cancer biomarker studies (approximately 4 
tablespoons). A biomarker is a molecule or cell in your body that can be found in your 
blood, body fluid or tissue and a biomarker can be used to measure your health. 
• 
Cerebral spinal fluid (CSF) standard evaluation – the study doctor will obtain a CSF sample 
to assess cell count, evidence of tumor in fluid, and cancer research biomarkers.    
• 
Blood draw to test for Hepatitis B and Hepatitis C (approximately 2 teaspoons). If this 
test is positive you may be asked to have another test to confirm the first result 
• 
Tumor assessment by CT scan or MRI that takes cross-sectional pictures (slices) of your 
body  
• 
MRI of your brain and spine 
• Pregnancy Test (blood or urine) – only for participants of childbearing potential.  
 
Each cycle visit, Day 1 
• History and physical exam (performed by medical oncologist) 
• Neurologic physical exam (performed by a medical oncologist and/or neurologist/neuro-
oncologist) 
• Performance status 
• Vital signs (blood pressure, heart rate, temperature, and breathing rate) 
• Blood tests – CBC with differential, ALT, AST, alkaline phosphatase, total bilirubin, 
BUN/creatinine. 
• Treatment will be given  
• CSF samples  
• Routine blood samples  
• Symptom Burden and Quality of Life (QOL) Questionnaires  
 
 


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During Cycles 1 and 2 only – Days 1-2 
• Pharmacokinetic (PK) studies to examine study drug levels in blood and CSF 
 
Every 2 cycles (42 days) 
• MRI brain and spine 
 
Every 4 cycles (84 days) 
• CT chest/abdomen/pelvis (CAP) and bone scan or PET/CT 
 
End of Study 
• History and physical exam (performed by medical oncologist) 
• Performance status 
• Vital signs (blood pressure, heart rate, temperature, and breathing rate) 
• Neurologic physical exam (performed by a neuro-oncologist or neurologist) 
• CSF standard evaluation 
• MRI brain and spine 
• Symptom Burden and Quality of Life (QOL) Questionnaires 
 
Biospecimen samples  
 
Biospecimens will be collected in this study. Biospecimens may include any of the following: blood, 
tissue, saliva, urine, bone marrow, cells, CSF, etc.  Most biospecimens contain DNA, which is the 
genetic code for each person. In this study, the planned biospecimen samples are blood and spinal 
fluid. As part of this study, we may collect DNA (genetic information) about you and these data will 
be used for research purposes.  
 
If you would like to review the information for this study, ask the study team doctor for the 
ClinicalTrials.gov study registration number. Also, the results of the trial will be available on the 
Translational Breast Cancer Research Consortium website.  
 
HOW LONG WILL I BE IN THIS STUDY? 
 
The study is expected to last for 3 years. Clinical trial participants will receive treatment until disease 
progression or unacceptable toxicity or death. 
 
Clinical trial participants will be followed every 6 weeks via telephone call and/or chart review for 6 
months after leaving the study, or until death, whichever occurs first. Participants who discontinue the 
study for unacceptable side effects will be followed in the same method.  
In the event that a participant does not continue her post-study care at the clinic, every attempt will be 
made to collect this post study follow up information either by direct contact or through 
communication with your outside physician(s). 
 
 


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WHO WILL BE ON MY PATIENT CARE TEAM DURING THE COURSE OF THE STUDY?  
 
• Breast medical oncologist  
o Perform physical exam (may include neurologic exam) 
o Review blood tests 
o Review imaging studies 
• Neurologist/neuro-oncologist 
o Perform neurologic physical exam 
o Review imaging studies 
o Review CSF studies  
• Procedure list 
o Depending on the institution where you enroll, there may be a separate team who helps 
with collection of CSF from the ommaya reservoir.  
• Study coordinator and/or research nurse 
o Follow-up 
o Coordinate blood tests, imaging studies, collection of research samples, and treatments.  
 
Your breast medical oncologist and neurologist/neuro-oncologist will work together to 
determine if it is safe for you to proceed with the next cycle of treatment and to determine 
disease status and benefit from treatment. If and when you discontinue treatment, the study 
coordinator/research nurse will call you via telephone or review your chart to perform study-
related follow up.  
 
WHAT ARE THE RISKS OF PARTICIPATING IN THE STUDY? 
 
Your condition may not improve and could even worsen if you take part in this study. 
 
You may have side effects as a result of your participation in this study. A side effect is an unwanted 
or unintended problem that may be caused by taking a drug.   
 
If you take tucatinib, capecitabine and trastuzumab certain side effects and discomforts may happen 
after you take tucatinib, capecitabine and trastuzumab. Tucatinib, capecitabine and trastuzumab may 
affect several organs (or parts) of your body including, but not limited to, effects on your cancer cells. 
Side effects that you may have during this study may be minor, life-threatening, or even cause your 
death sooner than would have been expected from your cancer. You may also have other side effects 
that doctors don’t know about yet. Your study doctor and other medical staff will be performing the 
procedures to reduce any side effects that may occur; however, you may have unforeseen side effects. 
You will be monitored closely (with blood tests, physical exams, and heart scans) for any side effects 
and the study therapy will be stopped if serious side effects happen. You will be asked to report any 
side effects or changes in your health to your doctor, no matter how minor the changes may seem to 
you. 
 
 


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Taking other drugs (including alcohol, over-the-counter medications, prescriptions, illegal drugs, 
herbal preparations, or nutritional supplements) may cause additional side effects or even life-
threatening reactions when combined with the drugs or experimental agents used in this study. It is 
very important that you discuss ALL medications that you are taking with your study doctor. 
 
RISKS ASSOCIATED WITH TUCATINIB 
The most common side effects reported in patients with cancer treated with tucatinib include:  
• 
Feeling sick to your stomach (nausea) 
• 
Watery poop (diarrhea) 
• 
Feeling tired (fatigue) 
• 
Throwing up (vomiting) 
• 
Rash 
• 
Difficulty pooping (constipation) 
• 
Cough 
• 
Pain in your arms or legs (pain in the extremity) 
• 
Back pain 
• 
Headache 
• 
Infection that could cause frequent and painful urination (urinary tract infection) 
• 
Muscle pain (myalgia) 
• 
Muscle and bone pain in your chest (musculoskeletal chest pain) 
• 
Belly pain (abdominal pain) 
• 
High levels of liver enzymes (increased liver function tests). This may mean you have a 
problem with your liver. 
• 
Not wanting to eat (anorexia) 
• 
Feeling dizzy (dizziness) 
• 
Feeling out of breath (dyspnea) 
• 
Patchy redness on your skin (erythema) 
• 
Low levels of magnesium in your blood (hypomagnesemia). You may feel weak, have an 
abnormal heartbeat, muscle cramps, or seizures. 
• 
Heavy sweating while sleeping (night sweats) 
• 
Infection in the nose, sinuses or throat (upper respiratory tract infection). You may have 
fever, pain, or a hard time breathing. 
 
Liver Function Problems 
Some patients who took tucatinib had problems with their liver. Your doctor will run tests to 
check that your liver is working properly during your treatment with tucatinib. Your doctor 
may change your tucatinib dose based on the test results. 
 
Diarrhea 
Tucatinib can cause severe watery poop (diarrhea). If you have watery poop, tell your doctor 
right away. Your doctor may change your tucatinib dose if you have watery poop. 
 
 


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Kidney Function Problems 
Some patients who got tucatinib had higher creatinine levels. This could mean that there are 
problems with your kidneys. If this happens, it’s usually within the first treatment cycle. 
Patients who have had increased levels of creatinine had these levels stay increased while 
they were getting treated. The levels went back down after treatment stopped. 
 
Other Important Side Effects 
 
Interactions with Other Medications 
Tucatinib may change how your body reacts to some other drugs, which could stay in your 
body longer than usual. While you are taking part in this study, you might need to stop some 
medications or replace them with other medications. If you can’t stop taking these 
medications, your doctor might need to change how much you take. Your doctor might also 
need to watch your health more closely while you are taking part in this study. 
 
Fertility, Pregnancy, and Breastfeeding Risks 
Tucatinib could hurt or kill a baby developing in the womb. You should not try to get 
pregnant or get your partner pregnant while you are in this clinical trial or for 30 days after 
your last dose of tucatinib.  
If you are pregnant or breastfeeding, you can’t be in this study. We will remove anyone who 
becomes pregnant while on study from the study treatment immediately. 
Tucatinib could hurt a breastfeeding baby. You must not breastfeed during the study or for 30 
days after you stop treatment with tucatinib. 
Tell your study doctor right away if  
• you or your partner become pregnant while you are in this study 
• you think that you are pregnant while taking part in this study 
• you or your partner become pregnant within 30 days after being treated with 
Tucatinib.  
 
Seattle Genetics would like to follow any pregnancy that happens during this study during 
the pregnancy and for some time after the birth of any child. If you give permission, we will 
follow your baby for up to 8 weeks after birth, or longer if there are problems. If your partner 
becomes pregnant, we will ask for their consent to follow their pregnancy and the health of 
the baby. 
RISKS ASSOCIATED WITH CAPECITABINE 
 
The most common side effects associated with capecitabine include: 
• Nausea 
• Diarrhea 
• Abdominal pain 
• Tiredness 


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• Acid reflux 
• Eye tearing 
• Fatigue (tiredness) 
• Changes in taste 
• Mouth sores 
• Hair thinning 
• Hand-foot syndrome (rash or skin changes on the hands and feet)  
• Peripheral neuropathy (numbness and tingling in fingers and toes) 
• Low blood counts 
• Hyperbilirubinemia (abnormal liver function) 
 
Management of capecitabine side effects may include temporary interruption, dose reduction, or 
treatment discontinuation with capecitabine. 
 
RISKS ASSOCIATED WITH TRASTUZUMAB 
 
Trastuzumab has different side effects that your study doctor will discuss with you. The             
most common side effects are: 
 
• Allergic reaction to infusion 
• Nausea/vomiting 
• Tiredness  
• Fever/chills 
• Swelling of the legs and arms 
• Anemia (low red cell count) 
• Neutropenia (low white blood count) 
• 
Congestive heart failure (damage to heart) 
 
Note: Management of left ventricular dysfunction (heart failure), or infusion reactions may include 
temporary interruption or stopping treatment of trastuzumab permanently. 
 
RISKS OF DRAWING BLOOD: 
 
Drawing blood may cause pain, bruising, lightheadedness, and on rare occasions, infection. 
 
MANDATORY OMMAYA RESERVOIR PLACMENT 
 
All patients enrolled on the first stage of the study, MUST undergo MANDATORY placement of an 
ommaya reservoir if you do not already have one in place. An Ommaya reservoir is a small drum-like 
device that is placed under the skin of the skull to give chemotherapy and/or medicines. Placement of 
an Ommaya reservoir is usually recommended as standard of care in patients with newly diagnosed 
leptomeningeal disease and will be covered by your insurance. Although the reservoir is not being 
used to deliver chemotherapy to the brain in this study, it will be useful to assess your response to  


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treatment, as determined by your doctor.  If you have one and/or have one placed, it will also be used 
to collect the study-required CSF samples rather than needing to undergo repeated lumbar punctures. 
To collect samples from the reservoir, it works similar to a port in that it is tapped or accessed with a 
needle to remove or collect CSF fluid.  This fluid is then sent to the lab to detect any abnormal cells 
or collected for the research study. The risks of drawing CSF fluid are also as noted above. Your doctor 
can explain the standard of care ommaya reservoir placement procedure and discuss the risks with 
you. 
 
How is the Ommaya reservoir is placed? 
 
An Ommaya reservoir is implanted by a brain surgeon while you’re under general anesthesia. 
 
Preparation: 
 
Getting an Ommaya reservoir implanted does require some preparation, such as: 
 
• 
Not drinking alcohol once the procedure is scheduled 
• 
Not taking vitamin E supplements within 10 days of the procedure 
• 
Not taking aspirin or medications containing aspirin during the week before the procedure 
• 
Telling your doctor about any additional medications or herbal supplements you take 
• 
Following your doctor’s guidelines about eating and drinking before the procedure 
 
Recovery 
 
Once the Ommaya reservoir is placed, you’ll feel a small bump on your head where the reservoir is. 
You’ll likely need a CT scan or an MRI scan within a day of your surgery to make sure it’s correctly 
placed. If it needs to be adjusted, you may need a second procedure. 
 
While you recover, keep the area around the incision dry and clean until your staples or stitches are 
removed. Be sure to tell your doctor about any signs of infection, such as: 
 
• 
Fever 
• 
Headaches 
• 
Redness or tenderness near the incision site 
• 
Oozing near the incision site 
• 
Vomiting 
• 
Neck stiffness 
• 
Fatigue 
 
Once you have healed from the procedure, you can return to all of your normal activities. Ommaya 
reservoirs don’t require any care or maintenance. 
 
 


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Is it safe? 
 
Ommaya reservoirs are generally safe. However, the procedure to place them carries the same risks 
as any other surgery involving your brain, including: 
 
• 
Infection 
• 
Bleeding into your brain 
• 
Partial loss of brain function 
To prevent infection, your doctor might prescribe you antibiotics following the procedure. Talk to 
your doctor about any concerns you have about complications. They can go over their approach with 
you and let you know about any additional steps they’ll take to lower your risk of having 
complications. 
 
Can it be removed? 
Ommaya reservoirs usually aren’t removed unless they cause problems, such as an infection. 
Though at some point in the future you may no longer need your Ommaya reservoir, the process to 
remove it carries the same risks as the process to implant it. Generally, removing it isn’t worth the 
risk. 
 
If you have an Ommaya reservoir and are considering having it removed, make sure you go over the 
potential risks with your doctor. 
 
RISK OF DRAWING CSF FROM OMMAYA RESERVOIR  
 
• Pain 
• Bleeding 
• Infection 
• Headache 
• Nausea/Vomiting 
• Others as explained to me by my doctor 
 
o Note: This procedure is required for the first stage or the first 15 patients to enroll on 
the study so that your CSF can be collected for standard evaluation and to study drug 
levels in the fluid. If you are enrolling in the study on the 2nd stage, it is strongly 
recommended that you have an ommaya reservoir placed to help with collection of 
your CSF during the study for standard evaluations, which help determine if you are 
responding to the treatment. Alternatively, this can be done via lumbar puncture. 
Your study doctor will clearly discuss the stage of the study in which you will be 
enrolled. 
 
 


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RISK OF DRAWING CSF FROM OMMAYA RESERVOIR OR VIA LUMBAR 
PUNCTURE:  
 
• Pain 
• Bleeding 
• Infection 
• Headache 
• Nausea/Vomiting 
• Others as explained to you during the procedure 
 
RADIATION RISKS ASSOCIATED WITH SCANS AND X-RAYS: 
 
While you are in this research study, CT scans, PET/CT scans, bone scans, x-rays, and/or other 
radioactive agents may be used to evaluate your disease status. The frequency of these exams is similar 
to that which you would receive as standard care.  There is thought to be a small but increased risk of 
cancers associated with radiation in the long term over many years.  
 
Risks Associated with CT Scans: 
 
In this study, you will be exposed to some radiation from the CT scan[s]. The total radiation from each 
[combined chest, abdominal and pelvic] CT scan is approximately equal to [five years] of exposure to 
natural background radiation. Background radiation is radiation normally received from sources such 
as cosmic rays and natural radioactivity in building materials and the ground. There is a small risk that 
the radiation may cause cancer or other radiation effects in several years. 
 
To prepare you for your CT scan, a liquid called a “contrast dye” may be injected into your veins to 
improve the quality of the image.   There is a small possibility that you could have a severe allergic 
reaction to this dye that could cause injury or death.  If you have any kidney problems, the dye may 
cause other medical problems. 
 
• If you have any kidney problems or have ever had an allergic reaction to contrast dye, you must let 
the study physician know as soon as possible. 
  
RISKS ASSOCIATED WITH MRI SCANS:  
 
When having an MRI (Magnetic Resonance Imaging) scan, you will lie still on a table that slides into 
a tunnel slightly wider than your body. People who feel uncomfortable in confined spaces 
(claustrophobia) may feel uncomfortable in the narrow cylinder. If you feel uncomfortable in confined 
spaces, please tell your doctor. Your doctor may give you a medication to make you feel more 
comfortable in a confined space. A magnetic resonance imaging (MRI) exam is a test that uses 
magnetic fields and radio waves to generate images of the inside of your body.  You will be placed 
inside a scanner and asked to lie still for approximately 30 minutes.  This is a noisy exam; you will be 
given earplugs to protect your hearing. During the scan, a liquid will be injected into your vein to  


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improve the quality of the scan. 
  
MRI has negligible risks for most people; however, if you have any metal objects in your body MRI 
may not be safe for you and you will not be allowed to take part in this study. 
 
RISKS ASSOCIATED WITH MRI SCANS WITH GADOLINIUM AS A CONTRAST AGENT:  
 
A few side effects of gadolinium injection such as mild headache, nausea, and local pain may occur. 
Rarely (less than 1% of the time), low blood pressure and lightheadedness occurs. This can be treated 
immediately with intravenous fluids. Very rarely (less than on in one thousand), patients are allergic 
to gadolinium. These effects are most commonly hives and itchy eyes, but more severe reactions have 
been seen which result in shortness of breath. 
Patients with severe kidney disease sometimes have a bad reaction to gadolinium contrast. The 
condition is called nephrogenic sclerosing fibrosis (NSF). It can cause skin to tighten or scar and can 
damage internal organs. Sometimes it can be life threatening. There are no reports of NSF in patients 
with normal kidney function. Before you have a MRI scan requiring an injection of gadolinium 
contrast, you will have a blood test in order to check the function of your kidneys. Based on your 
medical history and the results of the test, a doctor will decide whether it is safe for you to undergo 
the MRI scans.   
 
REPRODUCTIVE RISKS:  
 
We do not know if the study drug will affect mother’s milk or an unborn fetus. Therefore, breast-
feeding and pregnant women are not allowed to take part in the study. If you are pregnant or become 
pregnant, there may be risks to the embryo or fetus. Administration of the drug resulted in harm to the 
fetus of pregnant animals and could cause harm or death to a baby developing in the womb. Women 
who can become pregnant must take a pregnancy test before the start of the study. 
While participating in this research study, you should not become pregnant or father a child, and should 
not nurse a baby as the treatment may indirectly affect an unborn child. If you are sexually active and 
are at risk of causing a pregnancy, you and your female partner(s) must use a method to avoid 
pregnancy that works well or you must not have sex. 
 
You must agree to use an adequate method of birth control during the study (such as surgical 
sterilization, IUDs or abstinence). Barrier methods such as diaphragms or condoms may also be used 
if a spermicide is used with them.  Women cannot use birth control pills due to effects that they cause 
on breast cancer.   
 
If you think you may be pregnant (have a missed or late menstrual period) at any time during this 
study, you must let the study doctor know immediately.  Women who become pregnant will be 
removed from the study.  Let your doctor know immediately if you become pregnant or find out that 
you are going to be the father of a child.  
 
 


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Birth Control Requirements 
 
If you can get pregnant, you must use a safe birth control method while you are taking part in this 
study. Safe birth control methods fail less than 1% of the time. This means that if 100 people used this 
birth control for a whole year, at most 1 person would get pregnant. You must use safe birth control 
methods while you take part in the study and keep using them for 30 days after stopping all study 
treatment. If you don’t use safe birth control methods while you take part in the study, we might decide 
that you can’t take part in the study anymore. 
The safe birth control methods that you can use are:  
• hormonal methods that have both estrogen and progestogen. These can be taken by mouth 
(birth control pills), inserted into the vagina, or absorbed through the skin (patches). 
hormonal methods that have only progestogen. These can be taken by mouth (birth control 
pills), injected, or implanted in your body. 
• intrauterine device (IUD) 
• intrauterine hormone-releasing system 
• tubal ligation for females (“tubes tied”) 
• vasectomy for males 
 
Talk with your doctor about your birth control options. You may also choose to not be sexually active 
(complete abstinence) while you take part in the study. 
 
If you are able to get someone pregnant, and your partner is able to get pregnant, you must use a barrier 
method such as a male or female condom when you are taking part in the study. You must keep using 
a barrier method for 30 days after finishing treatment with tucatinib. 
 
 
If you think you may be pregnant (have a missed or late menstrual period) at any time during this 
study, you must let the study doctor know immediately.  Women who become pregnant will be 
removed from the study.  Let your doctor know immediately if you become pregnant or find out that 
you are going to be the father of a child.  
 
Fertility Risks 
It is not known if patients in this trial will have problems getting pregnant after taking tucatinib.  
 
DRUG INTERACTIONS:  
 
The other medications you take may affect the study drug(s) in ways that we do not know.  For your 
safety, you must tell the study doctor or nurse about all the prescription drugs, herbal products, over-
the-counter (OTC) drugs, vitamins, and natural remedies that you are taking before you start the study 
and before taking any of these products while you are on the study.  Please be sure to tell us also about 
any changes you make with your medications during your participation. 
 
 


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QUESTIONNAIRES: 
 
The research study questionnaires ask about quality of life, including emotional issues.  On average, 
they are expected to take you approximately 30 minutes to complete.  Answering some of these 
questions may cause discomfort. You may choose not to answer one or any of the questions on the 
questionnaires. If you choose not to answer any questions, it will not negatively affect your status as 
a participant.  If one of the questionnaires that you are asked to fill out upsets you, please tell the 
research assistant who gave you the forms to fill out.    
 
NON-PHYSICAL RISKS:  
 
Because of side effects or the time required for tests and clinic visits while you are on this research 
study, you may be unable to keep up with your normal daily activities.  
 
During the research study, you will be provided with any new information that may affect your 
health or willingness to participate.  You may be asked to sign a new consent form that shows that 
you have been informed of new information relating to this research study. 
 
RISKS ASSOCIATED WITH GENOMIC TESTING 
 
Despite the GINA protections and the best efforts of the research team, there may still be a risk if 
information about you were to become known to people outside of this study. 
 
Genetic information is unique to you, even without your name or other identifiers. For this reason, 
genetic information like DNA may be used to identify you and possibly your family members.  We 
have procedures (such as, labeling your biospecimens with a password protected code known only to 
select research staff) to prevent people working with your DNA from discovering if it belongs to you. 
However, there is the risk this can happen as new ways of tracing genetic information are being 
developed that may make re-identification of genetic information possible. 
 
BENEFITS  
 
Taking part in this research study may or may not make your health better.  We hope the information 
learned from this research study will help doctors learn more about the combination of tucatinib and 
trastuzumab with capecitabine as a treatment for breast cancer in the future.  We hope the information 
learned from this research study will help breast cancer patients in the future. 
 
ALTERNATIVES 
 
There are other options to treat metastatic HER2 positive breast cancer with leptomeningeal disease 
that may include radiation, chemotherapy injected through the spinal canal, or chemotherapy given 
intravenously. Your doctor will discuss these other options with you. 
 
 


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SIGNIFICANT NEW FINDINGS 
 
You will be told by your doctor or the study staff if new information becomes available that might 
affect your choice to stay in the study. 
 
CONFIDENTIALITY 
 
Information obtained about you for this study will be kept confidential to the extent allowed by law. 
However, research information that identifies you may be shared with the UAB Institutional Review 
Board (IRB) and others who are responsible for ensuring compliance with laws and regulations related 
to research, including people on behalf of MD Anderson Cancer Center, Seattle Genetics, Inc., and 
Johns Hopkins University on behalf of the TBCRC; the Office for Human Research Protections 
(OHRP) and FDA. The information from the research may be published for scientific purposes; 
however, your identity will not be given out. This consent document will be placed in your file at UAB 
and the document will become part of your medical record chart. 
 
Information relating to this study, including your name, medical record number, date of birth and 
social security number, may be shared with the billing offices of UAB and UAB Health System  
 
affiliated entities so that the costs for clinical services can be appropriately paid for by either the study 
account or by the patient/patient’s insurance. 
 
Your medical record may indicate that you are on a clinical trial and will provide the name and contact 
information for the principal investigator. 
 
Monitors, auditors, the Institutional Review Board for Human Use, and regulatory authorities will be 
granted direct access to your original medical records for verification of trial procedures and/or data 
without violating confidentiality. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
U.S. Law. This Web site will not include information that can identify you. At most, the Web site will 
include a summary of the results. You can search this Web site at any time. 
 
A federal law, called the Genetic Information Nondiscrimination Act (GINA), generally makes it 
illegal for health insurance companies, group health plans, and most employers to discriminate against 
you based on your genetic information. This law generally will protect you in the following ways: 
 
• 
Health insurance companies and group health plans may not request your genetic information 
that we get from this research. 
• 
Health insurance companies and group health plans may not use your genetic information when 
making decisions regarding your eligibility or premiums. 
• 
Employers with 15 or more employees may not use your genetic information that we get from 
this research when making a decision to hire, promote, or fire you or when setting the terms of 
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Be aware that this new federal law does not protect you against genetic discrimination by companies 
that sell life insurance, disability insurance, or long-term care insurance, nor does it protect you against 
genetic discrimination by all employers. 
 
VOLUNTARY PARTICIPATION AND WITHDRAWAL 
 
Whether or not you take part in this study is your choice. There will be no penalty if you decide not to 
be in the study. If you decide not to be in the study, you will not lose any benefits you are otherwise 
owed. You are free to withdraw from this research study at any time. Your choice to leave the study 
will not affect your relationship with this institution. However, you should return to see the study 
doctor for safety reasons so you can be taken off the study drug and referred for follow-up care.  
 
You may be removed from the study without your consent if the study doctor decides it is not in the 
best interest of your health, or if you are not following the study rules. 
 
WHAT ARE MY COSTS FOR PARTICIPATING IN THIS STUDY? 
 
If you participate in this study, there may be additional costs to you. Participation in this study is not 
a substitute for health insurance. You, or your insurance company, will be responsible for paying for 
standard of care expenses associated with your cancer. Standard of care expenses are routine treatment 
costs you would have incurred even if you were not in the study (such as blood tests, X-rays, CT or 
MRI scans, or physician’s charges) and those used to manage or treat side effects of your cancer (such 
as transfusions, anti-nausea drugs, etc.). For this study, capecitabine and trastuzumab are also 
considered standard of care. Your insurance company may not pay for the standard of care costs when 
they are associated with studies like this one. You will be responsible for all of the costs linked with 
this study that are related to standard of care and not covered by other payers (HMO, health insurance 
company, etc.). You will be responsible for any co-payments or deductibles required by your insurance 
company.    
 
The study will pay for the following items while you participate in this study: 
• Tucatinib 
• Any study-related procedures which are required solely for this study and which are not 
considered standard of care 
 
If you are in Medicare Advantage (Medicare managed care plan), you should contact someone at 
your plan before you start a clinical trial. They can provide more information about additional costs 
you could incur from participating in clinical trials.   
 
WHAT ARE MY RIGHTS IF I TAKE PART IN THIS STUDY? 
 
If you take part in this study, you may leave the study at any time. No matter what decision you 
make, there will be no penalty to you and you will not lose any of your regular benefits. Leaving the 
study will not affect your medical care. You can still get your medical care from your medical team. 
 
 


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By signing this form, you do not waive any of your legal rights to seek payment in the case of 
injuries resulting from this study.  
   
The treating institution will receive direct and indirect payment from Seattle Genetics, Inc. and Johns 
Hopkins University on behalf of the TBCRC (the study supporters) for their time spent doing research 
and general administrative services for this study. Seattle Genetics, Inc., and other company(ies) 
involved in the research studies done on blood and tissue samples may benefit financially from this 
research. You will receive no financial benefit from this research.  
 
If you decide to sign this consent form, you are giving your bodily fluids and tissue samples collected 
during the study and any new drugs that may be developed from your fluids or samples.  
WILL I BE PAID FOR TAKING PART IN THIS STUDY? 
 
You will not be paid for taking part in this study. 
 
WHAT HAPPENS IF I AM INJURED BECAUSE I TOOK PART IN THIS STUDY? 
 
Side effects or harm are possible in any research study, and you might be injured or develop medical 
complications because you take part in this study.  Medical complications could occur through no fault 
of yours or the study doctors involved. Known side effects have been described in this consent form, 
and there may also be unexpected side effects. It is important that you tell your study doctor if you 
feel that you have been injured because of taking part in this study.  
 
In the event you have an injury, the treating hospital will offer you the care needed to treat injuries 
directly resulting from taking part in this research.  These treatments will be billed to your insurance 
company. You will be responsible for deductibles and co-payments. There are no plans to pay you or 
give you other compensation for the injury. 
 
Your health insurance company may or may not pay for treatment of injuries as a result of your taking 
part in this study.  You should consult with your insurance company if you have questions. Additional 
reimbursement or compensation for study-related injuries (such as payments for costs like lost wages, 
or for pain and suffering, or for expenses other than medical care) are not provided. 
 
You do not give up any of your legal rights to seek payment for study-related injuries by signing this 
form or by agreeing to participate in this study. 
 
HOW WILL I BE INFORMED OF TRIAL RESULTS? 
 
You will not be informed of the trial results. After the trial is completed, a summary of the results will 
be posted on the TBCRC (Translational breast cancer consortium) website. Additionally, you may 
visit clinicaltrials.gov and look up the trial with the NCI trial number. This can be provided to you 
from your medical team.  
 
 


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WILL I HAVE ACCESS TO THE STUDY DRUGS AFTER THE TRIAL IS OVER? 
 
You will have access to the treatment until the time of disease progression, death, or unacceptable 
toxicity. However, it is possible that the trial may be discontinued early by the sponsor and research 
team if the combination is found to be unsafe or if it is determined to not be working well.  
 
The trial may be stopped after the first 15 patients are enrolled if there are fewer than 2 patients with 
response to study therapy in the leptomeningeal disease. In the event, the trial is stopped for this reason, 
you will be allowed to continue on study as long as the treatment is continuing to benefit you; however, 
no additional patients will be allowed to enroll on the study.   
 
QUESTIONS 
 
If you have any questions, concerns, or complaints about the research or a research- related injury 
including available treatments, you may contact Dr. Erica Stringer-Reasor. She will be glad to answer 
any of your questions. Dr. Stringer-Reasor’s number is 205-975-2816. She may also be reached after 
hours by paging at 205-934-3411. 
 
If you have questions about your rights as a research participant, or concerns or complaints about the 
research, you may contact the UAB Office of the IRB (OIRB) at (205) 934-3789 or toll free at 1-855-
860-3789. Regular hours for the OIRB are 8:00 a.m. to 5:00 p.m. CT, Monday through Friday. You 
may also call this number in the event the research staff cannot be reached or you wish to talk to 
someone else. 
 
WHAT ARE MY LEGAL RIGHTS? 
 
You are not waiving any of your legal rights by signing this informed consent document. 
 
BIOSPECIMENS FOR RESEARCH 
 
Your bio-specimens (tissue and blood samples) are being used for this research study.  As part of the 
study, we may perform the following research studies on them.  In addition, we will ask your 
permission in the next section for the use of any leftover bio-specimens (that is, samples remaining or 
“leftover” after the research for this study is completed) to be used for future research and the option 
to contact you in the future.   
 
We may use genetic analysis in some of the research we do on your samples. Researchers can learn a 
lot by studying genes. Genes are pieces of DNA that give instructions for building the proteins that 
make our bodies work. DNA stores these instructions in the form of a code. This is the code that you 
inherit from your parents and that you pass on to your children.  
 
One of the methods we might use to study your samples is called whole genome sequencing. This 
allows us to look at some or all of your genetic code. Researchers may also use other methods as they 
are developed. Studying genes along with your health information will help us to better understand  
 
 


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what causes certain diseases. It may also help us to understand how different patients respond to 
treatment. This knowledge could help us to develop treatments for everyone.   
 
What we learn about you from your samples will not be put in your health record and will not be 
shared with you or your doctor.  No one else (like a relative, boss, or insurance company) will be given 
your test results.  Your samples will only be used for research and will not be sold.  Health insurance 
companies and group health plans may not request your genetic information that comes from this 
research.  
 
We will remove your name and any other information that could directly identify you from your 
samples and information.  We will replace this information with codes.  We will keep a master list that 
links those codes to your materials.  Only certain study staff can access this master list.  We will keep 
the samples in locked freezers in locked buildings. We will keep health information and research data 
on secure computers.  These computers have many levels of protection. 
 
The Genetic Information Nondiscrimination Act (GINA) may help protect you from health insurance 
or health-related employment discrimination based on genetic information.  The law provides that 
health insurance companies and group health plans: 
  
• May not ask for genetic information from this research and  
• May not use genetic information when making decision about eligibility or premiums 
 
The law will not stop health insurance companies from using genetic information to decide whether 
to pay claims. The law does not apply to other types of insurance (such as life, disability or long-term 
care).  
 
Despite the GINA protections and the best efforts of the research team to protect your information, 
you may still be at risk if information about you were to become known to people outside of this study. 
   
Q. WHAT ABOUT USE OF MY TISSUE AND BLOOD FOR FUTURE RESEARCH? - OPTIONAL 
 
If part of the tissue from the required biopsies or blood from the required draws in this study as 
described above is leftover after the proposed tests are done, we ask you to donate those left over 
samples for future research.  If you do not want to take part in this optional portion of this study, 
you may still take part in the main study as described above.   
 
If you agree, your samples and information about you may be made available to others to use for 
research.  To protect your privacy, we will not release your name.  You will not receive any benefit 
as a result of the tests done on your samples.   
 
What research will be done on my leftover samples and what information will be collected? 
The future research may also include looking at genes (DNA) and how they affect health and 
disease.  These tests may help us learn more about the causes, risks, treatments, or how to prevent 
this and other health problems. 
 
 


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In addition to your samples we will store some basic information about you. This will include 
things like age, sex, and race or ethnic group. We will store information about your family’s health 
history. If you agree, we will collect this information from your medical record. 
 
We will also collect information from your medical record that is related to your health and/or 
disease history. Some examples include results of tests, medical procedures, images (such as X-
rays), and medicines you take. Researchers will use this information to better understand how 
genes affect health and response to treatment. We will look at your medical record from time to 
time to update this information. This will take place for as long as your sample is stored, which 
may be many years, unless you tell us to stop. 
 
Who will have access to my leftover samples and information? 
We will store your samples and information in a tissue bank.  Your samples will be coded similarly 
as described previously.   
 
Researchers can ask to study the materials stored in the tissue bank.  This includes researchers 
from within the TBCRC Institutions, as well as from other universities, the government, and drug 
or health companies.  Some researchers will be from the U.S.; some may be from other countries 
around the world.  An oversight committee will review each request.   
This kind of review is to make sure that any risks are minimized and that your rights and welfare 
are protected.  If a study is approved, we might give a part of your sample and information to the 
researchers.  We would give them your materials along with samples and information from many 
other people.  We may also share your materials with other tissue bank and research projects. We 
will not share information that could directly identify you (like your name, social security number, 
and address) without your permission.  
 
There is no limit on the length of time we will store your samples and information. We may keep 
using them for research indefinitely unless you decide to withdraw from the project. 
 
Who else will have access to my genetic information?  
Researchers can do more powerful studies when they share with each other the information they 
get from studying human samples.  They share this information with each other by putting it into 
scientific databases.  These databases store information from many studies conducted in many 
different places.  Researchers can then study the combined information to learn even more about 
health and many different diseases. 
 
There are different kinds of databases; some are publicly accessible and some are restricted.  
Anyone on the Internet can access publicly accessible databases.  Only researchers who apply and 
are approved can access restricted databases.  There are many restricted databases; the researchers 
in this study maintain some, the federal government maintains some, and private companies 
maintain some. Some of your genetic and health information could be placed into one or more of 
these publicly accessible or restricted databases.  
 
Your name and other information that could directly identify you (such as address or social security 
number) will not be placed into any scientific database.   


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However, because your genetic information is unique to you, there is a small chance that someone 
could trace it back to you.  The risk of this happening is very small, but may grow in the future.  
Researchers will always have a duty to protect your privacy and to keep your information 
confidential.  
 
Will I find out the results of the research?  
You should not expect to get personal results from research done through the tissue bank.  
Researchers will study samples and information from many people and it may take many years 
before they know the results or if they have any meaning.  However, it is possible that researchers 
will learn something that might be important to your health, such as results of genetic or similar 
testing done on your samples.  We expect these situations to be very rare.  If this happens, we will 
 seek appropriate approvals from the IRB and/or ethics committee and may contact you directly or 
through your doctor to find out if you would like to learn more. However, even if we find 
something important to your health, we cannot guarantee that you will be contacted. The findings 
may lead to additional testing or changes to your care, and could be a stressful situation to you and 
your family.  If this happens, care will be taken to make sure the findings are carefully explained 
and that support is available for you. 
 
Will this future research cost me anything or will I be paid? 
You will not be asked to pay any costs related to this research.  You will not be paid for agreeing 
to allow your samples to be used for future research.   
 
The research done with your tissue and blood may lead to the development of new products in the 
future.  You will not own any product or idea created by the researchers working on blood or tissue 
obtained from you during this study.  You will not receive any financial benefit from the creation, 
use or sale of such a product or idea from blood or tissue obtained from you during this study. 
 
Your tissue and blood will be used only for research and will not be sold. 
 
What are the risks? 
One risk of giving samples for this research may be the accidental release of your name that could 
link you to the stored samples and/or the release of results of the tests run on your samples, 
including genetic testing.  There are safeguards in place such as coding your samples and 
information, secure buildings and equipment, and the Genetic Information Nondiscrimination Act 
(GINA) as described previously.   
 
What are the benefits? 
You will not receive any benefit as a result of the tests done on your samples.  These tests may 
help us learn more about the causes, risks, treatments, or how to prevent this and other health 
problems. 
 
Will I be contacted in the future about this or other research?  
We, the local site Study Team, may want to contact you in the future.  You can decide now whether 
or not you want to be contacted.  You can also change your mind later.  


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If you agree, we may contact you for several reasons.  For example, over time, stored samples may 
be used up or decrease in quality, so we may contact you to ask for more samples.  We may also 
contact you to update basic information or request information about your health.  
 
Additionally, we may want to contact you to see if you want to participate in other research.  We 
will not notify you every time your samples and information are used.  However, some researchers 
might apply to do a study for which they would need to contact you.  For example, they might 
want to ask you to give another sample or to fill out a survey, or they might ask you to do a phone 
interview or come in to be seen by a researcher or doctor.  If a study like this is approved, someone 
from this project will contact you.  They will tell you about the study so you can decide if you 
want to receive more information.  There will be a new consent process just for that study.  You 
can decide then to take part or not take part.  If at any time you decide you no longer want to be 
contacted about future studies, please tell us. 
 
Can I change my mind after I agree to let my samples be used? 
You have the right change your mind about the future use of your leftover bio-specimens and 
information at any time.  If you want to leave the project, let us know.  You will be given some 
options and can choose what you want us to do with your unused samples.  You can also tell us to 
stop using your medical records.  However, you cannot withdraw your samples and information 
from studies that have already begun.  We cannot get samples and information back once they are 
shared with other researchers.  In addition, it may not be possible to remove your genetic 
information from scientific databases once it has been de-identified. 
MAKING YOUR DECISION 
You have a say in how your leftover bio-specimens and information are used in future research.  
Donating samples for future research is your choice and you may be in the study even if you do 
not want your samples used or stored for future research. 
 
Please review each question below and choose the answer that is best for you: 
 
1. I permit leftover samples to be stored and used for future research to learn about, prevent, or 
treat cancer. 
 
  Yes   
 No    Please initial here:    
 
 
Date:    
 
 
 
 
2. I permit my samples to be stored and used for future research about other health problems (for 
example:  causes of diabetes, heart disease, and Alzheimer’s, or genetic links to alcoholism). 
 
  Yes   
 No    Please initial here:    
 
 
Date:    
 
 
 
 
3. I agree that someone may contact me in the future to ask me to take part in more research. 
 
  Yes   
 No    Please initial here:    
 
 
Date:    
 
 
 


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4. I agree to have my coded genetic information and coded medical information placed in 
password-protected secured databases for research analyses. 
 
  Yes   
 No    Please initial here:    
 
 
Date:    
 
 
 
 
SIGNATURES 
 
Your signature below indicates you agree to participate in this study. You will receive a copy of this 
signed consent form. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Participant 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Person Obtaining Informed Consent 
                                               Date 
 
 
 
 
                                                                                            
 
 


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University of Alabama at Birmingham 
AUTHORIZATION FOR USE/DISCLOSURE OF  
PROTECTED HEALTH INFORMATION (PHI) FOR RESEARCH 
 
Participant Name:   
 
_____________ 
UAB IRB Protocol Number:  IRB-300000290 
Research Protocol: A phase 2 non-randomized study to 
assess the safety and efficacy of the combination of tucatinib  
and trastuzumab with capecitabine for treatment of 
leptomeningeal metastases in HER2-neu positive breast 
cancer 
Principal Investigator:  Erica Stringer-Reasor, M.D. 
 
Sponsor:  University of Alabama at Birmingham  
 
 
What is the purpose of this form?  You are being asked to sign this form so that UAB may use and release your protected health information 
for research.  Participation in research is voluntary.  If you choose to participate in the research, you must sign this form so that your protected 
health information may be used for the research. 
 
Why do the researchers want my protected health information?  The researchers want to use your protected health information as part of 
the research protocol listed above and as described to you in the informed consent. 
 
What protected health information do the researchers want to use?  All medical information, including but not limited to information and/or 
records of any diagnosis or treatment of disease or condition, which may include sexually transmitted diseases (e.g., HIV, etc.) or communicable 
diseases, drug/alcohol dependency, etc.; all personal identifiers, including but not limited to your name, social security number, medical record 
number, date of birth, dates of service, etc.; any past, present, and future history, examinations, laboratory results, imaging studies and reports 
and treatments of whatever kind, including but not limited to drug/alcohol treatment, psychiatric/psychological treatment; financial/billing 
information, including but not limited to copies of your medical bills,  and any other information related to or collected for use in the research 
protocol, regardless of whether the information was collected for research or non-research (e.g., treatment) purposes. 
 
Who will disclose, use and/or receive my protected health information?  All Individuals/entities listed in the informed consent documents, 
including but not limited to, the physicians, nurses and staff and others performing services related to the research (whether at UAB or 
elsewhere); other operating units of UAB, HSF, UAB Highlands, Children’s of Alabama, Eye Foundation Hospital, and the Jefferson County 
Department of Health, as necessary for their operations; the IRB and its staff; the sponsor of the research, and its employees and agents, including 
any CRO; and any outside regulatory agencies, such as the Food and Drug Administration, MD Anderson Cancer Center, Seattle Genetics Inc., 
Johns Hopkins University on behalf of the Translational Breast Cancer Research Consortium (TBCRC), providing oversight or performing other 
legal and/or regulatory functions for which access to participant information is required. 
 
How will my protected health information be protected once it is given to others?  Your protected health information that is given to the 
study sponsor will remain private to the extent possible, even though the study sponsor is not required to follow the federal privacy laws. 
However, once your information is given to other organizations that are not required to follow federal privacy laws, we cannot assure that the 
information will remain protected. 
 
How long will this Authorization last?  Your authorization for the uses and disclosures described in this Authorization does not have an 
expiration date. 
Can I cancel this Authorization?  You may cancel this Authorization at any time by notifying the Principal Investigator, in writing, referencing 
the research protocol and IRB Protocol Number. If you cancel this Authorization, the study doctor and staff will not use any new health 
information for research. However, researchers may continue to use the protected health information that was provided before you cancelled 
your authorization. 
Can I see my protected health information?  You have a right to request to see your protected health information. However, to ensure the 
scientific integrity of the research, you will not be able to review the research information until after the research protocol has been completed. 
Signature of participant:  
 
 
 
 
 
 
 
Date:  
 
 
or participant's legally authorized representative:  
 
 
 
 
 
Date:  
 
 
Printed Name of participant’s representative:  
 
 
 
 
 
Relationship to the participant: