An Open Label, Pilot Study of Veliparib (ABT-888) and Lapatinib (Tykerb) in Patients With Metastatic, Triple Negative (ER, PR, and HER-2 Negative) Breast Cancer
Phase: NA
Conditions: Metastatic Triple Negative Breast Cancer
Sponsor: University of Alabama at Birmingham

 
UAB1372 Cover Page                                                                                                                                  Page 1 of 1  
                CT.gov document submission 
 
 
 
 
 
 
 
 
 
COVER PAGE 
 
 
 
 
DATE: 
        25 February 2025 
 
CT.gov  
IDENTIFIER:       NCT02158507 
 
            SPONSOR:            Erica Stringer-Reasor, MD 
          University of Alabama at Birmingham 
 
PROTOCOL:        An open label, pilot study of Veliparb (ABT-888) and Lapatinib (Tykerb) in  
patients with metastatic, triple negative (ER, PR, and HER-2 Negative) 
Breast Cancer 
 
            RE:                        Document Submission 
 
 
 
 
Study documents included in this submission: 
 
 
Cover Page 
 
 
Protocol Version 12.12.18 
 
 
Statistical Analysis (included in the attached protocol under Section 7.0 – 7.7) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 1 
 
 
COMPREHENSIVE CANCER CENTER 
UNIVERSITY OF ALABAMA AT BIRMINGHAM 
BIRMINGHAM, ALABAMA 
 
UAB 1372: An Open Label, Pilot Study of Veliparib (ABT-888) and Lapatinib (Tykerb) in Patients 
with Metastatic, Triple Negative (ER, PR, and HER-2 Negative) Breast Cancer 
 
Table of Contents: 
1.0 
Objectives of the study 
 
2.0 
Background and rationale 
 
3.0 
Study design 
 
4.0 
Patient selection criteria 
 
5.0 
Drug information 
 
6.0 
Treatment plan 
 
7.0 
Statistical considerations 
 
8.0 
Administrative Rules of the Protocol 
 
9.0 
Assessment of Safety 
 
10.0 
Bibliography 
 
Appendices: 
A.  
Toxicity criteria 
B.            ECOG performance status criteria 
C.            FDA MedWatch 3500A form 
D.  
RECIST criteria version 1.1 
E.  
Blood and Biopsy Procedures 
F. 
SOP for Investigator INDs Held by Physician Members of the 
UAB Comprehensive cancer Center 
G.        
Prohibited Medications 
H.       
Suggested Management of Dermatologic Toxicities 
I.            Diarrhea Management Guidelines 
 
 
 
 
 
 
 
CTRC Approval Date 
IRB Approval Date 
 
 
 
 
 
 
 
 
 
 
Erica M. Stringer- Reasor, M. D. 
   
    Scariot Foundation, Novartis__________                          
                                                                                     Pharmaceuticals Corporation, Abbvie 
 
 
PRINCIPAL INVESTIGATOR 
RESEARCH SUPPORT 
 
                                                     Veliparib (ABT-888); IND#061362 
 
Eddy S. Yang, M.D., Ph.D. 
 
 
Lapatinib (Tykerb); IND#77,104 
 
    CO-PRINCIPAL INVESTIGATOR 
 
 
STUDY AGENT 
 
               Pamela Dixon, R.N., B.S. N., O.C.N. 
          Valerie Caterinnichia, R.N., B.S.N., O.C.N.                       
 
                COORDINATORS 
 
 
DATA MANAGER 
 
 
Yufeng Li, Ph.D. 
STATISTICIAN 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 2 
 
 
 
 
 
  Christos Vaklavas,, M.D. 
 
Carolina Salvador,M.D. 
 
 
       Carla Falkson, M.D.                                     Lisle Nabell, M.D. 
 
Helen Krontiras, M.D. 
 
  
                        Gabrielle Rocque, M.D. 
     
UAB SUB-INVESTIGATORS 
 
 
 
 
                                       
          None 
 
 
 
SITE PARTICIPANTS 
 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 3 
 
 
1.0 
OBJECTIVES OF STUDY 
 
1.1 
Primary Objective 
 
In patients with metastatic, estrogen receptor (ER) negative, progesterone receptor (PR) negative, 
and human epidermal growth factor receptor 2 (HER-2-Neu) negative breast cancer (called triple 
negative breast cancer or TNBC), we will: 
 
 Characterize the safety profile and treatment tolerance of Veliparib (ABT-888) in combination 
with Lapatinib (Tykerb). 
 
1.2 
Secondary Objectives 
 
In patients with metastatic TNBC, who will be treated with the combination of Veliparib and 
Lapatinib, we will: 
 
 Estimate the objective response rate (ORR) (complete responses [CRs] plus partial responses 
[PRs]);  
 
 Determine progression free survival (PFS); 
 
 Correlate pre-treatment tumor gene expression profile, biomarkers of DNA repair (H2AX, 
BRCA localization), EGFR location and signaling, and apoptosis markers with the ORR and 
PFS;  
 
 Correlate serial measures of circulating tumor cells (CTCs) and serum levels of M30 with the 
ORR and PFS.  
 
 Determine the pharmacokinetics of Veliparib and Lapatinib when given in combination.  
 
2.0 
BACKGROUND AND RATIONALE 
 
2.1 
“Triple Negative” Breast Cancer Has a Poor Prognosis 
 
Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer deaths 
in American women. Despite recent advances in breast cancer therapy, metastatic disease remains 
incurable. One of the reasons for the lack of cure has been the inability to select subsets of patients 
most likely to benefit from specific therapies.  
 
The use of modern genomic techniques has significantly enhanced our understanding of breast 
cancer biology. Thus, five distinct breast cancer tumor subsets have been recognized, including 
hormone receptor (HR) positive luminal A and B, human epidermal growth receptor 2 (HER-2-Neu) 
positive, "normal"-like, and basal-like.1,2 Basal-like breast cancer (BBC) is typically TNBC, often 
demonstrates overexpression of the epidermal growth factor receptor-1 (EGFR1), is positive for 
cytokeratins 5/6/17, and is typically high grade.3-5 TNBC is a “special clinical interest” cancer 
because it represents a significant proportion of breast cancer patients (10-20%), has a very poor 
prognosis in a significant proportion of patients, and as yet, no targeted approach to therapy has been 
found.  

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 4 
 
 
Conforti and colleagues characterized the use of immunohistochemical analysis in the identification 
of BBC; in 800 breast cancer specimens from a single institution, triple-negative staining had 
positive and negative predictive values of 67% and 99%. This finding suggests that while not all 
TNBC are BBC, non-TNBC are almost never BBC.6,7 Thus, BBC comprise the majority of the 
tumors that fit the triple negative phenotype. These cancers are more commonly found in African 
American women, particularly pre-menopausal, as well as in individuals who harbor a deleterious 
mutation in the BRCA1 gene.8 
 
In addition, Pietenpol and her team have recently found that TNBC is a highly diverse group of 
cancers, and that subtyping may be necessary to better identify molecular-based therapies.9 In her 
study, they analyzed gene expression profiles from 21 breast cancer data sets and identified 587 
TNBC cases. Cluster analysis clearly identified 6 TNBC subtypes displaying unique gene expression 
and ontologies, including 2 basal-like (BL1 and BL2), an immune-modulatory (IM), a mesenchymal 
(M), a mesenchymal stem-like (MSL), and a luminal androgen receptor (LAR) subtype. Further, 
genomic expression analysis allowed them to identify TNBC cell line models representative of these 
subtypes. Predicted "driver" signaling pathways were pharmacologically targeted in these cell line 
models as proof of concept that analysis of distinct gene expression signatures can inform therapy 
selection. Thus, if validated, these data may be useful in biomarker selection, drug discovery, and 
clinical trial design that will enable alignment of TNBC patients to appropriate targeted therapies.  
 
Harris et al. retrospectively evaluated 474 patients with advanced breast cancer enrolled in the 
CALGB trial 9342 who received paclitaxel in three different schedules.10 Of the 136 patients in this 
study for whom complete biomarker data were available, 44 patients had tumors that were triple 
negative. They found that the majority of these patients had overexpression of p53, and the majority 
of them were African-American. The response rate to chemotherapy observed in these patients was 
26% (compared to 23% in other breast cancer subtypes), but the time to progression (TTP) was 2.8 
months (compared to 4.5 months for other breast cancer subtypes), and the overall survival (OS) 
was 8.6 months (compared to 12.8 months for other breast cancer subtypes).  
 
A similar retrospective analyses has been published including patients enrolled in different 
neoadjuvant clinical trials at the MDACC.11 In this retrospective evaluation they found that 258 out 
of 1143 (23%) were triple negative. Interestingly, the TNBC patients had a higher pathological 
complete response (pCR) (25%) compared with other breast cancer subtypes (11%). However, the 
5-year OS was lower for those patients with TNBC (66%) as compared with other subtypes of breast 
cancer (83%); clearly the best 5-year OS was observed in those patients that had a pCR. The authors 
concluded that triple negative expression constitutes an independent unfavorable prognostic factor 
with regard to overall survival unless achieving pCR after neo-adjuvant therapy.   
 
Carey et al. retrospectively examined the relationship of neoadjuvant chemotherapy response to 
outcome among breast cancer subtypes.12 They also found that triple negative tumors are more 
sensitive to anthracycline-based neoadjuvant chemotherapy than other types of breast cancers.  
Patients that had pCR to chemotherapy (27%) had a good prognosis regardless the subtype (including 
the triple negative subtype). However, the overall poorer prognosis of triple negative  
 
 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 5 
 
 
was due to the higher likelihood of relapse (73%) in those patients in whom pathologic CR was not 
achieved.  
 
Nam et al. from the National Cancer Center in Korea reported that women with TNBC have a higher 
risk of brain metastases than other breast cancer types.13 The study included 805 patients with 
advanced breast cancer who were treated between 2001 and 2006. Patients with TNBC had the 
highest rate of brain metastases (37%), the lowest survival following brain metastasis, and the lowest 
OS. 
 
Thus, given the lack of effective therapy (especially targeted therapy) in patients diagnosed 
with TNBC and the poor prognosis associated with it, new therapies for these patients are 
needed. As described, therapeutic strategies based on functional molecular abnormalities in 
tumor cells are warranted.  
 
2.2 
PARP Inhibition in Triple Negative Breast Cancer 
Poly (ADP-ribose)-polymerase (PARP) is a nuclear enzyme that recognizes deoxyribonucleic acid 
(DNA) damage and facilitates DNA repair.14, 15 Inactive PARPs 1 and 2 bind to damaged DNA, 
which leads to their auto-activation. The resulting activated PARP then poly (ADP-ribosyl)ates 
many nuclear target proteins, including those that facilitate DNA repair of both single-stranded or 
double-stranded DNA breaks. Thus, PARP inhibition will result in less efficient DNA repair 
following a DNA damage insult. DNA-damaging agents, chemotherapy and radiation therapy, 
remain as the main treatment for patients with cancer. Since cancer cells are genetically unstable, 
often exhibiting complex karyotypes (deletions, insertions, and unbalanced translocations of 
chromosomal fragment), these cells are more susceptible than normal tissues to cytotoxicity induced 
by DNA-damaging agents.16 Of these, deficiencies in mismatch repair and homologous 
recombination are associated with the largest number of malignancies. These deficiencies render 
cells more dependent on PARP for DNA repair and, hence, are more prone to cytotoxicity induced 
by PARP inhibition.17 In particular, tumor cells with BRCA1 or BRCA2 deficiencies are exquisitely 
sensitive to PARP inhibition, even in the absence of any other insults.18, 19 Recently, a new class of 
compounds, the PARP inhibitors, has gained attention for their ability to induce synthetic lethality 
in BRCA-associated tumors. PARP inhibitors induce synthetic lethality by targeting homologous 
recombination (HR)-mediated DNA repair deficient tumors while maintaining minimal normal 
tissue toxicity.20  
 
The proof-of-principle study was presented by Tutt and his team at the 2009 ASCO annual meeting; 
the study was a phase 2 single-arm study of Olaparib (a PARP inhibitor) in patients with metastatic 
breast cancer who also harbored a deleterious mutation in BRCA1 or BRCA2;21 A total of 54 patients 
were included in the trial. The first 27 patients received olaparib on a continuous daily schedule at a 
dose of 400 mg twice daily. The second 27 patients received olaparib at 100 mg twice daily. The 
entire patient population included 33 patients with mutations in BRCA1, 20 patients with BRCA2 
mutations, and 1 patient who had a mutation in both genes. More than half of the patients had triple-
negative disease and had received a median of 3 prior chemotherapy regimens. The ORR was 41% 
among patients treated at 400 mg twice daily and 22% in the population treated with the lower dose. 
The median PFS in the cohort treated at 400 mg twice daily was 5.7 (range, 4.6-7.4) months. In 
general, the treatment was well tolerated, although side effects were somewhat more prominent in 
women treated with the higher dose. Although the higher dose appeared to be somewhat more active, 
a formal comparison is not possible in this small, nonrandomized experience. Interestingly, the 
extent of prior treatment did not influence the likelihood of obtaining a response. 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 6 
 
 
 
However, this approach is only applicable to the 5-10% of all cancers with hereditary 
mutations in key proteins in the homologous recombination mediated DNA repair pathway. 
Thus, much effort has been undertaken to expand the utility of PARP inhibitors beyond the 
current realms of BRCA-associated tumors by combining with agents that alter the DNA 
damage/repair pathways. Specifically, in TNBC, which often demonstrates a “BRCAness” 
phenotype, PARP inhibitors showed initial promise when combined with DNA damaging 
chemotherapy (Iniparib in combination with gemcitabine and carboplatin) ,22, 23 but ultimately failed 
to improve outcomes over chemotherapy alone in a randomized phase III clinical trial.24 Thus, 
although the PARP inhibitor data looks promising in TNBC associated with BRCA mutations, new 
agents or combination of agents (especially targeting agents) or new combinations of agents are 
needed for all triple negative breast cancer patients in order to improve their prognosis. 
 
2.3 
EGFR Inhibition in Triple Negative Breast Cancer 
 
The EGFR/HER family of transmembrane type I receptor tyrosine kinases are enzymes that play an 
important role in cell proliferation, differentiation and survival. These receptor tyrosine kinases, 
which include HER1 (epidermal growth factor receptor, EGFR), HER2 (HER2/neu, c-erbB2), HER3 
and HER4 contain an extracellular domain and intracellular protein tyrosine kinase core. The 
ectodomain of HER1, HER3, and HER4 interacts with a specific set of ligands, whereas no natural 
ligand has been identified for HER2 which can be activated by heterodimerization with other ligand 
activated HER co-receptors. Upon ligand binding to the active domain of HER1, HER3, or HER4, 
these receptors preferentially recruit HER2 into a heterodimeric complex in which the HER2 kinase 
can modulate receptor internalization and prolong signal transduction. Upon dimerization, 
conformational changes lead to autophosphorylation and initiation of divergent signal transduction 
cascades.25 The type I receptors signal through Ras/Raf/MAPK/ERK pathway, stimulating cell 
division.26 Cell line evidence also suggests that the type I receptors modulate cell survival through 
activation of Akt/phosphoinositol 3-kinase (PI3-kinase) pathway.27  
 
HER1 is expressed or over-expressed in many human solid tumors including breast cancer, and plays 
an important role in progression to invasion and metastases.28 The HER1 tyrosine kinase is activated 
by binding of a variety of ligands to the external domain. In particular, HER1 overexpression is 
correlated with high metastatic rate, short survival time, and poor prognosis.29 Autophosphorylation 
by the HER1 tyrosine kinase initiates a signaling cascade that feeds downstream cell cycle control 
machinery regulating cell proliferation, and these reactions are a major component in growth factor–
induced proliferation of cancer cells.28 EGFR is often overexpressed or amplified in 45-70% of 
TNBC and is associated with aggressive disease phenotype.4, 30-32 For example, overexpression of 
EGFR is correlated with increased tumor size, lymph node involvement, and decreased survival in 
invasive breast cancers.33  
 
Based on the preclinical observations described before, anti-EGFR therapies (monoclonal antibodies 
against the receptor or small molecules inhibiting tyrosine kinases) have been evaluated in patients 
with metastatic TNBC. However, targeted therapy against EGFR using the anti-EGFR monoclonal 
antibody cetuximab had limited activity as a single agent in TNBC or in combination with different 
chemotherapy agents. The first trial was a randomized phase II study of cetuximab as a single-agent 
and in combination with carboplatin; in this trial, Carey et al. found that EGFR targeting alone is 
insufficient in the majority of TNBC patients (response rate of 6%) and combination with carboplatin 
produced responses in fewer than 20% of metastatic TNBC patients. Pathway analysis in tumor 
biopsies found that after one week of treatment with cetuximab, the EGFR pathway was inhibited in 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 7 
 
 
only 5 of 13 patients.34 Another clinical trial evaluated again cetuximab but in combination with 
irinotecan and carboplatin; in this second randomized trial, O’Shaughnessy et al. observed a similar 
improvement in the response rate, but there were no improvement in PFS or OS.35 Most recently, a 
third randomized phase II trial (BALI II Trial) evaluating the addition of cetuximab to cisplatin in 
patients with TNBC demonstrated a modest benefit in PFS but a non-significant response rate.36]   
 
Additionally, trials evaluating EGFR tyrosine kinase inhibitors have been disappointing. As an 
example, Baselga et al. evaluated the antitumor activity of gefitinib (an oral nonpeptide 
anilinoquinazoline compound that inhibits the tyrosine kinase activity of EGFR) in patients with 
previously treated, advanced breast cancer.37 Of 31 assessable patients, 12 (38.7%) had stable 
disease, including 3 (9.7%) with recurrent breast cancer that stabilized for 6 months. No complete 
or partial responses were observed. Sequential immunohistochemical studies in skin and tumor 
biopsies demonstrated complete inhibition of EGFR phosphorylation in both healthy and malignant 
tissues. The downstream consequences of receptor blockade were distinct in skin and tumor samples: 
while phosphorylation of mitogen-activated protein kinase was inhibited in both tissues, gefitinib 
treatment induced p27 and a decrease in Ki67 in skin but not in tumors. Furthermore, gefitinib did 
not inhibit the activated form of Akt in the tumors. This study demonstrated a good correlation 
between the degree of inhibition of EGFR in skin and in breast tumors. The lack of significant 
clinical activity of gefitinib is not due to lack of receptor inhibition in these tumors but rather to lack 
of EGFR dependence in the tested population Another example was a clinical trial in which erlotinib, 
an EGFR tyrosine kinase inhibitor, and bevacizumab were combined. In this trial, the combination 
was well-tolerated by metastatic breast cancer patients, but had limited survival benefit and EGFR 
expression levels were not indicative of response.38  
 
Targeting EGFR is problematic due to many TNBC harboring RAS and PTEN (30%) mutations,39, 
40 which activate signaling downstream of EGFR. Alternatively, compensatory up-regulation of 
other receptor tyrosine kinases, such as HER2, could account for resistance to targeting EGFR.41-43 
Together these studies demonstrate that targeting EGFR alone is problematic, thus 
necessitating new therapeutic approaches. 
 
2.4 
EGFR and PARP inhibition in triple negative breast cancer 
2.4.1 EGFR/HER2 Inhibition and DNA Repair  
 
 
One important consideration of the EGFR signaling is its role in regulating the DNA damage 
response; this mechanism does not depend on wild-type p53 or ras status. In particular, the effects 
of  EGFR inhibition on the DNA repair pathways have been shown to occur in tumor cells 
independent of p53 or ras status.44-47 As shown in Figure 1a-c, EGFR/HER2 inhibition with 
lapatinib, the oral dual EGFR/HER2 tyrosine kinase inhibitor, attenuated homologous 
recombination (HR) repair in the TNBC cell lines MDA-MB231, MDA-MB468, and MDA-MB-
453 as measured by radiation induced rad51 foci, a marker for HR repair.48 Furthermore, our 
laboratory has found that the mechanism by which EGFR/HER2 inhibition with lapatinib attenuates 
DNA repair may be through altering protein-protein interactions between EGFR and BRCA1 (Figure 
2a-b).  Additionally, the nuclear localization of EGFR is reduced by lapatinib (Figure 3a-b). 
 
 
 
 
 
 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fig 3 Lapatinib reduces nuclear 
EGFR while increasing cytosolic 
EGFR in MDA-MB231 TNBC cells. 
(A) sub-cellular fractionation (B) 
Quantification.   
Fig 1 Lapatinib reduces homologous 
recombination repair in the TNBC 
cell lines (A) MDA-MB231, (B) 
MDA-MB453, and (C) MDA-MB-
468 as measured by radiation-induced 
Rad51 foci, a marker for HR repair. 
 
Fig 2 Lapatinib reduces EGFR-
BRCA1 interaction in MDA-MB231 
TNBC cells. (A) BRCA1 is found in 
immunoprecipitates with EGFR. (B) 
Reciprocally, EGFR is found in 
immunoprecipitates with BRCA1.   

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 9 
 
 
2.4.2 Induction of cytotoxicity by combining lapatinib and veliparib in triple negative breast 
cancer cell lines. 
 
Importantly, because EGFR inhibition attenuated homologous recombination repair, we 
hypothesized that lapatinib could induce a synthetic lethal interaction with the PARP inhibitor 
veliparib, which targets HR defective cells.   Indeed, we recently  reported a contextual synthetic 
lethality in vitro with combined EGFR and PARP inhibition with lapatinib and veliparib, 
respectively, in multiple TNBC cell lines (Figure 4a-c and 46, 48 ). The mechanism of cytotoxicity 
involves persistent DNA damage and activation of the intrinsic pathway of apoptosis (Figure 5a-b). 
Further dissection of the mechanism reveals that EGFR and BRCA1 can be found in the same protein 
complex, which is reduced by lapatinib (Figure 2 a-b). Interestingly, lapatinib also increases 
cytosolic BRCA1 and EGFR, away from their nuclear DNA repair substrates (Figure 3a-b, and data 
not shown48). These results were observed in triple negative breast cancers that possessed p53, ras, 
PI3K, or PTEN mutations. Taken together, these results reveal a novel regulation of homologous 
recombination repair involving EGFR and BRCA1 interaction and alteration of subcellular 
localization. Additionally, a contextual synthetic lethality may exist between combined EGFR and 
PARP inhibition that can be investigated in TNBC patients. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.4.3 In 
vivo 
anti-tumor 
efficacy 
of 
combining 
EGFR 
and 
PARP 
inhibition 
(lapatinib/veliparib) in orthotopic breast cancer xenografts 
 
To further validate our intriguing results in vivo, we tested the combination of lapatinib and veliparib 
in mice bearing orthotopic xenografts of TNBC cell line MDA-MB231 cells.  As shown in Figure 
6, a significant tumor growth delay was observed in combination treated mice versus no response in 
mice given either agent alone.   
Fig 4. Lapatinib induces synthetic lethality in TNBC cell lines (A) MDA-MB231, (B) MDA-MB453, and (C) MDA-
MB-468 as measured by colony formation assays 
Fig 5. Combination lapatinib and veliparib induces apoptosis in the TNBC cell line MDA-
MB231 as measured by cleaved (A) caspase 3 or (B) caspase 9 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.4.4 DNA damage and repair proteins may be a putative biomarker for sensitivity to 
combination EGFR/PARP inhibition. 
 
Recent evidence suggests that nuclear EGFR participates in development of resistance to cancer 
therapeutics, like gefitinb,49 radiation50 and even cetuximab.51 The first link between nuclear EGFR 
and cancer was proposed in 1994, two independent studies demonstrated that nuclear EGFR was 
significantly associated with tumor grade, mitotic frequency, and proliferation.52, 53 Breast cancer 
patients with elevated nuclear EGFR were found to have decreased overall survival54 and also related 
to tumor size, lymph node involvement, and Nottingham prognostic index.33 Our laboratory has 
recently reported that EGFR inhibition, and subsequent reduction in EGFR phosphorylation, 
decreases EGFR nuclear fraction while simultaneous increasing cytosolic fraction. Interestingly, we 
also observed reduced BRCA1 nuclear localization following Lapatinib.  Thus, we believe assessing 
EGFR and BRCA1 staining and subcellular localization may be a biomarker for sensitivity to 
response to combination lapatinib/veliparib.  Additionally, as combining EGFR and PARP inhibition 
resulted in persistent DNA double strand break damage, we can be readily measure by 
immunofluorescence persistent 
-H2AX foci, a well-characterized marker for DNA double strand 
breaks, as another marker to correlate with response. 
 
2.4.5 Summary of EGFR and PARP inhibition 
 
Based on these exciting preclinical results showing induced synthetic lethal interactions 
between EGFR and PARP inhibition with lapatinib and veliparib, respectively, in human 
triple negative breast cancer, we propose to evaluate the combination of lapatinib and 
veliparib in patients with metastatic TNBC who have failed no more than 2 chemotherapy 
regimens in an open label, pilot study. The trial will evaluate the safety and efficacy of the 
combination of (Lapatinib and Veliparib). 
 
 
 
Fig 6. Combination lapatinib and veliparib induces 
synthetic lethality in orthotopic MDA-MB-231 
xenografts 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 11 
 
 
2.5 
Veliparib  
 
 
Veliparib Pre-Clinical Data Veliparib (ABT-888) is a novel, orally bioavailable, small molecule 
that is a potent PARP inhibitor that delays the repair of DNA damage induced by chemotherapeutic 
agents.14, 15, 55 Veliparib increases sensitivity of tumor cells to DNA-damaging agents in vitro and in 
vivo and inhibits PARP in murine tumors in vivo and human peripheral blood mononuclear cells 
and human tumors ex vivo. Veliparib inhibits both, PARP-1 and PARP-2. In vitro, veliparib 
increases sensitivity of tumor cells to DNA-damaging agents including chemotherapy agents (such 
as TMZ, irinotecan, cyclophosphamide, BCNU, cisplatin, and carboplatin), and radiation therapy. 
In addition, the combination of veliparib and chemotherapy agents (such as TMZ, carboplatin, 
paclitaxel) has demonstrated significant efficacy in a variety of preclinical tumor models, including 
settings where chemotherapy alone is ineffective and in both BRCA1- or BRCA2-competent and 
BRCA1- or BRCA2-mutated backgrounds. 
 
Veliparib Pharmacokinetics In rats and dogs, veliparib is primarily cleared in the urine as intact 
parent drug, with a small fraction of clearance from metabolism.55 The renal clearance and minimal 
metabolism observed in rats and dogs and the minimal metabolism observed in vitro in all species 
evaluated are consistent with the low molecular weight and good solubility of veliparib.55  
 
Preliminary clinical pharmacokinetic (PK) data available from 6 human studies indicate that 
exposure of veliparib is approximately dose-proportional over 10 through 150 mg BID dose range.55 
The absorption of veliparib after oral dosing is relatively fast where veliparib plasma concentrations 
peak at approximately 1 to 2 hours after dosing across dose levels. The terminal half-life of veliparib 
is about 6 hours, with minimal accumulation following multiple BID dosing. Food does not have a 
significant effect on veliparib bioavailability. The mean total urinary recovery of veliparib is 86%, 
which indicates that renal excretion is an important pathway in veliparib elimination. Potential drug-
drug interactions (DDI) of veliparib are being evaluated in veliparib combination studies. Veliparib 
is not a potent inhibitor, nor an inducer, of the major human cytochrome P450s (CYPs), suggesting 
a minimal potential for DDIs at the anticipated therapeutic concentrations. A Phase 0 Study A10-
161 of Veliparib in patients with advanced cancer demonstrated that Veliparib is orally bioavailable 
and primarily cleared through renal excretion, with a half-life of 4 to 5 hours.56 Substantial inhibition 
of PARP activity (>90%) was observed in tumor biopsies collected 3 to 6 hours after dosing with 
either 25 mg or 50 mg of veliparib. Complete inhibition of PARP activity in PBMCs, maintained 
through 24 hours after dosing, was achieved in 3 of the patients who received 50 mg veliparib. 
Interestingly, no serious adverse events, dose-limiting toxicities, or deaths were reported for this 
study.56 
 
Veliparib Toxicology The toxicological profile of veliparib has been characterized in animal models 
(6 and 9 months duration in rats and dogs respectively), in genotoxic studies and in embryo-fetal 
development studies.55 The primary target organs of veliparib are the central nervous system 
(convulsions and other CNS-related signs), the hematologic system (decreased red and white blood 
cells), the bone marrow (hypocellularity), the lymphoid tissues (lymphocyte depletion), and the male 
(germ cell depletion) and the female (corpora lutea decrease and minimal degeneration of granulosa 
cells in follicles) reproductive tissues, with lesser effects on the cardiovascular system (10% QTc 
prolongation) and the gastrointestinal tract (single cell necrosis). Convulsions and other CNS-related 
signs were considered exposure-dependent and were generally self-limiting, ameliorated by dose 
reduction or cessation of dosing, or respondent to treatment. All other findings were dose-dependent 
and reversible upon discontinuation of veliparib administration. Veliparib was genotoxic (induced 
chromosomal aberrations in vitro and increased micronuclei formation in vivo) and was toxic to the 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 12 
 
 
developing fetus (increased incidence of fetal, visceral, skeletal malformations and/or variations). 
Veliparib also absorbs ultraviolet light and is distributed to both the skin and the eyes following 
systemic exposure, which poses a potential photo-toxicity risk.55 
 
Veliparib Safety Multiple clinical studies have been conducted at this time using Veliparib as a 
single agent and in combination with chemotherapy and radiation therapy; safety profile has been 
defined in these studies.55 At present, there have been more than 800 patients exposed to Veliparib. 
From the single agent studies conducted in patients with cancer, the most common reported side 
effects with veliparib as a single agent were: nausea, fatigue, anemia, lymphopenia, hyperglycemia, 
diarrhea, decrease appetite and headache. As described before, in the Phase 0 Study A10-161 of 
Veliparib in patients with advanced cancer no serious adverse events, dose-limiting toxicities, or 
deaths were reported for this study.34 In the Phase 1 Study M10-128, patients received Veliparib 
(10 to 300 mg) in combination with whole-brain radiation therapy; again, Veliparib was well 
tolerated and the most commonly reported adverse events were fatigue, headache, and nausea.56 
 
Safety data is also available using the combination of Veliparib and chemotherapy regimens 
including TMZ as a single agent, carboplatin and paclitaxel, and FOLFIRI.55, 57 Study M06-862 was 
a dose-escalating phase I trial of Veliparib in combination with TMZ; doses ranged from 10 mg 
veliparib BID/150 mg/m2 TMZ once daily to 80 mg veliparib BID/200 mg/m2 TMZ once daily; in 
addition to neutropenia and thrombocytopenia, the other most commonly reported adverse events 
were nausea, fatigue, vomiting, constipation, decreased appetite, and headache. A follow-up trial, 
study M10-440, was conducted; this trial was a Phase 2 randomized, double-blind, placebo-
controlled study of veliparib (20 or 40 mg BID) in combination with TMZ and showed that the most 
common treatment-emergent adverse events were nausea, fatigue, constipation, thrombocytopenia, 
and vomiting. In the Phase 1 Study M11-070, a trial that evaluated subjects with metastatic 
castration-resistant prostate cancer treated with veliparib in combination with TMZ, the most 
frequent secondary effects were fatigue, nausea, platelet thrombocytopenia, and constipation. In the 
Phase 1 dose-escalation Study M10-758, veliparib, starting at a dose of 30 mg twice a day, was 
administered in combination with carboplatin/gemcitabine; the most commonly reported adverse 
events were thrombocytopenia, anemia, nausea, neutropenia, constipation, fatigue, and headache. In 
the Phase 1 Study M10-977, subjects with advanced solid tumors were treated with veliparib in 
combination with FOLFIRI; the most common treatment-emergent adverse events were diarrhea, 
nausea, fatigue, alopecia, vomiting, and constipation. In the Phase 1/2 Study M10-190, veliparib was 
administered in combination with radiation therapy with concurrent and adjuvant TMZ; the most 
commonly reported adverse events were fatigue, thrombocytopenia, nausea, headache, and 
insomnia. Lastly, in the Phase 1 Study M11-846, a trial evaluating the bioavailability and food effect 
of 3 formulations of veliparib on pharmacokinetics in subjects with solid tumors, the most common 
secondary effects were anemia, fatigue, dyspnea, abdominal distension, constipation, diarrhea, 
nausea, pain, and cough.  
 
Thus, Veliparib has been well tolerated as a single agent and in combination with 
chemotherapy and radiation therapy; interestingly, Veliparib does not add additional toxicity 
to the one seen with chemotherapy or radiation therapy. 
Veliparib Activity in Breast Cancer The therapeutic potential of PARP inhibitors in breast cancer 
was suggested by two clinical trials. In the first trial, patients with metastatic breast cancer were 
treated with Veliparib and TMZ; an ORR of 50% was seen in patients with BRCA1/2 mutations.57 
Interestingly, a single-arm trial evaluating a different PARP inhibitor (Olaparib) in metastatic breast 
cancer patients with BRCA1/2 mutations demonstrated single-agent activity, with an ORR of 38% 
in heavily pretreated patients.58 A similar trial in BRCA1/2 mutation carriers with metastatic ovarian 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 13 
 
 
cancer showed a response rate of 33%.38 Notably, both single-agent studies demonstrated increased 
response rates with higher doses of PARP inhibitor (olaparib 100 mg BID and 400 mg BID), where 
both doses are considered biologically active. Together, these results validate the proof of concept 
that PARP inhibition is an attractive therapeutic target in breast and other cancers. In the ongoing 
Phase 2 trial in metastatic breast cancer, a 50% CBR (14/28; 1 CR, 6 PR, 7 SD) has occurred to date 
in patients with deleterious BRCA mutations; this is in contrast to historical clinical data that suggest 
that TMZ monotherapy has low activity in breast cancer (two Phase 2 studies with a dose-dense 
TMZ regimen demonstrated no responses in patients with metastatic breast cancer and 2 responses 
(2/51) in patients with brain metastases from histologically confirmed breast cancer59, 60). 
 
2.6    Lapatinib 
 
Lapatinib Pre-Clinical Data Lapatinib (Tykerb, GW572016) is an orally active dual HER1/HER2 
kinase inhibitor that blocks signal transduction pathways.61 This dual inhibition is an attractive 
therapeutic strategy for epithelial cancers, as ligand-induced HER1/HER2 dimerization triggers off 
potent proliferative and survival signals. In vitro studies with Lapatinib have shown marked activity, 
leading to growth arrest and apoptosis in HER1 and HER2 overexpressing cell lines. Lapatinib 
markedly reduced tyrosine phosphorylation of HER1 and HER2; in addition, lapatinib also reduced 
the activation of MAP kinase and Akt, the downstream effectors of proliferation and survival, 
respectively.61 Lapatinib has demonstrated activity against human breast cancer xenografts in animal 
models.62-64 
 
Lapatinib Toxicology A range of toxicology studies has been conducted to support the oral 
administration of lapatinib to humans.65 Repeat oral dose toxicity studies have been completed in 
rats and dogs for up to 6 and 9 months, respectively. The effects of lapatinib on fertility in the rat 
and embryo-fetal development in the rat and rabbit have been investigated. A range of genetic 
toxicity studies has been performed in vitro and in vivo. The significant findings from the toxicology 
studies are summarized below. 
 
Following single oral administration, lapatinib was well-tolerated by both CD-1 mice and Wistar 
Han rats at doses up to 2000 mg/kg.65 Treatment-related findings consisted of reversible changes in 
body weight and body weight gain as well as reversible GI effects. A 13-week oral dose ranging 
pilot carcinogenicity study in mice showed that treatment with lapatinib at doses up to 200 
mg/kg/day was generally well tolerated. Microscopic changes attributable to treatment with lapatinib 
were noted in the liver and preputial gland of males and large intestines (cecum and colon) of males 
and females. 
 
Administration of lapatinib to rats and dogs for up to 6 months or 9 months resulted primarily in 
exaggerated pharmacologic effects and organ toxicities generally associated with degenerative 
and/or inflammatory epithelial changes (GI tract and accessory digestive organs, skin, mammary 
gland, liver and prostate).65 Other treatment-related effects included clinical signs, decreased body 
weight and food consumption, organ weight changes and alterations in clinical pathology 
parameters. Following the recovery period, treatment-related changes were either significantly 
improved or completely reversed. There were no effects on male or female rat gonadal function, 
mating, fertility or pregnancy nor were there any increases in the number or incidence of any 
malformations when rats or rabbits were given lapatinib during the period of major organogenesis. 
At maternally toxic doses ( 60 mg/kg/day in rats and rabbits), lapatinib treatment was associated 
with growth retardation and developmental variations. In genetic toxicity studies, lapatinib was 
demonstrated to be non-mutagenic and nonclastogenic. 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 14 
 
 
Lapatinib Pharmacokinetics The pharmacokinetics of lapatinib are similar in healthy volunteers 
and patients, demonstrating oral absorption that is incomplete, highly variable, and sometimes 
delayed.65 After dosing, plasma concentrations rise to a peak at approximately 4 h and thereafter 
decline with measured half-lives averaging up to 14 h. However, accumulation with daily dosing 
achieves steady state in 6-7 days, which suggests a true elimination half-life on the order of 24 h. 
Administration of the same daily dose in a BID schedule results in 2-fold greater systemic exposure 
than a QD schedule. Despite this inconsistency, systemic exposure generally increases with 
increasing dose. Absorption is increased by ingestion with food. Elimination of lapatinib is 
predominantly through metabolism by CYP3A4/5 with negligible renal excretion. Significant 
changes in systemic exposure to lapatinib result from co-administration of drugs that are potent 
inhibitors or inducers of CYP3A. 
 
Lapatinib Safety Safety results from Phase I monotherapy studies in cancer patients indicate that 
lapatinib administered on a QD schedule was generally well tolerated at doses of lapatinib ranging 
from 175 mg to 1800 mg QD. Doses of 500 and 750 BID were better tolerated than 900 mg BID.65 
The majority of AEs were Grade 1 or 2 gastrointestinal and/or skin toxicities. The incidence of 
diarrhea increased with increasing dose, whereas the incidence of rash was not related to dose. The 
Phase II/Phase III program had enrolled a total of 1581 subjects. Of these, 1001 subjects were 
enrolled in Phase II monotherapy studies. Data suggest that lapatinib administered as monotherapy 
at doses of 1250 mg QD, 1500 mg QD, and 500 mg BID is generally well tolerated. For the 
completed and ongoing Phase II and Phase III studies, the preliminary safety data was similar to 
what has been observed in the Phase I monotherapy studies and combination studies. The most 
common AEs considered related by the investigator were gastrointestinal (diarrhea, nausea, 
vomiting), rash, fatigue, and anorexia. The majority of all AEs were Grade 1 and Grade 2. 
 
SAE data from ongoing lapatinib studies (all phases) are from 2312 subjects treated with lapatinib.65 
For the ongoing studies, a total of 831 SAEs were reported from 405 individual subjects. The most 
frequently reported SAE was diarrhea, with a total of 47 reports, 37 of which were assessed as related 
to investigational product. Dyspnea, vomiting, dehydration, and nausea were also among the most 
frequently reported SAEs regardless of relatedness. Overall, 24.6% of the SAEs reported were 
assessed as related to investigational product by the investigator. The most frequently reported drug-
related events were: diarrhea, neutropenia, vomiting, nausea, dehydration, and decreased ejection 
fraction. Diarrhea which may lead to dehydration, nausea, and vomiting are all included in the 
development core safety information for lapatinib. Interstitial pneumonitis and two cases of 
interstitial pneumonia have been reported in the lapatinib program. Subjects on the lapatinib program 
have experienced a decrease in LVEF, giving an approximate incidence for this event of 1.4%.  
 
Lapatinib Activity in Breast Cancer   In clinical trials, lapatinib has demonstrated activity in 
heavily pre-treated women with trastuzumab- and chemotherapy-resistant breast cancer.66, 67 In the 
first-line setting, lapatinib appears to have substantial activity in women with HER2-positive breast 
cancer, based on an ongoing phase 2 study.68 Results from this study indicate an objective response 
rate of approximately 30% in patients not previously treated with chemotherapy for metastatic 
disease.  
 
A pivotal study, comparing the efficacy of capecitabine with or without lapatinib, randomized 
patients with metastatic breast cancer to receive either lapatinib in combination with capecitabine or 
single agent capecitabine.69, 70 All patients had metastatic disease that had progressed following 
treatment with an anthracycline, a taxane, and a trastuzumab-containing regimen. Time to 
progression in patients receiving the combination of lapatinib and capecitabine was nearly double 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 15 
 
 
that of patients receiving capecitabine alone. The combination arm showed a median time to disease 
progression of 8.5 months, compared with 4.5 months for those treated with single-agent 
capecitabine. Moreover, fewer patients in the combination arm had disease recurrence in the brain. 
Side effects associated with lapatinib were found to be relatively minimal, with the most frequently 
reported toxicities being mild-moderate diarrhea and hand and foot syndrome. Given the theoretical 
risk of cardiotoxicity in patients receiving HER2-targeted therapy, all patients were closely 
monitored for the development of cardiac events. Of the 161 patients in the combination arm, four 
developed minor heart problems that reversed upon lapatinib discontinuation. No patients were 
withdrawn from study due to cardiotoxicity.70 
 
2.7 
Rationale 
 
TNBC represents a significant proportion of breast cancer patients, has poor prognosis in a 
considerable number of patients and, no targeted approach to therapy is available at this time.  The 
luminal breast cancer type category derive major clinical benefit from agents target ER; this therapy 
improved cure rates in the adjuvant setting and prolonged disease control in the metastatic setting. 
Similarly, the HER-2-neu category have had substantial clinical benefit from targeting the HER-2 
receptor plus chemotherapy including dramatic reduction in disease recurrence rate in the adjuvant 
setting and enhanced response rate and duration of response in the metastatic setting. Thus, new 
targeting agents in TNBC are needed! 
 
As presented in the background, there is strong provocative preclinical data demonstrating the 
activity of the combination of an EGFR inhibitor (lapatinib) and a PARP inhibitor (veliparib) in 
basal-like breast cancer. These preclinical data provide a strong rationale for the testing of this 
combination in patients with metastatic or recurrent triple negative breast cancer in whom taxane 
and anthracycline therapy has failed.  
 
In addition, the clinical data supports the hypothesis that the combination of lapatinib plus veliparib 
will be safe and have efficacy in patients with metastatic triple negative breast cancer. Because there 
is no suggestion in the published literature that the toxicities of the two targeted agents will overlap, 
the known active and non-toxic doses of both agents will be used. For lapatinib, the dose was chosen 
at 1250 mg daily as this is the current recommended dose used for breast cancer in combination with 
capecitabine.69 We believe that combining this dose of lapatinib with veliparib will be better 
tolerated than capecitabine. The data obtained in this pilot study will be used to design a phase II 
clinical trial that will be conducted by the Translational Breast Cancer Research Consortium. 
The dose of veliparib at 200 mg BID is based on our preclinical studies where veliparib was given 
100mg/kg twice a day orally with lapatinib 30mg/kg twice a day orally. No toxicity was observed 
in mice with this combination, and per AbbVie Oncology, the 100mg/kg twice a day dose is 
equivalent to the 200mg PO twice a day dose in humans. Single agent dosing of veliparib is currently 
at 400mg BID. Additionally, the 200mg twice a day dose is well tolerated in combination with 
radiotherapy concurrently.56 Importantly, we have built in this trial a cohort with lower doses of both 
agents if toxicity is observed in the initial cohort using the standard doses described above.   
 
3.0 
STUDY DESIGN (Table 1 and Figure 7) 
The study is an open-label, single arm, single institution, pilot clinical trial of Veliparib (a PARP 
inhibitor) in combination with Lapatinib (an EGFR inhibitor) in patients with pathologically 
confirmed TNBC (ER negative, PR negative, HER-2-Neu negative by IHC [0, 1] or FISH) who have 
not received prior therapy in the metastatic setting (but failed anthracyclines and taxanes in the 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 16 
 
 
neoadjuvant or adjuvant setting) or who have failed prior chemotherapy in the metastatic setting 
(including anthracyclines and taxanes and no more than two prior regimens for metastatic disease as 
long as patients have adequate performance status – see Appendix B). The data obtained in this pilot 
study will be used to design a phase II clinical trial that will be conducted by the Translation Breast 
Cancer Research Consortium.  
 
As described in Figure 7, patients will receive Lapatinib (1250 mg PO daily continuously) in 
combination with Veliparib (200 mg PO every 12 hours continuously). A cycle of therapy is defined 
as 28 days of PO therapy. Lapatinib will start Day 1 cycle 1 and Veliparib will start on Day 2 Cycle 
1 (for better understanding of the PK of the drugs as well as to induce a DSB repair defect first with 
Lapatinib). Dose reductions of Lapatinib and Veliparib will be allowed. Patients developing grade 
1 and 2 toxicities will be permitted to take a drug holiday of up to 14 days; after the drug holiday, if 
the adverse event has resolved to the satisfaction of the investigator, the study drugs may be resumed 
at the same level. In the event of recurrent toxicity, there will be two dose reductions permitted (dose 
reduction minus one will be Lapatinib 1000 mg PO daily continuously and Veliparib 150 mg PO 
every 12 hours continuously); dose reduction minus two will be Lapatinib 750 mg PO daily and 
Veliparib 100 mg PO every 12 hours continuously. If the adverse event recurs after dose reduction 
two, the patient will be taken off the study. Patients developing grade 3 and 4 toxicities will be 
interrupted for up to 14 days; after the drug holiday, if the adverse event has resolved to the 
satisfaction of the investigator, the study drugs may be resumed at a reduced dose (Lapatinib 1000 
mg PO daily continuously and Veliparib 150 mg PO every 12 hours continuously). If the adverse 
event recurs, the patient will be taken off the study.  
 
The primary endpoint of the trial is safety of the combination of Lapatinib and Veliparib. Objective 
response rate (ORR) and progression free survival (PFS) will be secondary endpoint. Patients will 
be evaluated for response every 2 cycles (8 weeks) using the RECIST 1.1 criteria (see Appendix D); 
patients with stable disease, PR or CR may continue therapy until disease progression or intolerance 
to the combination. Patients with progressive disease (PD) at any time will go off the study. The 
total enrollment goal is 20 patients; patients will be enrolled in a single site (University of Alabama 
at Birmingham) over a projected 12-18 months accrual interval. A biopsy of an accessible metastatic 
lesion will be obtained in appropriate patients (see inclusion criteria).  Tissue obtained in this trial 
will be analyzed for global gene array analysis or other comprehensive genomic analysis (“Next-
Gen” genomic analysis) at UAB and HudsonAlpha Institute for Biotechnology, and 
immunohistochemistry (ER, PR, HER2, Ki67), biomarkers of DNA repair such as H2AX and BRCA 
localization, EGFR location and signaling, and apoptosis markers; data obtained from the biopsies 
will be correlated with ORR and PFS. Plasma DNA and serum levels of M30 will be obtained and 
correlated with the efficacy data. Adverse events (toxicity) will be assessed continuously while the 
patient is in active therapy with appropriate adjustments of Lapatinib and Veliparib doses as 
described above. The protocol will be approved by the UAB Institutional Review Board (IRB).  
 
 
 
 
 
 
 
 
 
 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 17 
 
 
Figure 7: Treatment Plan 
 
 
Table 1 
Pre-study Evaluation 
(Section 4) 
 
Eligibility 
 Pathologically confirmed ER/PR 
negative, HER-2-Neu negative (by 
IHC 
[0,1] 
or 
FISH) 
breast 
carcinoma – metastatic stage 
 Measurable disease by RECIST 1.1 
criteria (see Appendix D) 
 Patients who have not been treated 
for metastatic disease or who have 
progressed 
on 
chemotherapy 
regimens in the metastatic setting 
are eligible 
 Prior use of anthracyclines and 
taxanes in the adjuvant/neoadjuvant 
settings or metastatic disease is 
required.  
 Adequate organ function 
 PS: ECOG 0-2 (see Appendix B) 
 Life expectancy > than 12 weeks 
 At least 19 years of age 
 Biopsy of metastatic lesion is 
mandatory, if appropriate 
Therapy 
(Section 6) 
 
Lapatinib: 1250 mg PO daily 
continuously  in combination with 
 
Veliparib: 200 mg PO twice a day 
continuously. Veliparib starts Day 2 
Cycle 1   
 
A cycle is defined as a 28 day 
period. 
Initial 
evaluation 
for 
response will occur after 2 cycles of 
therapy; 
patients 
with 
stable 
disease, PR or CR may continue 
until 
disease 
progression 
or 
intolerance to the combination. Re-
evaluation 
of 
tumor 
status 
(response) will occur every 2 cycles 
of therapy. Patients with PD at any 
time will be taken off study. 
Follow-up 
 
 
 Assessment of response every 2 
cycles (clinical and imaging). 
 Standard 
therapy 
toxicity 
monitoring. 
 Lapatinib 
and 
Veliparib 
pharmacokinetics. 
 
 
This trial includes a continuous assessment stopping rule in order to have a high probably of stopping 
early if the toxicity rate is unacceptably high, say 60%, while having low probability of stopping 
early if the toxicity rate is acceptable, say 30%. This rule is based on a Pocock-type boundary as 
described by Ivanova et al (Anastasia Ivanova, Bahjat F. Qaqish, and Michael J. Schell. Continuous 
Toxicity Monitoring in Phase II Trials in Oncology. Biometrics 61, 540–545, 2005).  This stopping 
rule is considered a guideline with the final decision of termination of the study to be made by the 
data safety committee 
 
   D1      to     D28 
Ö   D1     to      D28 
   D1      to        D28 
Ö   D2     to        D28 
Follow-up 
Treatment 
Restage 
Cycle 1 
28 Days 
 
Cycle 2 
28 Days 
Stable Disease or 
Better May Receive 
Additional Cycles 
Lapatinib  
 Ö      Veliparib 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 18 
 
 
Table 2: Minimum number of toxicities (X) required to consider stopping the study after N 
subjects, for 20 patients 
 
X 
3 
4 
4 
5 
5 
6 
6 
7 
7 
7 
8 
8 
9 
9 
9 
10 10 11 
N 
3 
4 
5 
6 
7 
8 
9 
10 11 12 13 14 15 16 17 18 19 20 
 
This rule will provide a probability of 0.10 of stopping early if the true toxicity rate is 30%.  In that 
case the expected number of subjects on the trial will be 18.87 and the expected number of toxicities 
will be 5.7.  If, on the other hand, the true toxicity rate is 60%, then the probability of stopping early 
is 0.87 with an expected sample size of 9.8 and 5.9 expected toxicities. Table 2 is the stopping 
guideline if ‘X’ out of ‘N’ has a pre-defined toxicity. As an example, if we enroll 3 patients and all 
have toxicity, then we will consider stopping the trial; if we enroll 6 patients and 5 patients have 
toxicity then the trial will be stopped. 
 
Drug related toxicities for the safety analysis described above are defined as: a) any grade 3 or 4 
non-hematologic toxicity except anorexia, alopecia, nausea, fatigue, fever without neutropenia; b) 
failure to recover to baseline (except alopecia) after delaying the next dose by more than 14 days; c) 
grade 3 or 4 neutropenia complicated by fever > 38.50 C or infection, or grade 4 neutropenia of a 
least 7 days duration; or d) grade 4 thrombocytopenia, or grade 3 thrombocytopenia complicated by 
hemorrhage. Toxicity evaluation of the patients enrolled in the trial will be done using the NCI 
Common Toxicity Criteria, Version 4.0, and will be presented to the Clinical Protocol Monitoring 
Committee (UAB Safety and Monitoring Plan).  
 
If toxicity meets the stopping rule at any time during the first 5 patients enrolled in the pilot 
study (see table 2), the protocol will allow the investigators to open a new 20 patient cohort 
using Lapatinib 1000 mg PO a day and Veliparib 150 mg PO twice a day. The new cohort will 
follow the same rules used in the original cohort (Cohort -1).  Patients developing grade 1 and 2 
toxicities will be permitted to take a drug holiday of up to 14 days; after the drug holiday, if the 
adverse event has resolved to the satisfaction of the investigator, the study drugs may be resumed at 
the same level. In the event of recurrent toxicity, there will be one dose reduction permitted (dose 
reduction minus one will be Lapatinib 750 mg PO daily continuously and Veliparib 100 mg PO 
every 12 hours continuously). If the adverse event recurs after dose reduction two, the patient will 
be taken off the study. 
 
Patient Selection Criteria 
 
4.1 
Inclusion Criteria 
 Patients must have pathologically documented breast cancer which is stage IV.  
 Tumor must be HER-2-neu negative (defined as 0 or 1+ staining by immunohistochemistry or 
gene amplification ratio < 2.0, by FISH), estrogen and progesterone receptors  negative (< 1%). 
Patients with BRCA 1 or 2 mutations will NOT be included. 
 Patients must have measurable disease, defined as at least one lesion that can be accurately 
measured in at least one dimension (longest diameter to be recorded) (RECIST criteria 1.1 – see 
Appendix D).  
 Biopsy of a metastatic lesion is not required for protocol entry but all patients with reasonably 
accessible lesions (chest wall, breast, skin, subcutaneous, superficial lymph nodes, bones and 
liver metastases) must agree to biopsy (lung and brain metastasis will not be biopsied):  

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 19 
 
 
o Biopsies may be done with local anesthesia or intravenous conscious sedation, according to 
standard institutional guidelines.   
o If a biopsy requires general anesthesia, then it is only allowed if acquisition of tissue is 
necessary for clinical reasons (i.e. is clinically indicated), and excess tissue that would 
otherwise have been discarded is then used for research purposes.  If a biopsy requires 
general anesthesia, then a biopsy of that site for research purposes only, without a coexisting 
clinical indication is not allowed on this protocol. 
o Patients with reasonably accessible lesions as described above, who will not agree with the 
biopsy, will not be enrolled in the trial.   
o Patients with NO reasonably accessible lesions as described above can be enrolled in the 
trial.   
 Prior Therapy: 
o No more than two regimens in the metastatic setting as long as patients have adequate 
performance status. Patients with no prior chemotherapy for metastatic disease may be 
included in the trial if they received anthracyclines and taxanes in the adjuvant or 
neoadjuvant settings. Chemotherapy naïve patients with metastatic disease must have failed 
anthracyclines and taxanes.   
o Chemotherapy treatment prior to enrollment must be discontinued for at least 3 weeks prior 
to study entry. 
o Patients must have completed radiation therapy at least 21 days prior to beginning protocol 
treatment. 
 Patients must have recovered from all reversible toxicities related to prior therapy before 
beginning protocol treatment, and may not have any pre-existing treatment-related toxicities 
greater than grade 2.  Patients must have < grade 2 pre-existing peripheral neuropathy.  
 Patients may receive bisphosphonates; however, if used, bone lesions may not be used for 
progression or response.  
 At least 19 years of age.  
 Life expectancy of greater than 12 weeks. 
 ECOG performance status < 2 (See Appendix B).  
 Patients must have normal organ and marrow function as defined below: 
o Absolute neutrophil count: > 1,000/µL, 
o Hemoglobin: > 9 mg/dL,  
o Platelets: > 100,000/µL, 
o Total bilirubin: < 1.5 X institutional upper limit of normal, 
o AST(SGOT)/ALT(SGPT): < 2.5 X institutional upper limit of normal without liver 
metastases, OR, < 5 X institutional upper limit of normal if documented liver metastases, 
o Creatinine: < 1.5 mg/dL, OR calculated creatinine clearance > 40 mL/min (calculated by the 
modified Cockcroft and Gault method). 
 Ability to understand and the willingness to sign a written informed consent document. 
  Use of an effective means of contraception in subjects of child-bearing potential.  
 Negative serum or urine beta-HCG pregnancy test at screening for patients with childbearing 
potential. 
 Ejection fraction must be > 50% 
 
4.2       Exclusion Criteria 
 
 Patients may not be receiving any other investigational agents. 
 No prior use of anthracyclines and taxanes for metastatic disease or in the adjuvant or 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 20 
 
 
neoadjuvant setting.  
 Metastatic lesions identifiable only by PET. 
 QTc > 470 msec. Excluded are patients who may develop prolongation of QTc. These 
conditions include patients with hypokalemia or hypomagnesemia, patients with congenital 
long QT syndrome, patients taking anti-arrhythmic medicines or other medicinal products that 
lead to QT prolongation, and cumulative high-dose anthracycline therapy.  
 Patients may not be receiving concurrent chemotherapy for treatment of metastatic disease. 
 Active brain metastases: evidence of progression < 3 months after local therapy (patients should 
be asymptomatic and off corticosteroids and anticonvulsants for at least 3 months prior to study 
entry). 
 Patients with brain metastases must have at least one site of measurable disease outside of the 
central nervous system. 
 Uncontrolled concurrent illness including, but not limited to, ongoing or active infection, history 
of recent myocardial infarction, symptomatic congestive heart failure, unstable angina pectoris, 
cardiac arrhythmia, interstitial lung disease or psychiatric illness/social situations that would 
limit compliance with study requirements. 
 Uncontrolled seizure disorder. 
 Pregnant or lactating women are excluded. Because there is an unknown but potential risk for 
adverse events in nursing infants secondary to treatment of the mother, breastfeeding should be 
discontinued if the mother is treated. These potential risks may also apply to other agents used 
in this study. 
 A prior invasive malignant disease within five years except for skin cancer (squamous cell or 
basal cell carcinoma). 
 Patients with known history of HIV or Hepatitis B because of potential for added toxicity from 
treatment regimen. 
 Dementia or altered mental status that would prohibit the understanding of informed consent. 
 
4.3 
Withdrawal of Patients 
 
A patient should be withdrawn from the trial treatment if, in the opinion of the investigator, it is 
medically necessary, or if it is the wish of the patient. If a patient does not return for a scheduled 
visit, every effort should be made to contact the patient. In any circumstance, every effort should be 
made to document patient outcome. Patients should be removed from therapy if any of the following 
occurs: 
 Disease progression in patients receiving the combination of Lapatinib and Veliparib. Every 
effort should be made to document objective evidence of tumor progression radiographically and 
not solely based on clinical and/or tumor marker suggestions of progression. 
 The occurrence of unacceptable toxicity indicating the need for cessation of treatment.  Patients 
will be followed until stabilization or resolution of the toxicity. 
 The physician feels it is in the best interest of the patient to stop treatment. 
 Patient refusal to continue with therapy. 
 Non-compliance by the patient with protocol requirements. 
 Patient is lost to follow-up. If a patient does not return for scheduled visits, every effort should 
be made to re-establish contact. In any circumstance, every effort should be made to document 
patient outcome, if possible. 
 Patient becomes pregnant. 
 Termination of the study by investigator industry partners. 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 21 
 
 
Treatment may be delayed for up to 2 weeks beyond planned resumption of the next cycle. If a 
patient does not fulfill re-treatment criteria by that time, they will be removed from the trial; if 
unacceptable toxicity to one of the agents used in this combination occurs in a patient enrolled in the 
study, then patient will NOT continue on a single agent.  
 
4.4 
Pregnancy 
 
Prior to study enrollment, women of childbearing potential must be advised of the importance of 
avoiding pregnancy during trial participation, the potential risks of an unintentional pregnancy and 
should practice an effective method of birth control. Women of childbearing potential must have a 
negative pregnancy test within 7 days of initial dosing. The minimum sensitivity of the pregnancy 
test must be 25 IU/L or equivalent units of HCG. If the pregnancy test is positive, the patient must 
not receive investigational product and must not be enrolled in the study. In addition, all women of 
childbearing potential must be instructed to contact the Investigator immediately if they suspect they 
might be pregnant (e.g., missed or late menstrual period) at any time during study participation. The 
Investigator must immediately notify our industry partners (AbbVie and Novartis Pharmaceuticals 
Corporation) in the event of a confirmed pregnancy in a patient participating in the study. 
 
5.0 
DRUG INFORMATION 
 
5.1 
Veliparib or ABT-888 
 
Veliparib is an oral potent inhibitor of PARP which is a nuclear enzyme that recognizes DNA 
damage and facilitates DNA repair. PARP activity is essential for the repair of single-stranded DNA 
breaks through the base-excision repair pathways and is important modulator of the non-homologous 
end-joining and homologous recombination double-stranded break repair pathways.  The patient’s 
weight will NOT be used to determine the dose of Veliparib to be used for the study.  
 
5.1.1 Pharmaceutical Formulation 
 
The chemical name of Veliparib is 1H-Benzimidazole-7-carboxamide,2-[(2R)-2-methyl-2-
pyrrolidiny]-, and it molecular weight is 244.29. Veliparib will be provided by AbbVie as immediate 
release capsules (strengths: 10, 20, 40, 50, and 100 mg). The components of the capsules are 
microcrystalline cellulose, colloidal silicon dioxide, magnesium stearate, gelatin, sodium lauryl 
sulfate, and titanium dioxide (may contain FD&C blue#1, FD&C yellow#6, or FD&C yellow#5.  
 
5.1.2 Labeling and Packaging 
 
Veliparib will be provided by AbbVie free of charge for this study. Veliparib will be packaged in 
bottles containing the capsules. Each bottle label will include all the information, as required by 
local regulations and must remain affixed to the bottle. The site staff must complete all blank spaces 
on the label prior to dispensing drug to the patient. AbbVie will provide the study site with detailed 
instructions and training for the handling of study supplies. 
 
5.1.3 Dispensing Procedures and Storage Conditions 
 
All clinical supplies provided by AbbVie must be stored in a secure place at the proper storage 
conditions until they are dispensed for patient use or are returned to AbbVie. Upon receipt of a 
shipment, the pharmacist will open and inspect the shipment, verify that the Veliparib has been 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 22 
 
 
received intact/in the correct amounts/at the correct address, sign/date the proof of receipt, and 
register the shipment.    
 
The investigational product is for investigational use only and is to be used only within the context 
of the study. Capsules must be stored in the original container at 15º to 25ºC (59º to 77ºF). Patients 
will receive enough capsules every 28 days (every cycle); patients must keep a diary indicating time 
and date of each dose. Patient diary will be reviewed by the study coordinator every 28 days and the 
diary will be kept within the study records at the end of the active therapy of the patient. Patients 
will be instructed to bring their used bottles of Lapatinib to each return visit, along with any unused 
tablets. The site will record the bottle number and dose of Veliparib given to each patient in the 
source documents. 
 
Accountability for investigational clinical supplies at the site rests with the Investigator at the 
participating site. The investigational product will be shipped to a designated person at the study site 
and must be stored in a pharmacy, or other locked and secured in a storage facility, accessible only 
to those individuals authorized by the site’s Principal Investigator.  The study product will be 
administered in accordance with the protocol, only to patients participating in the clinical trial.  It is 
a violation of the regulations to use unapproved study products for purposes other than those 
described in the protocol.   
 
The site will complete the required documentation, provided by UAB to account for investigational 
product dispensation.  Each time the study product is dispensed to a patient; all information must be 
recorded immediately on a drug dispensation form(s). 
 
Unused capsules will be destroyed on site at the conclusion of the study and suitably documented 
by the study team.  Empty bottles and partially used bottles with capsules should be recorded and 
destroyed as per institutional SOP’s after study drug administration.  All returns of study product 
will be accurately recorded on the provided form(s). 
 
5.1.4 Adverse Events Associated With Veliparib 
 
At present, there have been more than 800 patients exposed to ABT-888, however only one study 
tested this drug as a single agent. From this single agent study, conducted in subjects with cancer, 
the most common reported side effects (≥10%) with veliparib as a single agent were: nausea (50), 
fatigue (43), anemia (32), hyperglycemia (27), lymphopenia (24), hypoalbuminemia (22), abdominal 
pain (22), diarrhea (22), decreased appetite (22), headache (20), low sodium (19), increases in liver 
enzymes (17), back pain (15), ascites (15), constipation (15), thrombocytopenia(12), leukopenia 
(12), dizziness (12), increased creatinine (10), dyspnea (12), insomnia (10), and dry mouth (10), hot 
flushes (10). Less frequent, but potentially severe events include dehydration (6.9). Based upon 
events of seizures in preclinical studies using high doses (much higher of what it will be used in this 
study) seizures are a potential risk; however, in ongoing clinical studies, uncommon events of seizure 
have been observed. In preclinical studies also it has been demonstrated that Veliparib absorbs 
ultraviolet light; therefore, the potential exists that Veliparib may contribute to a risk of reddening 
or tanning of the skin when exposed to direct sunlight. In addition, as with any drug, allergic 
reactions are a possibility from a simple rash to anaphylactic shock. Side effects on an unborn or 
nursing infant are not known; however, in preclinical studies harmful effects on fetal development 
have been noted in experimental pregnant animals. 
 
 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 23 
 
 
5.1.5 Veliparib Dosing 
 
The daily dose of Veliparib will be 200 mg PO every 12 hours continuously for 28 days (a cycle), 
starting on Day 2 Cycle 1. Patients developing grade 1 and 2 toxicities will be permitted to take a 
drug holiday of up to 14 days; after the drug holiday, if the adverse event has resolved to the 
satisfaction of the investigator, the study drug may be resumed at the same level. In the vent of 
recurrent toxicity, there will be two dose reductions permitted (Veliparib 150 mg PO every 12 hours 
continuously and Veliparib 100 mg PO every 12 hours continuously). If the adverse event recurs, 
the patient will be taken off the study. Patients developing grade 3 and 4 toxicities will be interrupted 
for permitted for up to 14 days; after the drug holiday, if the adverse event has resolved to the 
satisfaction of the investigator, the study drugs may be resumed at a reduced dose (Veliparib 150 
mg PO every 12 hours continuously). If the adverse event recurs, the patient will be taken off the 
study. Veliparib will start on day 2.   
 
5.2 
Lapatinib (GW572016 or Tykerb®) (See also Lapatinib Package Insert) 
 
Lapatinib is an orally active dual HER1/HER2 kinase inhibitor that blocks signal transduction 
pathways. This dual inhibition is an attractive therapeutic strategy for epithelial cancers, as ligand-
induced HER1/HER2 dimerization triggers off potent proliferative and survival signals. Lapatinib 
will be provided free of charge by Novartis Pharmaceuticals Corporation for this pilot study.   
5.2.1 Packaging, Labeling, and Storage of Study Drug 
 
Lapatinib will be supplied by Novartis Pharmaceuticals Corporation as lapatinib ditosylate 
monohydrate tablets. The tablets contain 250 of the active drug, and they are oval, biconvex, orange, 
film-coated, and are debossed on one side with FL HLS. The tablets contain 400 mg of lapatinib 
ditosylate monohydrate, equivalent to 250 mg lapatinib free base per tablet. Lapatinib must be stored 
at room temperature, in accordance with manufacturer guidelines. 
 
All clinical supplies provided by Novartis Pharmaceuticals Corporation must be stored in a secure 
place at the proper storage conditions until they are dispensed for patient use or are returned to them. 
Upon receipt of a shipment, the pharmacist will open and inspect the shipment, verify that the 
lapatinib has been received intact/in the correct amounts/at the correct address, sign/date the proof 
of receipt, and register the shipment.    
 
The investigational product is for investigational use only and is to be used only within the context 
of the study. Capsules must be stored in the original container at 15º to 25ºC (59º to 77ºF). Patients 
will receive enough capsules every 28 days (every cycle); patients must keep a diary indicating time 
and date of each dose. Patient diary will be reviewed by the study coordinator every 28 days and the 
diary will be kept within the study records at the end of the active therapy of the patient. The site 
will record the package number and dose of Lapatinib given to each patient in the source documents. 
 
Accountability for investigational clinical supplies at the site rests with the Investigator at each 
participating site. The investigational product will be shipped to a designated person at the study site 
and must be stored in a pharmacy, or other locked and secured in a storage facility, accessible only 
to those individuals authorized by the site’s Principal Investigator.  The study product will be 
administered in accordance with the protocol, only to patients participating in the clinical trial.  It is 
a violation of the regulations to use unapproved study products for purposes other than those 
described in the protocol.   
 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 24 
 
 
The site will complete the required documentation, provided by UAB to account for investigational 
product dispensation.  Each time the study product is dispensed to a patient; all information must be 
recorded immediately on a drug dispensation form(s). 
 
Unused capsules will be destroyed on site at the conclusion of the study and suitably documented 
by the study team.  Empty bottles and partially used bottles with capsules should be recorded and 
destroyed as per institutional SOP’s after study drug administration.  All returns of study product 
will be accurately recorded on the provided form(s).   
 
5.2.2 Adverse Events Associated With Lapatinib  
 
Expected non-hematologic toxicities for the use of Lapatinib include diarrhea, rash, mucositis, dry 
skin, elevation of the liver enzymes (especially in patients with prolonged use) and nausea. The 
majority of these events have been grade 1 and 2 and very rarely grade 3 or 4. Hematological toxicity 
has not been associated with this agent.  
 
Diarrhea, including severe diarrhea, has been reported during treatment with Lapatinib. Diarrhea 
generally occurs early during treatment, with almost half of those patients with diarrhea first 
experiencing it within 6 days. This usually lasts 4 to 5 days. Lapatinib-induced diarrhea is usually 
low-grade, with severe diarrhea of NCI CTCAE Grades 3 and 4 occurring in <10% and <1% of 
patients, respectively. Early identification and intervention is critical for the optimal management of 
diarrhea. Patients should be instructed to report any change in bowel patterns immediately. Prompt 
treatment of diarrhea with anti-diarrheal agents (such as loperamide) after the first unformed stool 
is recommended. Severe cases of diarrhea may require administration of oral or intravenous 
electrolytes and fluids,use of antibiotics such as fluoroquinolones (especially if diarrhea is persistent 
beyond 24 hours, there is fever, or Grade 3 or 4 neutropenia), and interruption or discontinuation of 
therapy (see Appendix I for diarrhea management guidelines). 
 
Lapatinib has been reported to decrease LVEF; in clinical trials, the majority (>57%) of LVEF 
decreases occurred within the first 12 weeks of treatment; however, data on long-term exposure are 
limited. Caution should be taken if Lapatinib is to be administered to patients with conditions that 
could impair left ventricular function. LVEF should be evaluated in all patients prior to initiation of 
treatment to ensure that the patient has a baseline LVEF that is within the institution’s normal limits. 
LVEF should continue to be evaluated during treatment with Lapatinib to ensure that LVEF does 
not decline below the institution’s normal limits. 
 
Hepatotoxicity (ALT or AST >3 times the upper limit of normal and total bilirubin >2 times the 
upper limit of normal) has been observed in clinical trials (<1% of patients) and post-marketing 
experience. The hepatotoxicity may be severe and deaths have been reported. Causality of the deaths 
is uncertain. The hepatotoxicity may occur days to several months after initiation of treatment. Liver 
function tests (transaminases, bilirubin, and alkaline phosphatase) should be monitored before 
initiation of treatment, every 4 to 6 weeks during treatment, and as clinically indicated. If changes 
in liver function are severe, therapy with lapatinib should be discontinued and patients should not be 
retreated. 
 
No pulmonary toxicity has been noted with lapatinib. However, interstitial lung disease (ILD) has 
been described in mainly lung cancer patients receiving tyrosine kinase inhibitors against HER1, 
like gefitinib. Interstitial lung disease, which may be acute in onset, has been observed uncommonly 
in patients treated with gefitinib. These patients usually present with a fairly acute onset of dyspnea, 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 25 
 
 
sometimes associated with cough or low-grade fever. This may become quite severe within a short 
period of time and usually results in hospitalization. Radiological investigations, often including CT 
scan, frequently show pulmonary infiltrates or interstitial shadowing with ground-glass appearance. 
There is often respiratory distress with arterial oxygen desaturation. Cultures are frequently negative 
for bacterial growth. If patients present with an acute worsening of respiratory symptoms such as 
dyspnea, cough, and fever, lapatinib will be interrupted and the patient promptly investigated for 
ILD. If ILD is confirmed, lapatinib will be discontinued and the patient treated appropriately. 
 
QT prolongation was observed in an uncontrolled, open-label dose escalation study of lapatinib in 
advanced cancer patients. Lapatinib should be administered with caution to patients who have or 
may develop prolongation of QTc. These conditions include patients with hypokalemia or 
hypomagnesemia, with congenital long QT syndrome, patients taking anti-arrhythmic medicines or 
other medicinal products that lead to QT prolongation, and cumulative high-dose anthracycline 
therapy. Hypocalcemia, hypokalemia, and hypomagnesemia should be corrected prior to lapatinib 
administration. 
5.2.3 Lapatinib Dosing 
 
The daily dose of Lapatinib will be 1250 mg PO every 24 hours continuously for 28 days (a cycle).  
Patients developing grade 1 and 2 toxicities will be permitted to take a drug holiday of up to 14 days; 
after the drug holiday, if the adverse event has resolved to the satisfaction of the investigator, the 
study drug may be resumed at the same level. In the vent of recurrent toxicity, there will be two dose 
reductions permitted (Lapatinib 1000 mg PO every 24 hours continuously and Lapatinib 750 mg PO 
daily). If the adverse event recurs, the patient will be taken off the study. Patients developing grade 
3 and 4 toxicities will be permitted to take a drug holiday of up to 14 days; after the drug holiday, if 
the adverse event has resolved to the satisfaction of the investigator, the study drugs may be resumed 
at a reduced dose (Lapatinib 1000 mg PO every 12 hours continuously). If the adverse event recurs, 
the patient will be taken off the study. Lapatinib will start on day 1. 
 
Patients should be carefully instructed by study personnel on how to take lapatinib. Patients will be 
instructed to take lapatinib, 1250 mg (5 tablets) PO on a daily basis, at approximately the same time 
each day. Lapatinib must be taken on an empty stomach—either 1 hour (or more) before a meal or 
1 hour (or more) after a meal. Patients may not use anything but water to help them swallow their 
lapatinib. Medications that modify gastric pH, while not prohibited, are restricted and further 
described in the table of prohibited medications. Histamine H2 antagonists and proton pump 
inhibitors are allowed.  NOTE: Lapatinib is not to be taken with grapefruit or grapefruit juice. 
Grapefruit and grapefruit juice should not be taken at any time during the study. If the patient vomits 
after their lapatinib dose, the patient should be instructed not to retake the dose. Patients should take 
the next regularly scheduled dose of lapatinib. If vomiting persists, the patient should contact their 
study doctor. 
 
In vitro data suggest the possibility of drug-drug interactions with lapatinib involving metabolic 
enzymes and transporter proteins. Because lapatinib is predominantly eliminated by metabolism 
through CYP3A4/5, drugs that inhibit or induce these enzymes may alter systemic exposure. 
Ketoconazole, a CYP3A4 inhibitor, has been shown to elevate lapatinib plasma concentrations 3.5-
fold. Carbamazepine, a CYP3A4 inducer, has been shown to reduce lapatinib plasma concentrations 
by 72%. Therefore, use of lapatinib with drugs that alter CYP3A4/5 activity should be undertaken 
with caution. Lapatinib has been shown to modestly inhibit CYP3A4 and Pgp, and potently inhibit 
BCRP at in vitro concentrations near the high end of those expected clinically. In the absence of 
clinical data, use of lapatinib with drugs that are substrates for CYP3A4, Pgp, and BCRP should 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 26 
 
 
proceed with caution. For a comprehensive list of prohibited medications, please refer to Appendix 
H. 
 
In August 2011, the lapatinib prescribing information was revised to include information regarding 
potential interactions with midazolam and digoxin. Following co-administration of lapatinib and 
midazolam, 24-hour systemic exposure of orally administered midazolam increased by 45%, while 
24-hour systemic exposure of intravenously administered midazolam increased by 22%. The use of 
midazolam for a procedure (e.g. port placement) is permitted; however, investigators and patients 
should be aware of the potential interaction. Following co-administration of lapatinib and digoxin, 
systemic concentration of oral digoxin increased approximately 2.8-fold. Concomitant use of 
digoxin is not prohibited; however, every effort should be made to switch the patient to a suitable 
alternative. In the event that an alternative to digoxin is not available, serum digoxin concentrations 
should be monitored prior to the initiation of lapatinib therapy, and throughout co-administration. If 
the digoxin serum concentration is greater than 1.2 ng/mL, the digoxin dose should be reduced by 
half. 
 
5.3 Compliance 
 
Compliance with Lapatinib and Veliparib will be evaluated by a physical pill count at the scheduled 
clinic visits on Weeks 4, 8, 12, 16, 20, and 24. Patients will be instructed to bring their used bottles 
of Lapatinib and Veliparib to each return visit, along with any unused tablets. The 
investigator/designee will count the number of remaining tablets at each visit to assess compliance. 
In the event that the patient forgets to bring their used study meds to their clinic visit, compliance 
will be assessed by direct questioning of the subject. In this case, patients should be counseled to 
bring their used drug bottles to their next scheduled appointment so that compliance may be 
confirmed by pill count. Patients should be instructed to report any missed doses of either Lapatinib 
or Veliparib to the study coordinator. 
 
Compliance with Lapatinib and Veliparib will be calculated by the ratio of number of pills actually 
taken to the number of pills that should have been taken. Compliance will be defined as a ratio ≥ 
0.75. Subjects with ratios between 1.00 and 0.75 will be allowed to continue on study. Study staff 
should ensure patient understanding of dosing instructions for patients whose compliance is less than 
100%. In addition, the importance of compliance with anticancer therapy should be reinforced. 
Patients found to be in less than 75% compliance on more than one occasion will be taken off study 
for non-compliance. Subjects who miss doses as a result of physician prescribed drug holidays will 
not be considered non-compliant. Calculation of the compliance ratio should thus be adjusted such 
that the “number of pills that should have been taken” reflects the drug holiday. 
 
6.0 
TREATMENT PLAN 
 
6.1 
Introduction 
 
Patients with pathologically confirmed TNBC (estrogen receptor negative, progesterone receptor 
negative, HER-2-Neu negative – see definitions in section 4.2) who have metastatic disease and have 
not been treated previously for metastatic disease (but received anthracyclines and taxanes in the 
adjuvant or neoadjuvant settings) or have failed one or more chemotherapy regimens in the 
metastatic setting (anthracyclines and taxanes) will be offered participation in this trial with 
appropriate informed consent. It is mandatory for the patients enrolled in the trial to have a biopsy 
of one of the metastatic lesions before they will be treated with the research schema (see eligibility 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 27 
 
 
criteria) if biopsy sites are appropriate; patient advocates will play a very important role in this task 
of the protocol. Patients with NO reasonably accessible lesions as described above can be enrolled 
in the trial.   
 
6.2 
Pilot Trial 
 
Twenty patients evaluable for response will be entered into this phase pilot trial; they will receive 
Lapatinib (1250 mg a day continuously for 28 days) in combination with Veliparib 200 mg every 12 
hours for 28 consecutive days, starting on Day 2 Cycle 1). No blinding will be used in this study. 
Patients will be evaluated for response every 2 courses (every 8 weeks) according to the RECIST 
criteria version 1.1 (see Appendix D). Treatment will be administered on an outpatient basis. 
Treatment may continue without interruption in patients with CR, PR or SD until progression of the 
disease or unacceptable toxicity. Patients cannot receive any other concomitant therapy: 
chemotherapy, targeted therapy, radiation therapy, or other investigational agent while participating 
in the study. There are some restrictions on concomitant medications which must be recorded (see 
Appendix H). Patients may receive bisphosphonates; however, if used, bone lesions may not be used 
for progression or response. Patient with PD at any time will be taken off the study.  
 
Investigators will maintain a confidential screening log of all potential study candidates that includes 
limited information about the patients (initials, sex, age), date, and outcome of screening process: 
enrolled in the study, reason for ineligibility or refused to participate. Investigators will be expected 
to maintain an enrollment log for all patients enrolled in the study indicating their assigned study 
number. A patient will be considered enrolled upon assignment of a patient number. Each patient 
will sign an informed consent provided by the site.  
 
6.2.1 Study Entry 
 
Principal investigator will hold the IND for the trial. All patients must be registered with the Clinical 
Trials Network and Monitoring Office of the UAB Comprehensive Cancer Center (Pam Dixon, 
O.C.N.) before enrollment in study. Prior to initiation of therapy eligibility criteria must be 
confirmed. At the time of registration, a study identification number will be generated. All 
subsequent case report forms will use this study identification number. 
 
6.2.2 Pre-study Assessments 
 
Informed consent will be obtained before study-specific screening evaluations are performed.  
Screening evaluations must be performed within 4 weeks prior to day 0.  
 
Within the 4 weeks prior to therapy initiation patients will undergo baseline clinical evaluation 
(including history, physical evaluation, vital signs, and performance status) and all enrolled patients 
will undergo biopsy of a selected lesion according to the guidelines described in eligibility criteria. 
Additional pre-study evaluations include: CBC with differential and platelets, CMP (fasting), 
CA27.29, pregnancy test (within 7 days if indicated), tumor measurements by images or staging 
studies which are defined as studies contributing to response evaluation, e.g. CTs (chest, abdomen, 
and pelvis), MRI, bone scan, PET, or plain x-rays, EKG and echocardiogram, and concomitant 
medication assessment.  The ejection fraction will be confirmed as normal before proceeding with 
the first dose of lapatinib.   
 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 28 
 
 
Patients with reasonably accessible lesions as described above, who will not agree with the biopsy, 
will not be enrolled in the trial. Patients with NO reasonably accessible lesions as described above 
can be enrolled in the trial.  
  
6.2.3 Treatment and Assessments 
 
Patients will not be randomized; patients will be treated as described before. For this pilot study, a 
course of therapy is 28 day. We are allowing a treatment window of ± 1-3 days.  Lapatinib will be 
administered before Veliparib. Patients will be restaged with the same images or staging studies used 
in the baseline evaluation (staging studies are defined as studies contributing to response evaluation, 
e.g. CTs (chest, abdomen, pelvis), MRI, bone scan, PET, or plain x-rays every 8 weeks (as an 
example, before course 3, 5, 7, 9, ..), and tumor response defined by RECIST criteria version 1.1. 
Patients with SD, PR or CR may continue therapy until disease progression or intolerance to therapy. 
An EKG will be obtained on day 2 and 3 of cycle one. Also, an EKG will be obtained on day one of 
each subsequent cycle.  Echocardiogram will be obtained every 3 months.  
 
In addition, patients will undergo performance status, CBC with differential and platelets, CMP, 
concomitant medication assessment; and assessment of adverse events on day 1 of each cycle. 
Hypocalcemia, hypokalemia, and hypomagnesemia will be corrected prior to lapatinib 
administration.  Physical evaluation, vital signs, and weight will be performed day 1 of each cycle. 
CA27.29 will be obtained every 8 weeks. Pharmacokinetic samples are described in section 6.3. 
 
Patients who have a ≥20% decrease in left ventricular cardiac ejection fraction relative to baseline, 
and the ejection fraction is below the institution's lower limit of normal, should have a repeat 
evaluation of ejection fraction 1-2 weeks later while still receiving investigational product. 
If the repeat ejection fraction evaluation confirms a ≥20% decrease in left ventricular cardiac ejection 
fraction, and the ejection fraction is below the institution's lower limit of normal, then lapatinib 
should be temporarily discontinued. If the left ventricular ejection fraction recovers during the next 
3 weeks, the patient may be restarted on investigational product at a reduced dose. For such patients, 
monitoring of left ventricular ejection fraction will then be performed 2 weeks and 4 weeks after 
rechallenge, and then every 4 weeks thereafter. If repeat ejection fraction evaluation still shows a 
decrease ≥20% in left ventricular ejection fraction relative to baseline, and the value is below the 
institution's lower limit of normal, then the subject should be withdrawn from investigational 
product. Patients with an NCI CTCAE grade 3 or 4 LVEF relative decrease must be withdrawn from 
study medications. Patients will be monitored closely for pulmonary toxicity.  Patients with an NCI 
CTCAE Grade 3 or 4 interstitial pneumonitis must be withdrawn from study medications.  
 
6.2.4 Post-treatment/Follow-up Assessments 
 
Patients will be taken off study treatment following progression; patients will also be taken off 
treatment for treatment delay of more than 2 weeks, or concurrent illness that in the opinion of the 
investigator would affect clinical assessment or endanger the patient. In the event of refusal of further 
therapy, the patient will continue to be followed for outcome. Only if the patient withdraws consent 
will outcome data cease to be collected. 
  
The following evaluations and procedures will be performed at early termination (discontinuation 
for any reason before documentation of disease progression): clinical evaluations (weight, physical 
examination, vital signs and performance status); there must be a complete and clear documentation 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 29 
 
 
of objective response or disease progression (staging studies are defined as studies contributing to 
response evaluation, e.g. CTs (chest, abdomen, pelvis), MRI, bone scan, PET, or plain x-rays using 
the RECIST criteria version 1.1 (reason(s) for discontinuation must be documented); laboratory 
assessment (CBC with differential and platelet count, and CMP); concomitant medication 
assessment; and assessment of adverse events (if the patient has an ongoing toxicity, the patient 
should be followed until resolution or stabilization. Serious and non-serious adverse events 
occurring within 30 days of day 0 of the last treatment should be reported on the appropriate adverse 
event CRF).   
 
6.3 
Ancillary Studies 
 
Pharmacokinetics for Lapatinib and Veliparib In this pilot trial, pharmacokinetics will be done 
in all patients enrolled in the trial. Pharmacokinetics will be carried out during the first course of 
therapy. Samples for the first day will be collected 5 minutes before start of the therapy, 30 and 60 
minutes after the first dose of Lapatinib and then 2, 4, 6, 8, and 24 hours after the start of the therapy 
with Lapatinib, On day 2, patients will take the dose of Lapatinib and Veliparib at the same time of 
day 1 and samples will be taken 30 and 60 minutes after the first dose of Lapatinib and Veliparib, 
then 2, 4, 6, 8, and 24 hours. Additional samples will be taken on day 3, before the third day dose of 
Lapatinib and Veliparib. Same schema will be followed on days 8, 9 and 10 as on days 1, 2, and 3. 
A total of 3-5 mL of blood will be collected in red top tubes at each of the described time points. 
The actual time of administration of each agent and sample collection should be recorded. See 
section 7.6 of the protocol for statistical analysis of pharmacokinetics. PK analysis will be conducted 
at UAB: PK/PD Shared Facility of the UAB Comprehensive Cancer Center. 
 
MicroRNA Profiling Serum (serum separator tubes) will be sent to Dr. Anton Wellstein’s lab at 
Georgetown University to establish microRNA profiles in serum that can predict treatment response 
or resistance. A genome wide analysis of the microRNA’s that are detectable in serum to derive a 
subset of informative microRNA’s will be run. A genomic wide analysis will be run on a subset of 
5 patients before and after treatment to find the most informative microRNA’s (Before initiation of 
therapy and then on day 8, 15 and 29). Informative microRNA’s are defined by: the effect of 
treatment (longitudinal=before/after treatment); and disease status or inter-individual differences 
among the patients (horizontal comparison). From the serum samples sent for this analysis, only a 
small amount of serum is needed for this analysis. Serum that is left over after this analysis is 
completed will be sent back to UAB to facilitate the other correlative work for this protocol. No 
funding is necessary to conduct the evaluation in the laboratory; funds are needed only for shipping. 
 
Biopsies –  
A tumor biopsy of one of the metastatic lesions (see eligibility criteria for biopsy guidelines) will be 
obtained before initiation of therapy. Biopsy samples will preferably be obtained using a 14-18 
gauge core needle; at least two core biopsies will be obtained and snap frozen individually for gene 
expression; a third core will be used for the preparation of paraffin-embedded blocks or formalin 
fixed tissue. 
  
Biopsy of a metastatic lesion is not required for protocol entry but all patients with reasonably 
accessible lesions (chest wall, breast, skin, subcutaneous, superficial lymph nodes, bones and liver 
metastases) must agree to biopsy. Lung biopsies are not acceptable for research only.  Biopsies may 
be done with local anesthesia or intravenous conscious sedation, according to standard institutional 
guidelines. If a biopsy requires general anesthesia, then it is only allowed if acquisition of tissue is 
necessary for clinical reasons (i.e. is clinically indicated), and excess tissue that would otherwise 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 30 
 
 
have been discarded is then used for research purposes.  If a biopsy requires general anesthesia, then 
a biopsy of that site for research purposes only, without a coexisting clinical indication is not allowed 
on this protocol. Patients with reasonably accessible lesions as described above, who will not agree 
to the biopsy, will not be enrolled in the trial.  Patients with NO reasonably accessible lesions as 
described above can be enrolled in the trial.  
Two of the snap frozen research biopsies will be sent to Dr. Yang’s laboratory located at the Hazelrig 
Salter Radiation Oncology Center (176F, Suite 2222G, phone 975-2881, lab pager 2677#) where 
biopsies will be stored for batching.  All samples will be indelibly labeled with the appropriate study 
number, and date of acquisition; these data will be correlated with clinical efficacy including 
complete response and objective response. One of the frozen research biopsies will be processed for 
targeted gene expression analysis, tumor microRNA profiling, and copy number variation of 
commonly amplified or deleted genes in cancer using the Nanostring nCounter DX system with 
FLEX configuration (Yang Lab). This system will also allow for the analysis of the Prosigna Breast 
Cancer Prognostic Gene Signature Assay (based on the PAM50 gene set established by Charles 
Perou et al., Nature 2000) that provides intrinsic subtyping information as well as prognostic 
information as it relates to drug response. Targeted gene expression will be performed using prebuilt 
gene panels by Nanostring including the Human Kinase (519 kinases), Human Immunology (594 
immunology genes), Human Cancer Reference (236 cancer related genes), and Human Inflammation 
(184 inflammation gene) kits. Tumor microRNA profiles will also be analyzed using total RNA 
from tumor biopsies (800 human miRNAs).  Lastly, copy number variation of commonly altered 
genes in cancer will be investigated from DNA harvested from the tumor. For each analysis, as little 
as 100ng of total RNA or 300ng of genomic DNA is needed for highly reproducible results. 
Additionally, if available, formalin-fixed paraffin-embedded tissues from the original primary tumor 
will also be subjected to this analysis to investigate the evolution of the tumor from primary to 
metastatic.  
Fifteen slides will also be prepared from the formalin-fixed paraffin embedded tissue for analysis  
by conventional IHC of ER, PR, Her-2, EGFR, PARP, Ki67, apoptotic markers, and biomarkers of 
DNA repair such as H2AX, PARP, and BRCA localization. All samples will be indelibly labeled 
with the appropriate study number, and date of acquisition; these data will be correlated with clinical 
efficacy including complete response and objective response. 
 
The second frozen core research biopsy will be sent to Hudson Alpha Institute at a later designated 
time point to be used for comprehensive genomic analysis such as Next-GEN genomic analysis.71 
“Next-GEN genomic analysis will be done at HudsonAlpha Institute for Biotechnology in 
Huntsville, Alabama (Shared Facility of the UAB Comprehensive Cancer Center) by Dr. Richard 
Myers’ group. No funding is necessary to conduct the evaluation in the laboratory at this time or 
macro-dissection; funds are needed only for shipping. 
 
Researchers at HudsonAlpha Institute for Biotechnology led by Dr. Richard M. Myers will obtain 
tissues from Dr. Erica M. Stringer-Reasor and colleagues at UAB from patients with TNBC enrolled 
in the pilot Study.  HudsonAlpha Institute for Biotechnology will analyze the tissues for several 
functional genomics features on a genome-wide scale, as well as whole exome DNA sequencing, to 
identify genetic variants. The functional genomics readout and genetic variation measurements will 
be assessed to help identify differences associated with TNBC itself, subtypes of TNBC and/or 
responses to drug treatments.  The researchers at Hudson will utilize their expertise in applying six 
different genome-wide functional genomics measurements, as well as whole exome sequencing, 
whole genome sequencing and specialized array-based genotyping to measure genomic and genetic 
variants for cancers, brain diseases, autoimmune diseases and drug responses. 
 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 31 
 
 
The functional genomics measurements will include the use of ultrahigh throughput sequencing to 
measure mRNAs and long non-coding RNAs (RNA-seq), microRNAs (miRNA-seq), DNA 
methylation (a combination of two approaches, RRBS and Methyl1450 arrays), protein:DNA 
interations (ChIP-seq), chromatin markers (also ChIP-seq) and chromatin accessibility 
measurements (DNase-seq). 
 
To measure DNA sequence variation, two types of ultrahigh throughput DNA sequencing will be 
performed: whole exome sequencing, where all the exons and exon:intron boundaries in the human 
genome are sequenced deeply; and whole genome sequencing, to be used on a modest number of 
samples due to expense. A combination of exome and whole genome sequencing with inexpensive 
genotyping of 1 million or more polymorphic DNA markers around the genome may be used to 
supplement the DNA sequencing and to improve the ability to identify large DNA sequence variants 
known as copy number variants. 
 
Fifteen slides will be prepared from the paraffin blocks or formalin fixed tissue by a designated 
pathologist at UAB for analysis by conventional IHC of ER, PR, Her-2, EGFR, Ki67, apoptotic 
markers, and biomarkers of DNA repair such as H2AX and BRCA localization. All samples will be 
indelibly labeled with the appropriate study number, and date of acquisition; these data will be 
correlated with clinical efficacy including complete response and objective response.  
Any leftover study blood and tissue samples may be stored for future research studies.  The subjects 
will consent to the future use of samples in the consent form for the study.  Any samples will only 
be released for use in future studies after approval by the Principal Investigator and other regulatory 
bodies, as appropriate. 
 
Pharmacogenomic Analyses – Blood samples for pharmacogenomic analyses will be collected on 
a first day before initiation of research agents. Blood will be collected into one 6 ml K2EDTA 
polypropylene blood collection tube (Becton-Dickinson) and into one PAX gene tube. The 6 mL 
polypropylene K2EDTA tube will be placed in an ice bath immediately following collection and 
stored upright in a freezer set at -20ºC (+/- 10ºC) until sending to the laboratory. It is important to 
collect a full tube of whole blood. The PAX gene tube should be stored upright at room temperature 
for a minimum of 2 hours or a maximum of 4 hours before processing or transferring to a freezer. 
They should be stored upright in a wire rack and stored at -20 degrees Celsius or colder until sending 
to the laboratory. Blood samples should be sent to The University of Alabama (Attention: The 
University of Alabama at Birmingham; Center for Clinical Translation Science (CCTS) Laboratory, 
Jefferson Tower, Room 1531, 625 19th Street south,  ; Birmingham, AL 35233) as soon as logistically 
possible following blood draws. The University of Alabama will store the samples until assays are 
to be performed. Samples will be shipped to The HudsonAlpha Institute for Biotechnology. The 
Hudson Alpha Institute may conduct pharmacogenomic assays possibly including, but not limited 
to, DNA sequencing of exons as well as DNA sequencing from RNA transcripts, DNA methylation 
screens, and tests for specific single nucleotide polymorphisms. These tests on normal tissue may 
provide reference values for comparison against similar tests previously approved for the patients’ 
tumor tissue. The protocol will provide the tubes (EDTA and PAX gene tubes). 
 
Plasma Tumor DNA (ptDNA)- 
 
Successful treatment depends on the ability to monitor disease burden and response to therapies. 
Recently, a proof of principle study has shown that plasma tumor DNA (ptDNA) can be used as a 
reliable breast cancer biomarker in metastatic disease, due to its sensitivity and wide dynamic range. 
ptDNA more accurately reflects changes in response to therapies, and absolute levels of ptDNA 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 32 
 
 
demonstrate prognostic significance. Thus, ptDNA as a liquid biopsy shows great promise in the 
clinical management of metastatic breast cancer. The key is to maximize removal of contaminating 
cells and genomic DNA form these cells as large genomic DNA fragments hinder plasma DNA 
analysis.  
 
It is now well-established that cells naturally secrete or shed small DNA fragments into the 
circulation with most of this DNA being compartmentalized in the plasma component of whole 
blood. Small amounts of cell-free circulating DNA can be detected in plasma from healthy 
individuals,79,80 is often highly elevated in metastatic cancer patients 79,81 and correlates with disease 
burden.78,82,83 Interestingly, how ctDNA enters the plasma is not precisely known. While the 
fragment size of circulating DNA in healthy individuals suggests that it originates from apoptotic 
cells,80 circulating DNA is also shed from non-apoptotic cells and in this instance it is often larger 
and more variable in size.84,85,86 For clarity, we prefer and will henceforth use the term plasma tumor 
DNA (ptDNA) over ctDNA since there is confusion regarding ctDNA versus DNA derived from 
CTCs, which are distinctly different. In addition, ptDNA is more specific as it is a subset of ctDNA, 
since ctDNA also includes urine tumor DNA (utDNA) as well as ctDNA in other bodily fluids. 
Recent work, including that from our own group, supports the utility of ptDNA as a facile means for 
liquid biopsy. 78,81,87Ben Park’s group and others have shown that cancer specific somatic mutations 
can be detected in ptDNA from metastatic breast cancer patients with up to a 100% concordance 
when blood is taken concurrently with tissue biopsy. 78,81,87 In contrast, Dr. Park’s group also 
demonstrated that mutational discordance can occur between ptDNA and primary breast cancer 
tissues when there is a prolonged period (greater than 3 years) between initial diagnosis and 
recurrence.87 This speaks to the now proven concept of tumor heterogeneity and clonal evolution. 
ptPtDNA has also been used to identify treatment associated mutational changes . 77,81Thus, 
assessment of ptDNA can relay the mutational status of a patient’s cancer with the ability for serial 
testing. 
 
Blood will be collected in three cell-free DNA BCT tubes (Streck) per time point: at baseline before 
drug administration, on days 15 and 29 (day 1 of cycle 2 pre-treatment). Samples collected in the 
DNA BCT tubes are stable for up to 14 days at temperatures between 6-37O C.  Once tubes are filled 
completely the tube should be mixed by gently inverting 8 to 10 times.  The tubes will be transferred 
to Dr. Yang’s lab for processing and freezing of the samples which will be batched and sent at a later 
date for analysis to Ben Park’s lab at the Sidney Kimmel Comprehensive Cancer Center, Johns 
Hopkins University.  
 
Serum Marker of Apoptosis - Serum levels of M30 will be drawn pre-dose, Day 8, and Day 15of 
cycle one only.  The changes of the serum levels of M30 at each time point will be correlated with 
levels of M30 in CTCs as well as with efficacy parameters. M30 serum evaluations will be conducted 
at the Mayo Clinic by Dr. Paul Haluska. Activation of the intrinsic apoptotic pathway involves 
release of cytochrome c to the cytosol, activation of caspases (specifically caspase 9 followed by 
caspase 3), and cleavage of hundreds of substrates by caspase 3.72, 73  Among the caspase 3 substrates 
is cytokeratin 18, which yields a fragment that is uniquely detectable using the monoclonal antibody 
M30 upon caspase cleavage.74  When apoptotic cells lyse, all of these proteins (cytochrome c, 
cleaved/activated caspase 3 and cleaved cytokeratin 18) are released to the circulation, where they 
can be detected by ELISA to provide an assessment of the degree of epithelial cell apoptosis.  
Samples will be sent to Mayo Clinic for later analysis. No funding is necessary to conduct the 
evaluation in the laboratory; funds are needed only for shipping. 
 
 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 33 
 
 
6.4 
Subject Discontinuation/Early Termination 
 
Patients may withdraw from this study at any time. Any patient who withdraws will be encouraged 
to return to the study center for the post-dose evaluations. The termination visit consists of all 
evaluations scheduled for the termination visit. The primary reason(s) for discontinuation must be 
recorded on the appropriate CRF page.  The PI may discontinue a patient from treatment.  Reasons 
may include, but are not limited to, the following: clinically significant deterioration, 
noncompliance, persistent grade 3 or 4 adverse event or any significant adverse event that 
compromises the patient’s ability to participate in the study, requirement of a significant surgical 
procedure or radiation therapy during the treatment period of the study, investigator’s determination 
that it is not in the patient’s best interest to continue participation, development of brain metastases, 
or pregnancy. Patients will be monitored for 30 days following the end of treatment and will be 
removed from the study at the end of this follow-up period Patients who have an ongoing research-
related Grade 4 or serious adverse event at the time of discontinuation from study treatment will 
continue to be followed until resolution of the event or until the event is considered irreversible.  
 
6.5  
Study Discontinuation 
 
The principal investigator and/or UAB CCC and/or Novartis Pharmaceuticals Corporation and/or 
AbbVie have the right to terminate the study for any reason, including: the incidence or severity of 
adverse events indicates potential health hazard for patients, subject enrollment is unsatisfactory; 
data recording is inaccurate or incomplete, or other reasons discussed with the principal investigator 
and the UAB CCC. 
 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 34 
 
 
6.6 
Study Parameters 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pre-Treatment 
(within 4 weeks 
of  initiation) 
+/- 
Day 1 
of  each 
cycle 
Day 8  
of  cycle 
1 
Day 15 
of  cycle 
1 
 
Every 8 
weeks 
+/- 
At 
Progression 
+/- 
End of 
Treatment/ 
Early 
Termination 
Informed Consent 
X 
 
 
 
 
 
 
 
History/Height 
X 
 
 
 
 
 
 
 
Physical Exam/Vital Signs/Weight 
X 
X 
 
 
 
 
X 
X 
Performance Status 
X 
X 
 
 
 
 
X 
X 
Toxicity Assessment10 
 
X 
 
 
 
 
X 
X 
CBC/Differential/Platelets11 
X 
X 
 
 
 
 
X 
X 
CMP (fasting)11 
X 
X 
 
 
 
 
X 
X 
Magnesium 
 
X 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
 
 
 
 
X 
X 
Pregnancy Test1 
X 
 
 
 
 
 
 
 
Staging Studies2 
X 
 
 
 
 
X 
X 
X 
Biopsy of a Metastatic Lesion3 
X 
 
 
 
 
 
 
 
Serum CA27.29 Level 
X 
 
 
 
 
X 
X 
X 
Lapatinib Administration7  
 
 
 
 
 
 
 
 
Veliparib Administration 7 
 
 
 
 
 
 
 
 
Pharmacokinetics4 
 
X 
X 
 
 
 
 
 
ptDNA5,6 and serum5 
 
X 
X 
X 
 
 
 
 
Echocardiogram and EKG8 
X 
X 
 
 
 
 
 
 
Pharmacogenomics 9 
 
X 
 
 
 
 
 
 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 35 
 
 
1 
Must be obtained within 7 days of initial dosing. Only for patients with childbearing potential. 
2 
Staging studies are defined as studies contributing to response evaluation, e.g. CTs (chest, abdomen, and pelvis), MRI, bone scan, PET, or plain x-rays. 
3 
Mandatory if metastatic site is accessible (see inclusion criteria), i.e. chest wall, breast, skin subcutaneous, superficial lymph node, bone or liver metastases (not lung or brain). 
Biopsy samples will preferably be obtained using a 14-18 gauge core needle; at least two core samples will be obtained and snap frozen and a third sample for the preparation 
of the paraffin-embedded blocks.  
4 
Samples for the first day will be collected 5 minutes before start of the therapy, 30 and 60 minutes after the first dose of Lapatinib and then 2, 4, 6, 8, and 24 hours after the start 
of the therapy with Lapatinib, On day 2, patients will take the dose of Lapatinib and Veliparib at the same time of day 1 and samples will be taken 30 and 60 minutes after the 
first dose of Lapatinib and Veliparib, then 2, 4, 6, 8, and 24 hours. Additional samples will be taken on day 3, before the third day dose of Lapatinib and Veliparib. Same schema 
will be followed on days 8, 9 and 10. A total of 3-5 mL of blood will be taken at each of the described time points. The actual time of administration of each agent and sample 
collection should be recorded.  
5 
Blood samples (see Appendix E for ptDNA sampling details) will be obtained from each patient at days 1 (baseline; before the initiation of the research medications), on days 
15 and 29 (day 1 of 2nd cycle pre-treatment) of the first cycle. Serum will obtained (5 ml blood sample) from each patient at days 1 (baseline; before the initiation of research 
medications), on days 8, 15, and 29 (day 1 of 2nd cycle pretreatment) of the first cycle (serum will be used for evaluation of micro RNA profiling and M30 protein).   
6 
Because shipments of ptDNA samples can only occur on Mondays through Thursdays, initiation of treatment cannot occur on Fridays.  
7 
Patients will receive Lapatinib (1250 mg PO daily continuously) in combination with Veliparib (200 mg PO every 12 hours continuously). A cycle of therapy is defined as 28 
days of PO therapy. Lapatinib starts on Day 1 and Veliparib on Day 2.  
8 
Echocardiogram will be obtained every 3 months while on active therapy. EKG will be obtained at baseline, day 2 and 3 of cycle one, and day one of each subsequent cycle.  
Patients who have a ≥20% decrease in left ventricular cardiac ejection fraction relative to baseline, and the ejection fraction is below the institution's lower limit of normal, 
should have a repeat evaluation of ejection fraction 1-2 weeks later while still receiving investigational product. If the repeat ejection fraction evaluation confirms a ≥20% 
decrease in left ventricular cardiac ejection fraction, and the ejection fraction is below the institution's lower limit of normal, then lapatinib should be temporarily discontinued. 
If the left ventricular ejection fraction recovers during the next 3 weeks, the patient may be restarted on investigational product at a reduced dose. For such patients, monitoring 
of left ventricular ejection fraction will then be performed 2 weeks and 4 weeks after rechallenge, and then every 4 weeks thereafter. If repeat ejection fraction evaluation still 
shows a decrease ≥20% in left ventricular ejection fraction relative to baseline, and the value is below the institution's lower limit of normal, then the subject should be withdrawn 
from investigational product. Patients with an NCI CTCAE grade 3 or 4 LVEF relative decrease must be withdrawn from study medications.  
9 
Blood samples for pharmacogenomic analyses will be collected Cycle 1 Day 1 only before initiation of research agents. Blood will be collected into one 6 ml K2EDTA 
polypropylene blood collection tube (Becton-Dickinson) and into one PAX gene tube. 
 
10 Patients with an NCI CTCAE Grade 3 or 4 interstitial pneumonitis must be withdrawn from study medications. 
11 Cycle 1, Day1 CBC and CMP only need to be obtained if prior labs are greater than 4 weeks. 
 
 
 
 
 
 
 
 
 
 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 36 
 
                                                         
 
  
 
 
 
 
6.7 
Efficacy and Safety Assessments 
 
Response and progression will be evaluated in this study using the international criteria proposed 
by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee; version 1.1 (see 
Appendix D).75 Changes in only the largest diameter (unidimensional measurement) of the tumor 
lesions are used in the RECIST criteria.  Note:  Lesions are either measurable or non-measurable 
using the criteria provided below.  The term “evaluable” in reference to measurability will not be 
used because it does not provide additional meaning or accuracy. 
 
6.7.1 Definitions 
 
Measurable Disease – Measurable lesions are defined as those that can be accurately measured 
in at least one dimension (longest diameter to be recorded) as >20 mm by chest x-ray, as > 10mm 
with CT scan, or > 10mm with calipers by clinical exam.  All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters). 
 
Definitions proved for normal: short axis < 10 mm, Measurable (Target): short axis ≥ 15mm, 
Non-measurable: short axis 10 to <15 mm, Target nodes measured in the short axis 
(perpendicular to longest diameter) more reproducible and predictive of malignancy.  Short axes 
of target nodes to be added to the sum of longest diameters. 
 
Non-Measurable Disease – All other lesions (or sites of disease), including small lesions (longest 
diameter <10mm or pathological lymph nodes with > 10 to <15mm short axis, are considered non- 
measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed 
by CT or MRI), are considered as non-measurable 
 
Target Lesions – All measurable lesions up to a maximum of two lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target lesions and 
recorded and measured at baseline.  Target lesions should be selected on the basis of their size 
(lesions with the longest diameter), be representative of all involved organs, but in addition 
should be those that lends themselves to reproducible repeated measurements.  It may be the case 
that, on occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected.  A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum.  If lymph nodes are to be included in 
the sum, then only the short axis is added to the sum.  The baseline sum LD will be used as 
referenced by which to characterize the objective tumor response. 
 
Non-Target Lesions – All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline. Measurements of these lesions are not required, but the presence, absence, or 
in rare cases unequivocal progression of each should be noted throughout the follow-up.   
 
All other lesions (or sites of disease) including any measurable lesions over and above the 5 target 
lesions should be identified as non-target lesions and should also be recorded at baseline. 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 37 
 
                                                         
 
  
 
 
 
 
Measurements of these lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout the follow-up. 
 
6.7.2 Guidelines for Evaluation of Measurable Disease 
 
General Aspects of Tumor Measurement - All measurements should be taken and recorded in 
metric notation using a ruler or calipers.  All baseline evaluations should be performed as closely 
as possible to the beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. Note: Tumor lesions that are situated in a previously irradiated area might or might not 
be considered measurable. 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. 
 
Specific Methods of Tumor Measurement: 
  
- Clinical lesions – Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes).  In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended.  
- Chest x-ray – Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable.  
- Conventional CT and MRI – This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5mm or less. If CT scans have slice thickness 
greater than 5mm, the minimum size for a measurable lesion should be twice the slice thickness. 
MRI is also acceptable in certain situations (e.g. for body scans).  
 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal resolution; 
however, there are many image acquisition variables involved in MRI, which greatly impact image 
quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI is variable 
globally. As with CT, if an MRI is performed, the technical specifications of the scanning 
sequences used should be optimized for the evaluation of the type and site of disease. Furthermore, 
as with CT, the modality used at follow-up should be the same as was used baseline and the lesions 
should be measured/assessed on the same pulse sequence. It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body parts, and 
diseases. Ideally, the same type of scanner should be used and the image acquisition protocol 
should be followed as closely as possible to prior scans. Body scans should be performed with 
breath-holding scanning techniques, if possible. 
 
- PET-CT – At present, the low dose or attenuation correction CT portion of a combined PET-
CT is not always of optimal diagnostic CT quality for use with RECIST measurements. 
However, if the site can document that the CT performed as part of a PET-CT is of identical 
diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-
CT can be used for RECIST measurements and can be used interchangeably with conventional 
CT in accurately measuring cancer lesions over time. 
 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 38 
 
                                                         
 
  
 
 
 
 
Note, however, that the PET portion of the CT introduces additional data which may bias an 
investigator if it is not routinely or serially performed. 
 
- Ultrasound (US) – Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date, and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT or 
MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead of C 
in selected instances. 
- Endoscopy, Laparoscopy – The utilization of these techniques for objective tumor evaluation 
is not advised.    However, such techniques can be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence following 
complete response (CR) or surgical resection is an endpoint.  
- Tumor Markers – Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered in 
complete clinical response.  
- Cytology, Histology – These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ 
cell tumors, where known residual benign tumors can remain). The cytological confirmation of the 
neoplastic origin of any effusion that appears or worsens during treatment when the measurable 
tumor has met criteria for response or stable disease is mandatory to differentiate between response 
or stable disease (an effusion may be a side effect of the treatment) and progressive disease. 
-FDG-PET – While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly  possible “new” disease. New lesions on the basis PF 
FDG-PER imaging can be identified according to the following: 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive 
FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up 
CT scans are needed to determine if there is truly progression occurring at that site (if so, the 
date of PD will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET 
at follow-up corresponds to pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images this is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases 
where a residual radiographic abnormality is thought to represent fibrosis or scarring. The use 
of FDG-PET in this circumstance should be prospectively described in the protocol and 
supported by disease-specific medical literature for the indication. However, it must be 
acknowledged that both approaches may lead to false positive CR due to limitations of FDG-
PET and biopsy resolution/sensitivity.  
 
Note:  A “positive” FDG-PET scan lesion means one which is FDG avid with uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image.  

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 39 
 
                                                         
 
  
 
 
 
 
6.7.3 Response Criteria 
 
6.7.3.1 Evaluation of Target Lesions 
 
- Complete Response (CR):  Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or not) must have reduction in short axis to < 10mm. 
- Partial Response (PR):  At least a 30% decrease in the sum of the longest diameter (LD) of 
target lesions, taking as reference the baseline sum diameters. 
- Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this included the baseline sum if that is 
the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5mm. (Note: the appearance of one or more new lesions is also 
considered progression.) 
 
- Stable Disease (SD):  Neither sufficient shrinkage to qualify or PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
 
6.7.3.2 Evaluation of Non-Target Lesions 
 
- Complete Response (CR):  Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10mm short axis). Note: If serum 
CA27.29 levels are initially above the upper normal limit, they must normalize for a patient to be 
considered in complete clinical response. 
- Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits.  
-Progressive Disease (PD):  Appearance of one or more new lesions and/or unequivocal progression of existing 
non-target lesions. Unequivocal progression should not normally trump target lesion status. It must 
be representative of overall disease status change, not a single lesion increase. 
Although a clear progression of “non-target” lesions only is exceptional, in such circumstances the 
opinion of the treating physician should prevail, and the progression status should be confirmed at 
a later time by the review panel (or study chair).  
 
6.7.4 Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started).  The patient’s best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
 
 
 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 40 
 
                                                         
 
  
 
 
 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target Lesions 
Non Target 
Lesions 
New Lesions 
Overall 
Response 
Best Overall 
Response when 
Confirmation is 
Required* 
CR 
CR 
No 
CR 
> 4 wks. 
confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
> 4 wks. 
confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at 
least once >4 
wks. from 
baseline** 
PD 
Any 
Yes or No 
PD 
No prior SD, PR 
or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* 
** 
*** 
 
 
Note: 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
Only for non-randomized trials with response as primary endpoint. 
In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration”.  Every effort should be made to document 
the objective progression even after discontinuation of treatment. 
 
For Patients with Non-Measurable Disease 
(i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
Not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* “Non-CR/non-PD” is preferred over “stable disease” for non-
target disease since SD is increasingly used as an endpoint for 
assessment of efficacy in some trials so to assign this category 
when non-lesions can be measured is not advised. 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 41 
 
                                                         
 
  
 
 
 
 
6.7.5 Duration of Response 
 
Duration of Overall Response – The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started).The duration of overall 
CR is measured from the time measurement criteria are first met for CR until the first date that 
recurrent disease is objectively documented. 
 
Duration of stable disease – Stable disease is measured from the start of  treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements. 
 
6.7.6 Definitions Related to Evaluation Unrelated to Objective Response 
 
Overall Survival is the observed length of life from entry into the study to death or the date of 
last contact. 
 
Progression-Free Survival is the period from study entry until disease progression, or death, 
whichever occurs first.   
 
Recurrence-Free Survival (non-measurable disease studies) is the period from study entry until 
disease recurrence, death or date of last contact. 
 
Subjective Parameters including performance status, specific symptoms, and side effects. 
 
Side effects are graded according to the National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.03 (see Appendix A). Any patient who receives 
treatment on this protocol will be evaluated for toxicity. Each patient will be assessed periodically 
according to the study parameters table for the development of any toxicity. Dose modifications 
will be made based on toxicities as described earlier. 
 
 
7.0 
STATISTICAL CONSIDERATIONS 
 
This is an open-label, single arm, single institution, pilot clinical trial. The primary objective is to 
characterize the safety profile and treatment tolerance of Veliparib (ABT-888) in combination with 
Lapatinib (Tykerb) in patients with metastatic, estrogen receptor (ER) negative, progesterone 
receptor (PR) negative, and human epidermal growth factor receptor 2 (HER-2-Neu) negative 
breast cancer. Secondary objectives will estimate the objective response rate (ORR) (complete 
responses [CRs] plus partial responses [PRs]); Determine progression free survival (PFS); 
correlate pre-treatment tumor gene expression profile, biomarkers of DNA repair (H2AX, BRCA 
localization), EGFR location and signaling, and apoptosis markers with the ORR and PFS; 
Correlate serial measures of CTCs and serum levels of M30 with the ORR and PFS and determine 
the pharmacokinetics of Veliparib and Lapatinib when given in combination. A total of 20 (maybe 
25 if an additional cohort is added) patients will be enrolled in a single site (University of Alabama 
at Birmingham) over a projected 12-18 months accrual interval.   

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 42 
 
                                                         
 
  
 
 
 
 
7.1 
Primary Endpoint  
 
We will characterize the safety profile and treatment tolerance of Veliparib (ABT-888) in 
combination with Lapatinib (Tykerb). Drug related toxicities for the safety analysis are defined as 
(see section 3.0 also): a) any grade 3 or 4 non-hematologic toxicity except alopecia, and nausea 
which is not refractory to anti-emetics; b) failure to recover to baseline (except alopecia) after 
delaying the next dose by more than 14 days; c) grade 3 or 4 neutropenia complicated by fever > 
38.50 C or infection, or grade 4 neutropenia of a least 7 days duration; or d) grade 4 
thrombocytopenia, or grade 3 thrombocytopenia complicated by hemorrhage. Toxicity evaluation 
of the patients enrolled in the trial will be done using the NCI Common Toxicity Criteria, Version 
4.0). 
 
7.2 
Secondary Endpoint 
 
In patients with metastatic TNBC, who will be treated with the combination of Veliparib and 
Lapatinib, we will estimate the ORR (CRs plus PRs); determine PFS; correlate pre-treatment 
tumor gene expression profile, biomarkers of DNA repair (H2AX, BRCA localization), EGFR 
location and signaling, and apoptosis markers with the ORR and PFS; correlate serial measures of 
CTCs and serum levels of M30 with the ORR and PFS; determine the pharmacokinetics of 
Veliparib and Lapatinib when given in combination.  
 
7.3 
Stratification 
 
No Stratification will be incorporated in this pilot study.  
 
7.4 
Sample Size and Power Justification  
 
This is a single arm pilot study to evaluate the safety of combination of Veliparib and Lapatinib in 
patients with metastatic TNBC. A total of 20 patients will be enrolled to evaluate the safety as 
treatment related toxicity rate and the objective response rate. The sample size is NOT determined 
by the statistical power but the feasibility and relative precision of estimate, e.g. standards error of 
the estimation is <=10%. Assuming the acceptable toxicity rate with combination therapy is no 
more than 30%; then, we will be able to have two sided 95% exact confidence intervals (Clopper-
Pearson intervals) of toxicity estimate from 11.8% to 54.3%. Meantime, this sample size will 
provide two-sided 95% exact confidence intervals (Clopper-Pearson intervals) of objective 
response rate estimation as follow: 
 
Table 2 Exact 95% Confidence Interval for Response Rate Estimation 
 
Response rate % 
Confidence interval (lower) % 
Confidence interval (Upper) % 
20 
5.73 
43.66 
25 
8.66 
49.10 
30 
11.89 
54.28 
 
If the response rate is equal or greater than 30%, we will propose a phase II trial to be conducted 
in the Translational Breast Cancer Research Consortium (TBCRC). 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 43 
 
                                                         
 
  
 
 
 
 
7.5       Analysis plan 
 
We will consider that any subjects enrolled to the study as intent-to -treat (ITT) population; patients 
must at least start therapy or they will be replaced. The ITT patients will be included for all efficacy 
analysis. We will consider any patients who received at least one dose of Lapatinib and/or 
Veliparib as safety analysis population. The safety analysis population will be used for safety 
evaluation. The final statistical analysis will be conducted after all patients that have completed 
treatment with documentation of toxicity, response and progression free survival. 
 
7.5.1 Analysis of Safety 
 
The primary analysis is of safety that will include any patients who receive at least one dose of 
Lapatinib and/or Veliparib. The treatment related toxicity rate will be estimated at the end of the 
study along with two sided 95% exact confidence intervals (Clopper-Pearson intervals). Analysis 
of safety data will be descriptive. Descriptive statistics will be calculated for quantitative safety 
data and frequency counts will be compiled for classification of qualitative safety data. Adverse 
event and serious adverse event (AE/SAE) (AE/SAE definition is in 9.1.1) reporting during the 
study will be summarized by relationship to study drug and intensity. Number and proportion of 
adverse event, serious adverse event and grade 3 or 4 lab toxicity will be reported by body system 
and by each study arm.  Patient’s baseline lab data and its change during treatment at each visit 
will be presented. Graphic statistics tool such as box plot will be used when it is appropriate. 
 
7.5.2 Analysis of Efficacy endpoints 
 
At the completion of the study, the secondary endpoint of ORR rate will be estimated along with 
two-sided 95% confidential intervals for Lapatinib and Veliparib combination group with exact 
method of Clopper-Pearson intervals. Secondary endpoint analysis will be descriptive. Mean, 
median, and range will be used to describe continuous demographic variables. Frequency and 
proportion will be used to describe categorical variables. The K-M estimator will be used to 
estimate median progression free survival along with 95% confidence intervals.  
 
Exploratory analysis will be conducted on the correlations between clinical outcomes and 
biomarkers or gene expression profiles. Gene expression profile, proliferation/apoptosis markers, 
and circulating level of tumor cells will be analyzed between responders and non-responders using 
two-sample t-test test assuming normal distribution for gene expression level. An appropriate 
normal transformation will be conducted prior analysis when it is necessary. Alternatively, one 
way analysis of variance (ANOVA) can be used to evaluate gene expression and biomarkers by 
responders. Logistic regression analysis will be used to predict response with these genes or 
biomarkers with or without adjustment for covariate, e.g. age. Two-sample log rank test will be 
used to compare PFS curves classified by biomarkers or gene expression profiles so that potential 
prognostic biomarkers or genes will be identified. Multivariate Cox proportional hazards model 
will be used to identify a set of biomarkers for prediction of time to disease progression between 
responders and non-responders. Hazards ratios with 95% confidence intervals will be calculated 
for each significant biomarker in terms of predicting time to disease progression. Since this is an 
exploratory pilot study which will be used as a hypothesis generator. We will include EGFR 
expression and location, and markers of apoptosis and DNA repair as covariate in all above 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 44 
 
                                                         
 
  
 
 
 
 
exploratory analysis. 
 
7.5.3 Analysis of Pharmacokinetics 
 
Non-compartmental pharmacokinetic parameters, including maximal plasma or serum 
concentration (Cmax),, area under the curve to the last collection point (AUClast), area under the 
curve for dose interval (AUC0-t), area under the curve extrapolated to infinity (AUCinf), time of 
maximal concentration (Tmax), elimination rate constant (kel), terminal half-life (t1/2), total 
clearance (CL), and a volume of distribution (Vss), will be determined using computer software 
such as SAS for Lapatinib and Veliparib. Compartmental and population pharmacokinetic analysis 
will also be conducted using different models such as one- or two- compartmental model with 
zero-order input, if warranted. Descriptive statistics including mean, standard deviation, 
coefficient of variation, geometric mean, median, minimum and maximum will be computed for 
each pharmacokinetic variable by dose group; descriptive statistics for natural-log transformed 
AUC (last), AUC (0-inf), Cmax, Tmax, Ceoi, kel, t1/2, CL and Vss for Lapatinib and Veliparib will also be 
provided for each dose group.  In addition, mean and median concentrations of research agents 
versus time graphs will be provided for each dose group and Cycle. The linearity of 
pharmacokinetic parameters will be explored. Descriptive statistics of the non-compartmental 
parameters will be calculated for Cycle 1 and cycle 2. The pre-dose-concentrations at Weeks 1-5 
for first 2 cycles may be plotted to explore the accumulation.  
 
7.6. 
Interim analysis 
 
There is no interim analysis for efficacy. This trial includes a continuous assessment stopping rule 
to limit the exposure of subjects to a potentially unacceptable toxic dose. Drug related toxicities 
for the safety analysis are defined as: a) any grade 3 or 4 non-hematologic toxicity except anorexia, 
alopecia, nausea, fatigue, fever without neutropenia; b) failure to recover to baseline (except 
alopecia) after delaying the next dose by more than 14 days; c) grade 3 or 4 neutropenia 
complicated by fever > 38.50 C or infection, or grade 4 neutropenia of a least 7 days duration; or 
d) grade 4 thrombocytopenia, or grade 3 thrombocytopenia complicated by hemorrhage. Toxicity 
evaluation of the patients enrolled in the trial will be done using the NCI Common Toxicity 
Criteria, Version 4.0. 
 
This trial includes a continuous assessment stopping rule in order to have a high probably of 
stopping early if the toxicity rate is unacceptably high, say 60%, while having low probability of 
stopping early if the toxicity rate is acceptable, say 30%. This rule is based on a Pocock-type 
boundary as described by Ivanova et al (Anastasia Ivanova, Bahjat F. Qaqish, and Michael J. 
Schell. Continuous Toxicity Monitoring in Phase II Trials in Oncology. Biometrics 61, 540–545, 
2005).  This stopping rule is considered a guideline with the final decision of termination of the 
study to be made by the data safety committee 
 
 
Table 3: Minimum number of toxicities (X) required to consider stopping the study after N 
subjects, for 20 patients 
 
X 
3 
4 
4 
5 
5 
6 
6 
7 
7 
7 
8 
8 
9 
9 
9 
10 
10 
11 
N 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 45 
 
                                                         
 
  
 
 
 
 
This rule will provide a probability of 0.10 of stopping early if the true toxicity rate is 30%.  In 
that case the expected number of subjects on the trial will be 18.87 and the expected number of 
toxicities will be 5.7.  If, on the other hand, the true toxicity rate is 60%, then the probability of 
stopping early is 0.87 with an expected sample size of 9.8 and 5.9 expected toxicities. 
 
Table 3 is the stopping guideline if ‘X’ out of ‘N’ has a pre-defined toxicity. As an example, if we 
enroll 3 patients and all have toxicity, then we will consider stopping the trial; if we enroll 6 
patients and 5 patients have toxicity then the trial will be stopped. 
 
7.7  
Study Accrual  
 
We plan to enroll a total of 20 subjects from a single institution (University of Alabama at 
Birmingham). We expect that the enrollment will be completed in 12-18 months. The study will 
be stopped 3 months after the last patient completes the therapy. 
 
7.8  
Data safety Monitoring  
 
This study will utilize the UAB Cancer Center Data and Safety Monitoring Plan with monthly 
reviews of adverse events, accrual and protocol problems by the Clinical Protocol Monitoring 
Committee (CPMC) in addition to the stopping guidelines described in 7.6.  The CPMC will 
continue to review all serious adverse events that occur during the course of the study on a monthly 
basis in addition to cumulative toxicity reports. It will provide recommendations regarding any 
safety or tolerability concerns that are discovered in the reviews. Final decision for stopping of the 
study due to safety is the responsibility of the CPMC and our industry partners, AbbVie and 
Novartis Pharmaceuticals Corporation. 
 
8.0 
ADMINISTRATIVE RULES OF THE PROTOCOL 
 
8.1 
Compliance with the Protocol and Protocol Revisions 
 
The study must be conducted as described in this approved protocol. Should amendments to the 
protocol be required, the amendments will be originated and documented by the Principal 
Investigator at UAB. The written amendment will be sent to the IRB at the investigator's site for 
approval. All revisions to the protocol will be provided to AbbVie and Novartis Pharmaceuticals 
Corporation by UAB. The Investigator should not implement any deviation or change to the 
protocol without prior review and documented approval/favorable opinion from the IRB of an 
Amendment, except where necessary to eliminate an immediate hazard(s) to study patients. 
Documentation of approval signed by the chairperson or designee of the IRB(s) must be sent to 
the UAB Clinical Protocols and Data manager Shared Facility Regulatory Office. If the revision 
is an Administrative Letter, Investigator must inform their IRB(s)/IEC(s). 
 
8.2 
Informed Consent 
 
The Investigator must ensure that patients or their legally acceptable representatives are clearly 
and fully informed about the purpose, potential risks and other critical issues regarding clinical 
trials in which they volunteer to participate. Preparation of the consent form is the responsibility 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 46 
 
                                                         
 
  
 
 
 
 
of the Investigator and must include all elements required by CFR 21 Part 50.25 and the local IRB. 
 
8.3 
Records and Reports 
 
An Investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
with the investigational product or entered as a control in the investigation. 
 
8.4 
Study Management 
 
8.4.1 Institutional Review Board (IRB) Approval and Consent 
 
Before study initiation, the Investigator must have written and dated approval/favorable opinion 
from the IRB for the protocol, consent form, patient recruitment materials/process (e.g., 
advertisements), and any other written information to be provided to patients.  The Investigator 
should provide the IRB with reports, updates, and other information (e.g., Safety Updates, 
Amendments, and Administrative Letters) according to regulatory requirements or Institution 
procedures. Copies of the initial IRB approval as well as annual re-approvals must be submitted 
to UAB. UAB will provide copies of IRB approval to AbbVie and Novartis Pharmaceuticals 
Corporation 
 
It is expected that the IRB will have the proper representation and function in accordance with 
federally mandated regulations. In obtaining and documenting informed consent, the investigator 
should comply with the applicable regulatory requirement(s), and should adhere to Good Clinical 
Practice (GCP) and to ethical principles that have their origin in the Declaration of Helsinki. Before 
recruitment and enrollment onto this study, the patient will be given a full explanation of the study 
and will be given the opportunity to review the consent form. Each consent form must include all 
the relevant elements currently required by the FDA Regulations and local or state regulations. 
Once this essential information has been provided to the patient and the investigator is assured that 
the patient understands the implications of participating in the study, the patient will be asked to 
give consent to participate in the study by signing an IRB-approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be signed 
and personally dated by the patient or the patient’s legally acceptable representative, and by the 
person who conducted the informed consent discussion. Documentation of IRB approval must be 
on file before any patient can be registered. All patients who sign informed consent, will be 
registered with UAB. 
8.4.2 Study Monitoring 
 
Data will be captured on electronic CRFs, and supporting documents will be faxed to the UAB 
Clinical Trials Network and Monitoring Office.  Personnel from the Clinical Trials Network and 
Monitoring office of the University of Alabama at Birmingham will monitor the trial in real time 
and will periodically visit the investigative site to ensure proper conduct of the trial and proper 
collection of the data.  
8.4.3 Adherence to the Protocol 
 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 47 
 
                                                         
 
  
 
 
 
 
Except for an emergency situation in which proper care for the protection, safety, and well-being 
of the study patient requires alternative treatment, the study shall be conducted exactly as described 
in the approved protocol. Any deviation from the protocol must have prior approval by the 
Principal Investigator and must be recorded and explained. 
 
8.4.4 Record Retention 
 
Study documentation includes all Case Report Forms, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory 
documents (e.g., protocol and amendments, IRB correspondence and approved signed patient 
consent forms). Source documents include all recordings of observations or notations of clinical 
activities and all reports and records necessary for the evaluation and conduction of the clinical 
research study. Government agency regulations and directives require that all study documentation 
pertaining to the conduct of a clinical trial must be retained by the study investigator. In the case 
of a study with a drug pursuing regulatory approval and marketing, these documents shall be 
retained for at least two years after the last approval of marketing application in an International 
Conference on Harmonization (ICH) region. In all other cases, study documents should be kept on 
file until three years after the completion and final study report of this investigational study. If the 
Investigator withdraws from the study (e.g., relocation, retirement), the records shall be transferred 
to a mutually agreed upon designee (e.g., another Investigator, IRB). Records of the patient’s 
participation in this study will be kept confidential so far as permitted by law.  However, the 
patient’s doctor and his/her staff, representatives of AbbVie, representatives of Novartis 
Pharmaceuticals Corporation, the U.S. Food and Drug Administration, and the IRB will be able to 
inspect patient records and have access to confidential information which identifies the patient by 
name.  Any publication of data will not identify the patient by name.  Should the patient’s medical 
record need to be reviewed by a foreign regulatory agency, a member of the IRB staff will observe 
the review so that the record is not removed, copied, or identifiable information recorded in any 
manner.  
 
8.4.5 Obligations of Investigators 
 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in accordance 
with Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki. The Principal 
Investigator is responsible for personally overseeing the treatment of all study patients. The 
Principal Investigator must ensure that all study site personnel, including sub-investigators and 
other study staff members, adhere to the study protocol and all FDA/GCP/NCI regulations and 
guidelines regarding clinical trials both during and after study completion. 
 
The Principal Investigator at each institution or site will be responsible for ensuring that all the 
required data will be collected and entered onto the Case Report Forms. Periodically, monitoring 
visits will be conducted and the Principal Investigator will provide access to his/her original 
records to permit verification of proper data entry. At the completion of the study, all case report 
forms will be reviewed by the Principal Investigator and will require his/her final signature to 
verify the accuracy of the data. 
 
 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 48 
 
                                                         
 
  
 
 
 
 
9.0 
ASSESSMENT OF SAFETY 
 
9.1 
Adverse Event Reporting and Definitions  
 
In the event of an adverse event the first concern will be for the safety of the subject.  Toxicities 
will be graded using the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 (see http://ctep.cancer.gov/reporting/ctc.html - see Appendix A). 
 
9.1.1 Adverse Events (AEs) 
 
Adverse events should be followed to resolution or stabilization, and reported as SAEs if they 
become serious. This also applies to patients experiencing AEs that cause interruption or 
discontinuation of investigational product or those experiencing AEs that are present at the end of 
their participation in the study. Such patients should receive post-treatment follow-up as 
appropriate as it has been described throughout the protocol. If an ongoing AE changes in its 
severity or in its perceived relationship to study drug, a new AE should be completed.  
 
The FDA has mandated that AbbVie be notified, at least one time per year, or at the agreed upon 
timeframe, of all non-serious adverse events that: (a) are grade 3-4 toxicity and (b) result in the 
subject’s premature discontinuation of the study. 
 
9.1.2 Serious Adverse Events (SAEs) 
 
A serious adverse event is an undesirable sign, symptom or medical condition which: 
 
 is fatal or life-threatening 
 results in persistent or significant disability/incapacity 
 constitutes a congenital anomaly/birth defect 
 requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
 routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes) 
 elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since the start of study drug 
 treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
 social reasons and respite care in the absence of any deterioration in the patient’s general 
condition 
 is medically significant, i.e., defined as an event that jeopardizes the patient or may require 
medical or surgical intervention to prevent one of the outcomes listed above 
 
The principal investigator has the obligation to report all serious adverse events to the FDA, 
IRB, and Novartis Pharmaceuticals Drug Safety and Epidemiology Department (DS&E).  
 
All events reported to the FDA by the investigator are to be filed utilizing the Form FDA 
3500A (MedWatch Form).  

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 49 
 
                                                         
 
  
 
 
 
 
To ensure patient safety, every SAE, regardless of suspected causality, occurring 
 after the patient has provided informed consent and until at least 30 days after the patient 
has stopped study treatment/participation 
 after protocol-specified procedures begin (e.g., placebo run-in, washout period, double-
blind treatment, etc.) and 30 days after the patient has stopped study treatment 
 after the start of any period in which the study protocol interferes with the standard 
medical treatment given to a patient (e.g., treatment withdrawal during washout period, 
change in treatment to a fixed dose of concomitant medication) and until 30 days after 
the patient has stopped study treatment  
 
must be reported to Novartis within 24 hours of learning of its occurrence  Information 
about all SAEs is collected and recorded on a Serious Adverse Event Report Form; all 
applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to 
each specific study treatment (if there is more than one study treatment), complete the 
SAE Report Form in English, and send the completed, signed form by fax to (fax: 877-
778-9739) within 24 hours to the oncology Novartis DS&E department with the 
provided FAX cover sheets. 
 
This includes serious, related, labeled (expected) and serious, related, unlabeled 
(unexpected) adverse experiences. All deaths during treatment or within 30 days 
following completion of active protocol therapy must be reported within 5 working days. 
 
Any SAEs experienced after this 30 days period should only be reported to Novartis if 
the investigator suspects a causal relationship to the study drug. Recurrent episodes, 
complications, or progression of the initial SAE must be reported as follow-up to the 
original episode within 24 hours of the investigator receiving the follow-up information. 
A SAE occurring at a different time interval or otherwise considered completely 
unrelated to a previously reported one should be reported separately as a new event.  The 
end date of the first event must be provided. 
 
The original copy of the SAE Report and the fax confirmation sheet must be kept within 
the Trial Master File at the study site. 
 
Follow-up information is sent to the same fax number as the original SAE Report Form 
was sent, using a new fax cover sheet, stating that this is a follow-up to the previously 
reported SAE, and giving the date of the original report. Each re-occurrence, 
complication, or progression of the original event should be reported as a follow-up to 
that event regardless of when it occurs. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated, whether the blind 
was broken or not (if applicable), and whether the patient continued or withdrew from 
study participation. 
 
If the SAE is not previously documented in the Lapatinib Investigator Brochure or 
Package Insert (new occurrence) and is thought to be related to the Novartis study drug, a 
DS&E associate may urgently require further information from the investigator for 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 50 
 
                                                         
 
  
 
 
 
 
Health Authority reporting. Novartis may need to issue an Investigator Notification (IN), 
to inform all investigators involved in any study with the same drug that this SAE has 
been reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be 
collected and reported to the competent authorities and relevant ethics committees in 
accordance with Directive 2001/20/EC or as per national regulatory requirements in 
participating countries. 
 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence. 
 
SAEs require expeditious handling and reporting to UAB to comply with regulatory requirements. 
Investigators are required to report within 24 hours of investigator’s knowledge (MedWatch Form 
3500A) to the principal investigator (UAB – Erica M. Stringer-Reasor), who will report to the 
FDA, UAB IRB, AbbVie, and Novartis Pharmaceuticals Corporation in accordance with 
regulatory requirements or contractual agreement ANY serious treatment emergent (occurring at 
any time during treatment, not present at baseline and related to study drug) adverse event (SAE) 
as soon as possible. SAEs must be reported to local IRB according to their institutional guidelines. 
All SAEs must be collected and reported until 30 days following patient discontinuation of dosing; 
if only limited information is initially available, follow-up reports are required. The original SAE 
form must be kept on file at the study site. 
 
 
The following events will be reported as SAE:   
 Cardiac dysfunction defined as any signs or symptoms of deterioration in left ventricular 
cardiac function that are Grade 3 (NCI CTCAE) or a ≥20% decrease in left ventricular cardiac 
ejection fraction relative to baseline which is below the institution's lower limit of normal.   
 Any signs or symptoms of pneumonitis that are Grade 3 (NCI CTCAE) (defined as 
radiographic changes and requiring oxygen).  
 ALT > 3XULN and total bilirubin > 2XULN (>35% direct; bilirubin fractionation required) or 
ALT > 3XULN and INR >1.5 (except patients receiving anticoagulants). 
 
9.1.3 Reporting of Serious Treatment Emergent Adverse Events  
 
All SAEs should be recorded on a MedWatch 3500A Form (can be accessed at: 
https://www.accessdata.fda.gov/scripts/MedWatch - see Appendix C) and faxed to: 
 
Pam Dixon 
 
 
 
 
 
Erica M. Stringer-Reasor  
Phone: 205-975-5387  
 
 
and 
Phone: 205-934-3411 
Fax: 205-975-9875 
 
 
 
 
Fax: 205-995-9996 
Once forms are reviewed, UAB will report to: 
 
MedWatch 
 
 
 
 
 
AbbVie 
5600 Fishers Lane 
 
 
 
 
Drug Safety 
Rockville, MD 20852-9787  
 
and 
Fax: (847) 775-6706 
Fax: 1-800-FDA-0178 (1-800-332-0178) 
 
Safetymanagement_oncology@abbvie.com 
 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 51 
 
                                                         
 
  
 
 
 
 
and 
UAB IRB  
and 
Novartis Pharmaceuticals Corporation 
Fax: (877) 778-9739 
-mail:  
MedWatch 3500A Reporting Guidelines: 
In addition to completing appropriate patient demographic and suspect medication information, 
the report should include the following information within the Event Description of the MedWatch 
3500A form: 
 Treatment regimen (dosing frequency, combination therapy) 
 Protocol description (and number, if assigned) 
 Description of event, severity, treatment, and outcome, if known 
 Supportive laboratory results and diagnostics 
 Investigator’s assessment of the relationship of the adverse event to each investigational 
product and suspect medication 
 
Follow-up information:   
Additional information may be added to a previously submitted report by any of the following 
methods: 
 
 Adding to the original MedWatch 3500A report and submitting it as follow-up 
 Adding supplemental summary information and submitting it as follow-up with the original 
MedWatch 3500A form  
 Summarizing new information and faxing it with a cover letter including subject identifiers 
(i.e. D.O.B., initials, subject number), protocol description and number, if assigned, suspect 
drug, brief adverse event description, and notation that additional or follow-up information is 
being submitted  (The subject identifiers are important so that the new information is added to 
the correct initial report) 
 
Occasionally the principal investigator and/or UAB may contact the reporter for additional 
information, clarification, or current status of the subject for whom an adverse event was reported.  
 
Assessing Causality: 
Investigators are required to assess whether there is a reasonable possibility that 
Lapatinib/Veliparib caused or contributed to an adverse event.  The following general guidelines 
may be used. 
Yes: 
if the temporal relationship of the clinical event to Lapatinib/Veliparib administration 
makes a causal relationship possible, and other drugs, therapeutic interventions or underlying 
conditions do not provide a sufficient explanation for the observed event. 
 
No: 
if the temporal relationship of the clinical event to Lapatinib/Veliparib administration 
makes a causal relationship unlikely, or other drugs, therapeutic interventions or underlying 
conditions provide a sufficient explanation for the observed event. 
 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 52 
 
                                                         
 
  
 
 
 
 
10.0 
BIBLIOGRAPHY 
 
1. 
Perou CM, Brown PO, Botstein D: Tumor classification using gene expression patterns from 
DNA microarrays. New Technologies for Life Sciences. A Trends Guide 2000: 67-76. 
 
2. 
Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, 
Johnsen H, Akslen LA, Fluge O, Pergamenschikov A, Williams C, Zhu SX, Lonning PE, 
Borresen-Dale AL, Brown PO, Botstein D. Molecular portraits of human breast tumors. 
Nature. 2000; 406: 747–752. PMID 10963602. 
 
3. 
Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de 
Rijn M, Jeffrey SS, Thorsen T, Quist H, Matese JC, Brown PO, Botstein D, Lonning PE, 
Borresen-Dale AL. Gene expression patterns of breast carcinomas distinguish tumor 
subclasses with clinical implications. Proc Natl Acad Sci USA 2001; 98: 10869-74. PMC 
58566. 
 
4. 
Nielsen TO, Hsu FD, Jensen K, Cheang M, Karaca G, Hu Z, Hernandez-Boussard T, Livasy 
C, Cowan D, Dressler L, Akslen LA, Ragaz J, Gown AM, Gilks B, van de Rijn M, Perou 
CM: Immunohistochemical and Clinical Characterization of the Basal-Like Subtype of 
Invasive Breast Carcinoma. Clin Cancer Res 2004; 10: 5367-5374. PMID 15328174. 
 
5. 
Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, Deng S, Johnsen H, Pesich 
R, Geisler S, Demeter J, Perou CM, Lønning PE, Brown PO, Borresen-Dale AL, Botstein 
D.: Repeated observation of breast tumor subtypes in independent gene expression data sets. 
Proc Natl Acad Sci USA 2003; 100: 8418-8423. PMC 166244. 
 
6. 
Conforti R, Bidard F-C, Michiels S, Boulet T, Tomasic G, Mathieu M-C, Delaloge S, Andre 
F: Discrepancy between triple negative phenotype and basallike tumor: an 
immunohistochemical analysis based on 150 “triple-negative” breast cancers. Breast Cancer 
Res Treat 2007; 106(1): S135, # 3030. 
 
7. 
Cheang MCU, Voduc D, Bajdik C, Leung S, McKinney S, Chia SK, Perou CM, Nielsen TO: 
Basal-Like Breast Cancer Defined by Five Biomarkers Has Superior Prognostic Value than 
Triple-Negative Phenotype. Clin Cancer Res 2008; 14: 1368-1376. PMID 18316557. 
 
8. 
Scheider BP, Winer EP, Foulkes WD, Garber J, Perou CM, Richardson A, Sledge GW, Carey 
LA.: Triple-Negative Breast Cancer: Risk Factors to Potential Targets. Clin Cancer Res 
2008; 14: 8010-8018. PMID 19088017. 
 
9. 
Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, Pietenpol JA. 
Identification of human triple-negative breast cancer subtypes and preclinical models for 
selection of targeted therapies. J Clin Invest 2011; 121(7):2750-67. PMC 3127435 
 
 
 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 53 
 
                                                         
 
  
 
 
 
 
10. Harris LN, Broadwater G, Lin NU, Miron A, Schnitt SJ, Cowan D, Lara J, Bleiweiss I, Berry 
D, Ellis M, Hayes DF, Winer EP, Dressler L. Molecular subtypes of breast cancer in relation 
to paclitaxel response and outcomes in woman with metastatic disease: results from CALGB 
9342. Breast Cancer Res 2006, 8:R66. PMC 1797029. 
 
11. Liedtke C, Mazouni C, Hess KR, Tordai A, André F, Symmans WF, Gonzalez-Angulo AM, 
Green M, Hortobagyi GN, Pusztai L: Differential response to primary chemotherapy and 
long-term survival in patients with triple-negative breast cancer. J Clin Oncol 2007; 25 (18S): 
#10519. 
 
12. Carey LA, Dees EC, Sawyer L, Gatti L, Moore DT, Collichio F, Ollila DW, Sartor CI, 
Graham ML, and Perou CM: The Triple Negative Paradox: Primary Tumor Chemosensitivity 
of Breast Cancer Subtypes. Clin Can Res 2007; 13: 2329-2334. PMID 17438091. 
 
13. Nam BH, Kim SY, Han HS, Kwon Y, Lee KS, Kim TH, Ro J.. Breast cancer subtypes and 
survival 
in 
patients 
with 
brain 
metastases. 
Breast 
Cancer 
Res 
2008; 
10:R20doi:10.1186/bcr1870. PMC 2374976. 
 
14. Chiarugi A. Poly(ADP-ribose) polymerase: killer or conspirator? The 'suicide hypothesis' 
revisited. Trends Pharmacol Sci. 2002; 23(3):122-9. PMID 11879679. 
 
15. Virág L, Szabó C. The therapeutic potential of poly(ADP-Ribose) polymerase inhibitors. 
Pharmacol Rev. 2002; 54(3):375-429.  PMID: 12223530. 
 
16. Sharpless NE, DePinho RA. Telomeres, stem cells, senescence, and cancer. J Clin Invest. 
2004; 113(2):160-8. PMC 311439. 
 
17. Curtin NJ, Wang LZ, Yiakouvaki A, Kyle S, Arris CA, Canan-Koch S, Webber SE, Durkacz 
BW, Calvert HA, Hostomsky Z, Newell DR. Novel poly(ADP-ribose) polymerase-1 
inhibitor, AG14361, restores sensitivity to temozolomide in mismatch repair-deficient cells. 
Clin Cancer Res. 2004; 10(3):881-9. PMID 14871963. 
 
18. Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, Santarosa M, Dillon 
KJ, Hickson I, Knights C, Martin NM, Jackson SP, Smith GC, Ashworth A. Targeting the 
DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005; 434:917-
21. PMID 15829967. 
 
19.  Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, Kyle S, Meuth M, 
Curtin NJ, Helleday T. Specific killing of BRCA2-deficient tumours with inhibitors of 
poly(ADP-ribose) polymerase. Nature. 2005; 434(7035):913-7. PMID 15829966. 
 
20. Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, Mortimer P, Swaisland H, 
Lau A, O'Connor MJ, Ashworth A, Carmichael J, Kaye SB, Schellens JH, de Bono 
JS.Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N 
Engl J Med 2009; 361: 123-134. PMID 19553641. 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 54 
 
                                                         
 
  
 
 
 
 
21. Tutt A, Robson M, Garber JE, Domchek S, Audeh W, Weltzel JN, Friedlander M, 
Carmichael J.. Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient advanced 
breast cancer. J Clin Oncol 2009; 27(15 suppl): Abstract # CRA501. 
 
22. O'Shaughnessy J, Osborne C, Pippen J, Yoffe M, Patt D, Monaghan G, Rocha C, Ossovskaya 
V, Sherman B, Bradley C. Efficacy of BSI-201, a poly (ADP-ribose) polymerase-1 (PARP1) 
inhibitor, in combination with gemcitabine/carboplatin (G/C) in patients with metastatic 
triple-negative breast cancer (TNBC): results of a randomized phase II trial. J Clin Oncol 
2009; 27(15 suppl): Abstract # 3.  
 
23. O'Shaughnessy J, Osborne C, Pippen J, Patt D, Rocha C, Ossovskaya V, Sherman B, Bradley 
C.  Final results of a randomized phase II study demonstrating efficacy and safety of BSI-
201, a PARP-inhibitor, in combination with gemcitabine/carboplatin in metastatic triple 
negative breast cancer. San Antonio Breast Cancer Symposium 2009: Abstract # 3122. 
 
24. O’Shaughnessy J, Schwartzberg L, Danso M, Rugo H, Miller K, Yardley A, Carlson RW, 
Finn RS, Charpentier E, Freese M, Gupta S, Blackwood-Chirchir A, Winer, EP.  A 
randomized 
phase 
III 
study 
of 
iniparib 
(BSI-201) 
in 
combination 
with 
gemcitabine/carboplatin (G/C) in metastatic triple-negative breast cancer (TNBC). J Clin 
Oncol 2011:  Abstract #1007. 
 
25. Riese, D.J., 2nd and D.F. Stern, Specificity within the EGF family/ErbB receptor family 
signaling network. Bioessays 1998; 20(1): 41-8. PMID 9504046. 
 
26. Amundadottir, L.T. and P. Leder. Signal transduction pathways activated and required for 
mammary carcinogenesis in response to specific oncogenes. Oncogene 1998; 16(6): 737-46. 
PMID 9488037. 
 
27. Okano J, Gaslightwala I, Birnbaum MJ, Rustgi AK, Nakagawa H. Akt/protein kinase B 
isoforms are differentially regulated by epidermal growth factor stimulation. J Biol Chem 
2000; 275(40): 30934-42. PMID 10908564. 
 
28. Harris, A.L., The epidermal growth factor receptor as a target for therapy. Cancer Cells 1990; 
2(10): 321-3. PMID 2282249. 
 
29. Pavelic K, Banjac Z, Pavelic J, Spaventi S. Evidence for a role of EGF receptor in the 
progression of human lung carcinoma. Anticancer Res 1993; 13(4): 1133-7. PMID 8394672. 
 
30. Nakajima H, Ishikawa Y, Furuya M, Sano T, Ohno Y, Horiguchi J, Oyama T. Protein 
expression, gene amplification, and mutational analysis of EGFR in triple-negative breast 
cancer. Breast Cancer 2012; 1-9. PMID 22481575. 
 
 
 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 55 
 
                                                         
 
  
 
 
 
 
31. Martin V, Botta F, Zanellato E, Molinari F, Crippa S, Mazzucchelli L, Frattini M. Molecular 
characterization of EGFR and EGFR-downstream pathways in triple negative breast 
carcinomas with basal like features. Histology and histopathology 2012; 27: 785. PMID 
22473698. 
 
32. Liu D, He J, Yuan Z, Wang S, Peng R, Shi Y, Teng X, Qin T.EGFR expression correlates 
with decreased disease-free survival in triple-negative breast cancer: a retrospective analysis 
based on a tissue microarray. Medical Oncology 2012; 29: 401-405. PMID 21264531. 
 
33. Hadzisejdic I, Mustac E, Jonjic N, Petkovic M, Grahovac B. Nuclear EGFR in ductal 
invasive breast cancer: correlation with cyclin-D1 and prognosis. Mod Pathol 2010; 23: 392-
403. PMID 20062009. 
 
34. Carey LA, Rugo HS, Marcom PK, Mayer EL, Esteva FJ, Ma CX, Liu MC, Storniolo AM, 
Rimawi MF, Forero-Torres A, Wolff AC, Hobday TJ, Ivanova A, Chiu WK, Ferraro M, 
Burrows E, Bernard PS, Hoadley KA, Perou CM, Winer EP.TBCRC 001: randomized phase 
II study of cetuximab in combination with carboplatin in stage IV triple-negative breast 
cancer. J Clin Oncol 2012; 30: 2615-2623. PMC 3413275. 
 
35. O’Shaughnessy J, Weckstein D, Vukelja S, McIntyre K, Krekow L, et al. Preliminary results 
of a randomized phase II study of weekly irinotecan/carboplatin with or without cetuximab 
in patients with metastatic breast cancer. Breast Cancer Res Treat 2007; 106: S32. 
 
36. Baselga J, Gomez P, Awada A, Greil R, Braga S, et al. The addition of cetuximab to cisplatin 
increases overall response rate (ORR) and progression-free survival (PFS) in metastatic 
triple-negative breast cancer (TNBC): results of a randomized phase II study (BALI-1). Ann 
Oncol 2010; 21. 
 
37. Baselga J, Albanell J, Ruiz A, Lluch A, Gascón P, Guillém V, González S, Sauleda S, 
Marimón I, Tabernero JM, Koehler MT, Rojo F. Phase II and tumor pharmacodynamic study 
of gefitinib in patients with advanced breast cancer. J Clin Oncol. 2005; 10; 23(23):5323-
33). PMID 15939921. 
 
38. Dickler MN, Rugo HS, Eberle CA, Brogi E, Caravelli JF, Panageas KS, Boyd J, Yeh B, Lake 
DE, Dang CT, Gilewski TA, Bromberg JF, Seidman AD, D'Andrea GM, Moasser MM, 
Melisko M, Park JW, Dancey J, Norton L, Hudis CA.A phase II trial of erlotinib in 
combination with bevacizumab in patients with metastatic breast cancer. Clin Cancer Res 
2008; 14: 7878-7883. PMC 2748748. 
 
39. Foulkes WD, Smith IE, Reis-Filho JS. Triple-Negative Breast Cancer. New England Journal 
of Medicine 2010; 363: 1938-1948. PMID 21067385. 
 
 
 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 56 
 
                                                         
 
  
 
 
 
 
40. Andre F, Job B, Dessen P, Tordai A, Michiels S, Liedtke C, Richon C, Yan K, Wang B, 
Vassal G, Delaloge S, Hortobagyi GN, Symmans WF, Lazar V, Pusztai L. Molecular 
characterization of breast cancer with high-resolution oligonucleotide comparative genomic 
hybridization array. Clinical Cancer Research 2009; 15: 441-451. PMID 19147748. 
 
41. Wheeler DL, Huang S, Kruser TJ, Nechrebecki MM, Armstrong EA, Benavente S, Gondi V, 
Hsu KT, Harari PM. Mechanisms of acquired resistance to cetuximab: role of HER (ErbB) 
family members. Oncogene 2008; 27: 3944-3956. 
 
42. Ciardiello F, Normanno N. HER2 signaling and resistance to the anti-EGFR monoclonal 
antibody cetuximab: a further step toward personalized medicine for patients with colorectal 
cancer. Cancer Discov 2011; 1: 472-474. PMID 22586650. 
 
43. Quesnelle KM, Grandis JR. Dual kinase inhibition of EGFR and HER2 overcomes resistance 
to cetuximab in a novel in vivo model of acquired cetuximab resistance. Clin Cancer Res 
2011; 17: 5935-5944. PMC3426303 
 
44. Myllynen L, Rieckmann T, Dahm-Daphi J, Kasten-Pisula U, Petersen C, Dikomey E, Kriegs 
M. In tumor cells regulation of DNA double strand break repair through EGF receptor 
involves both NHEJ and HR and is independent of p53 and K-Ras status. Radiotherapy and 
oncology: Journal of the European Society for Therapeutic Radiology and Oncology 2011; 
101: 147-151. PMID 21665306. 
 
45. Nowsheen S, Bonner JA, Yang ES. The poly(ADP-Ribose) polymerase inhibitor ABT-888 
reduces radiation-induced nuclear EGFR and augments head and neck tumor response to 
radiotherapy. Radiother Oncol 2011; 99: 331-338. PMC 3157293. 
 
46. Nowsheen S, Bonner JA, Lobuglio AF, Trummell H, Whitley AC, Dobelbower MC, Yang 
ES. Cetuximab augments cytotoxicity with poly (adp-ribose) polymerase inhibition in head 
and neck cancer. PLoS One 2011; 6: e24148. PMC 3166164. 
 
47. Li L, Wang H, Yang ES, Arteaga CL, Xia F. Erlotinib attenuates homologous 
recombinational repair of chromosomal breaks in human breast cancer cells. Cancer Res 
2008; 68: 9141-9146. PMC 2586988. 
 
48. Nowsheen S, Cooper T, Stanley JA, Yang ES. Synthetic Lethal Interactions between EGFR 
and PARP Inhibition in Human Triple Negative Breast Cancer Cells. PLoS One 2012; 7: 
e46614. PMC 3469581. 
 
49. Huang WC, Chen YJ, Li LY, Wei YL, Hsu SC, Tsai SL, Chiu PC, Huang WP, Wang YN, 
Chen CH, Chang WC, Chang WC, Chen AJ, Tsai CH, Hung MC. Nuclear translocation of 
epidermal growth factor receptor by Akt-dependent phosphorylation enhances breast cancer-
resistant protein expression in gefitinib-resistant cells. J Biol Chem 2011; 286: 20558-20568. 
PMC 3121497. 
 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 57 
 
                                                         
 
  
 
 
 
 
50. Dittmann K, Mayer C, Fehrenbacher B, Schaller M, Kehlbach R, Rodemann HP. Nuclear 
EGFR shuttling induced by ionizing radiation is regulated by phosphorylation at residue 
Thr654. FEBS Lett 2010; 584: 3878-3884. PMID 20692258. 
 
51. Li C, Iida M, Dunn EF, Ghia AJ, Wheeler DL. Nuclear EGFR contributes to acquired 
resistance to cetuximab. Oncogene 2009; 28: 3801-3813. PMC 2900381. 
 
52. Lipponen P, Eskelinen M. Expression of epidermal growth factor receptor in bladder cancer 
as related to established prognostic factors, oncoprotein (c-erbB-2, p53) expression and long-
term prognosis. Br J Cancer 1994; 69: 1120-1125. PMC 1969432. 
 
53. Tervahauta A, Syrjanen S, Syrjanen K. Epidermal growth factor receptor, c-erbB-2 proto-
oncogene and estrogen receptor expression in human papillomavirus lesions of the uterine 
cervix. Int J Gynecol Pathol 19994; 13: 234-240. PMID 7928056. 
 
54. Lo HW, Xia W, Wei Y, Ali-Seyed M, Huang SF, Hung MC. Novel prognostic value of 
nuclear epidermal growth factor receptor in breast cancer. Cancer Res 2005; 65: 338-348. 
PMID 15665312. 
 
55. Abbott. Information for Clinical Investigators (Clinical Brochure) for ABT-888 (A-861695), 
Edition 6. 22 June 2012. 
 
56. Kummar S, Kinders R, Gutierrez ME, Rubinstein L, Parchment RE, Phillips LR, Ji J, Monks 
A, Low JA, Chen A, Murgo AJ, Collins J, Steinberg SM, Eliopoulos H, Giranda VL, Gordon 
G, Helman L, Wiltrout R, Tomaszewski JE, Doroshow JH. Phase 0 clinical trial of the 
poly(AEP-ribose) polymerase inhibitor ABT-888 in patients with advanced malignancies. J 
Clin Oncol 2009; 27: 2705-11. Epub 2009 Apr 13.  PMC 2739635. 
 
57. Isakoff SJ, Overmoyer B, Tung NM, Gelman RS, Giranda VL, Bernhard KM, Habin KR, 
Ellisen LW, Winer EP, Goss, PE. A phase II trial of the PARP inhibitor veliparib (ABT888) 
and Temozolomide for metastatic breast cancer. J Clin Oncol. 2010; 28:15s (Suppl) Abstract 
#1019. 
 
58. Audeh MW, Carmichael J, Penson RT, Friedlander M, Powell B, Bell-McGuinn KM, Scott 
C, Weitzel JN, Oaknin A, Loman N, Lu K, Schmutzler RK, Matulonis U, Wickens M, Tutt 
A. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 
mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet 2010; 
376(9737):245-51. PMID 20609468. 
 
59. Sakai W, Swisher EM, Karlan BY, Agarwal MK, Higgins J, Friedman C, Villegas E, 
Jacquemont C, Farrugia DJ, Couch FJ, Urban N, Taniguchi T. Secondary mutations as a 
mechanism of cisplatin resistance in BRCA2- mutated cancers. Nature 2008; 451:1116-20. 
PMC 2577037. 
 
 
 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 58 
 
                                                         
 
  
 
 
 
 
60. Fong PC, Yap TA, Boss DS, Carden CP, Mergui-Roelvink M, Gourley C, De Greve J, 
Lubinski J, Shanley S, Messiou C, A'Hern R, Tutt A, Ashworth A, Stone J, Carmichael J, 
Schellens JH, de Bono JS, Kaye SB. Poly(ADP)-ribose polymerase inhibition: frequent 
durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval. J 
Clin Oncol 2010; 28: 2512-9. PMID 20406929. 
 
61. Rusnak DW, Affleck K, Cockerill SG, Stubberfield C, Harris R, Page M, Smith KJ, Guntrip 
SB, Carter MC, Shaw RJ, Jowett A, Stables J, Topley P, Wood ER, Brignola PS, Kadwell 
SH, Reep BR, Mullin RJ, Alligood KJ, Keith BR, Crosby RM, Murray DM, Knight WB, 
Gilmer TM, Lackey K. The characterization of novel, dual ErbB-2/EGFR, tyrosine kinase 
inhibitors: potential therapy for cancer. Cancer Res, 2001. 61(19): p. 7196-203. PMID 
11585755. 
 
62. Zhou H, Kim YS, Peletier A, McCall W, Earp HS, Sartor CI. Effects of the EGFR/HER2 
kinase inhibitor GW572016 on EGF and HER2-overexpressing breast cancer cell line 
proliferation, radiosensitization, and resistance. Int J Radiat Oncol Biol Phys 2004;58:344-
352, 2004. PMID 14751502. 
 
63. Blackwell K, Spector N, Snyder S, et al: GW572016, a novel dual EGFR/Her-2 small 
molecule, tyrosine kinase inhibitor induces regression and significant growth delay in 
tamoxifen-resistant, MCF-7 derived tumors. San Antonio Breast Cancer Symp 2002; 
(Abstract # 520). 
 
64. Xia W, Liu LH, Ho P, Spector NL. Truncated ErbB2 receptor (p95ErbB2) is regulated by 
heregulin through heterodimer formation with ErbB3 yet remains sensitive to the dual 
EGFR/ErbB2 kinase inhibitor GW572016. Oncogene 2004; 23:646-653. PMID 14737100. 
 
65. Novartis Pharmaceuticals Corporation group of companies. Information for Clinical 
Investigators (Investigator’s Brochure) for Lapatinib (GW572016), Version 08, 11 April 
2018.  
 
66. Blackwell KL, Kaplan EH, Franco SX, Marcom PK, Maleski JE, Sorensen MJ, Berger MS. 
A phase II, open-label, multicenter study of GW572016 in patients with trastuzumab-
refractory metastatic breast cancer. Proc Am Soc Clin Oncol 2004; 23: Abstract #3006. 
 
67. Dees EC, Burris H, Hurwitz H, Dowlati A, Smith D, Koch K, Stead A, Mangum S, Harris J, 
Spector N. Clinical summary of 67 heavily pre-treated patients with metastatic carcinomas 
treated with GW572016 in a phase Ib study. Proc Am Soc Clin Oncol 2004; 34. Abstract 
#3188. 
 
68. Gomez HL, Chavez MA, Doval DC, Chow LWC, Wood BA, Berger MS, Sledge GW. A 
phase II, randomized trial using the small molecule tyrosine kinase inhibitor lapatinib as a 
first-line treatment in patients with FISH-positive advanced or metastatic breast cancer. J 
Clin Oncol 2005; 23(16S):203s, Abstract #3046. 
 
 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 59 
 
                                                         
 
  
 
 
 
 
69. Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, Jagiello-Gruszfeld A, 
Crown J, Chan A, Kaufman B, Skarlos D, Campone M, Davidson N, Berger M, Oliva C, 
Rubin SD, Stein S, Cameron D. Lapatinib plus capecitabine for HER-2-positive advanced 
breast cancer. N Engl J Med. 2006; 355:2733–2743.  PMID 17192538. 
 
70. Cameron D, Casey M, Press M, Lindquist D, Pienkowski T, Romieu CG, Chan S, Jagiello-
Gruszfeld A, Kaufman B, Crown J, Chan A, Campone M, Viens P, Davidson N, Gorbounova 
V, Raats JI, Skarlos D, Newstat B, Roychowdhury D, Paoletti P, Oliva C, Rubin S, Stein S, 
Geyer CE.A phase III randomized comparison of lapatinib plus capecitabine versus 
capecitabine alone in women with advanced breast cancer that has progressed on 
trastuzumab: updated efficacy and biomarker analyses. Breast Cancer Res Treat. 2008; 112: 
533–543. PMID 18188694. 
 
71. Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits 
of human breast tumors. Nature 2000; 406: 747-52. 
 
72. Earnshaw, W. C., Martins, L. M., and Kaufmann, S. H. Mammalian Caspases: Structure, 
Activation, Substrates and Functions During Apoptosis. Annual Review of Biochemistry 
1999; 68: 383-424. 
 
73.  Fischer, U., Janicke, R. U., and Schulze-Osthoff, K. Many cuts to ruin: a comprehensive 
update of caspase substrates. Cell Death and Differentiation 2003; 10: 76-100. 
 
74.  Caulin, C., Salvesen, G. S., and Oshima, R. G. Caspase Cleavage of Keratin 18 and 
Reorganization of Intermediate Filaments During Epithelial Cell Apoptosis. Journal of Cell 
Biology 1977; 138: 1379-1394. 
 
75. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al.: New 
guidelines to evaluate the response to treatment in solid tumors. European Organization for 
Research and Treatment of Cancer, National Cancer Institute of the United States, National 
Cancer Institute of Canada. J Natl Cancer Inst 92:205-216, 2000. 
 
76. Meng S, Tripathy D, Shete S, Ashfaq R, Haley B, Perkins S, et al. HER-2 gene amplification 
can be acquired as breast cancer progresses. Proc Natl Acad Sci U S A 2004; 101(25): 9393-
8. 
 
77.  Misale S, Yaeger R, Hobor S, et al. Emergence of KRAS mutations and acquired resistance 
to anti-EGFR therapy in colorectal cancer. Nature 2012;486:532-6. 
 
78.  Dawson SJ, Tsui DW, Murtaza M, et al. Analysis of circulating tumor DNA to monitor 
metastatic breast cancer. N Engl J Med 2013;368:1199-209. 
 
79.   Shapiro B, Chakrabarty M, Cohn EM, et al. Determination of circulating DNA levels in 
patients with benign or malignant gastrointestinal disease. Cancer 1983;51:2116-20.  
 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 60 
 
                                                         
 
  
 
 
 
 
80.   Giacona MB, Ruben GC, Iczkowski KA, et al. Cell-free DNA in human blood plasma: length 
measurements in patients with pancreatic cancer and healthy controls. Pancreas 1998;17:89-
97. 
 
81.     Murtaza M, Dawson SJ, Tsui DW, et al. Non-invasive analysis of acquired resistance to 
cancer therapy by sequencing of plasma DNA. Nature 2013;497:108-12. 
 
82.     Diehl F, Schmidt K, Choti MA, et al. Circulating mutant DNA to assess tumor dynamics. 
Nat Med 2008;14:985-90. 
 
83.    Rago C, Huso DL, Diehl F, et al. Serial assessment of human tumor burdens in mice by the 
analysis of circulating DNA. Cancer Res 2007;67:9364-70. 
 
84.   Swarup V, Rajeswari MR. Circulating (cell-free) nucleic acids--a promising, non-invasive 
tool for early detection of several human diseases. FEBS Lett 2007;581:795-9. 
 
85.   Hodgson DR, Wellings R, Orr MC, et al. Circulating tumour-derived predictive biomarkers 
in oncology. Drug Discov Today 2010;15:98-101. 
 
86.    Casciano I, Vinci AD, Banelli B, et al. Circulating Tumor Nucleic Acids: Perspective in 
Breast Cancer. Breast Care (Basel) 2010;5:75-80. 
 
87.    Higgins MJ, Jelovac D, Barnathan E, et al. Detection of tumor PIK3CA status in metastatic 
breast cancer using peripheral blood. Clin Cancer Res 2012;18:3462-9. 
 
 
 
 
 
 
 
 
 
 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 61 
 
                                                         
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX A 
 
NCI Common Toxicity Criteria, Version 4.03 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40 
 
 
 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 62 
 
                                                         
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX B 
 
ECOG Performance Status Scale 
 
 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 63 
 
 
ECOG PERFORMANCE STATUS SCALE 
 
 
GRADE 
DESCRIPTION 
0 
Full activity, able to carry on all pre-disease performance 
without restriction 
 
1 
Restricted in physically strenuous activity but ambulatory 
and able to carry out work of a light or sedentary nature, 
e.g., light housework or office work. 
 
2 
Ambulatory and capable of all self-care but unable to 
carry out any work activities.  Up and about >50% of 
waking hours. 
 
3 
Capable of only limited self-care, confined to a bed or 
chair >50% of waking hours. 
 
4 
Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair. 
 
5 
Dead 
 
 
 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 64 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX C 
 
FDA MedWatch 3500A Form 
http://www.accesdata.fda.gov/scripts/MedWatch 
 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 65 
 
 
SAE Reporting 
 
 
 SAE reporting period begins at the signing of informed consent. 
 All SAEs, regardless of attribution must be reported by fax within 24 hrs of investigator’s 
knowledge: 
o MedWatch Form 3500A must be submitted, regardless of completeness of information. 
 Fax to Pam Dixon at 205-975-9875. 
o If only limited information is available, follow-up reports are required. 
 Affiliate SAEs must be reported to local IRB according to their institutional guidelines. (Not 
Applicable for this trial) 
 UAB is responsible for submitting all SAE MedWatch forms to FDA. 
 UAB is responsible for submitting all MedWatch forms to AbbVie and Novartis 
Pharmaceuticals Corporation 
 All SAEs must be collected and reported until 30 days following patient discontinuation of 
dosing. 
o If only limited information is initially available, follow-up reports are required.  
 The original SAE form must be kept on file at the study site. 
 
 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 66 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX D 
RECIST 1.1 Criteria 
 
http://www.recist.com/recist-in-practice/01.html 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 67 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX E 
Blood and Biopsy Procedures 
 
 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 68 
 
 
UAB 1372 - Blood Draw and Biopsy Schedule 
Paraffin blocks to UAB 
Frozen biopsies to UAB 
 
Blood for ptDNA to Dr. Park’s Lab at Johns Hopkins 
Blood for Pharmacokinetics to UAB 
Serum Marker of Apoptosis to Mayo Clinic 
 
A. Shipments to Johns Hopkins 
 
Whole blood samples for pt DNA analysis will be obtained at: pre-therapy, and on Day 15 of 
the first cycle and day 1 of cycle 2. The samples will be collected at each time point listed 
above: 
 
1. Pre-therapy:  into three Streck tubes (provided). 
2. At subsequent time points:  Three Streck tubes for each time point tubes (provided). 
 
Whole blood samples for ptDNA analysis will be obtained at pre-therapy  Day 1, Day 15 
and Day 29.  These samples are to be sent at room temperature to Dr. Yang’s Lab for 
processing.  
 
Inspect the tube prior to use for cracks, debris or discolored fluid inside.  Do not use the Streck 
tube if it is expired, broken or appears to be contaminated. Draw the Streck tubes first if 
multiple tube types are drawn for the protocol Perform venipuncture and fill the  tube until 
blood flow stops.  Mix the blood immediately by gently inverting the Streck tube 8- 10 times.  
Inadequate or delayed mixing may result in clotting and inaccurate test results. If blood is 
collected through an intravenous line, ensure that line has been cleared of I.V. solution before 
beginning to fill Streck tubes. 
 
PROTECT FROM EXTREME TEMPERATURES.  Store or transport samples at 
temperatures of 6-30oC. DO NOT REFRIGERATE OR FREEZE. 
 
The whole blood samples will be delivered to Dr. Yang’s lab at UAB for processing. His 
lab will store these samples and batch until ready to ship to Dr. Park’s lab. 
 
Dr. Yang’s lab should be notified of these samples. The lab pager number is 2677.  The 
laboratory address is: 
 
The Hazelrig Salter Radiation Oncology Center 
176F 
Suite 2222G  
(Phone: 205-975-2881) 
 
Notification that batched samples will be sent should occur on the day of shipping or 
Collect in Specified Tubes 
Pre-Therapy 
Day 1 
Post-Therapy 
Day  15 
Post-Therapy 
Day 29 
Three 10 ml – Streck tubes  
X 
X 
X 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 69 
 
 
before if possible by email to: bpark2@jhmi.edu. Follow IATA Packaging Instructions 
(See below, section E). Blood should be shipped attention to: 
 
Attention: Ben Park, M.D., Ph.D. 
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins 
1650 Orleans Street 
Room 151 
Baltimore, Maryland 21287 
TE:  443-287-4480 
Fax: 410-614-4073 
 
All sample tubes to be labeled with an indelible marker on the blue color label including 
1. Study Number (UAB 1372) 
2. Subject Study Number 
3. Date of Collection 
4. Time Point of Collection (pre-Rx; Day 15, or Day 29 (Day 1 of cycle 2; pre-Rx) 
 
B. UAB - Paraffin blocks (all patients) 
 
Pre-therapy paraffin blocks/Mandatory Research Block will be obtained: 
As a mandatory biopsy (referred to subsequently as PTMB) if accessible tumor site (per 
protocol).  If possible, this biopsy, when obtained, should be labeled with an indelible marker 
to include: 
 
1. The clinical trial identification number (UAB 1372) 
2. The subject’s study number  
3. The date of acquisition 
 
These paraffin blocks are to be collected for sectioning.  Approximately fifteen sections will 
be cut from each of these blocks by the designated pathologist.  
 
C. To UAB – Snap-Frozen research biopsies (all patients with accessible tumor sites) 
 
Prior to therapy, two tumor tissue core samples will be snap frozen for research studies.  Biopsy 
samples, preferably obtained with a 14-18 gauge core needle, should be flash (snap) frozen 
(close cap tightly), ideally within 5 minutes but not greater than 30 minutes from the biopsy 
procedure, and stored in liquid nitrogen or at -80C until shipping. One core sample will be 
placed in each vial. 
 
All cryovials (NALGENE® Cryoware™ 5000-0000) will be labeled with an indelible 
marker to include: 
 
1. The study identification number (UAB 1372);  
2. The subject’s study number;  
3. The date of acquisition 
 
 
 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 70 
 
 
Dr. Yang’s lab should be notified of these samples. The lab pager number is 2677.  The 
laboratory address is: 
 
The Hazelrig Salter Radiation Oncology Center 
176F 
Suite 2222G  
(Phone: 205-975-2881) 
 
 
Preparing Tissue in Frozen Cryovials 
 
 
Snap Freezing: Do not Cut the tissue and simply ship as is. Place each core of tissue into a 
labeled individual 2.0 ml   NALGENE® Cryoware™ cryovials.  The label should contain the 
UAB clinical trial number (UAB 1372) followed by the subject’s study number, as well as the 
date the specimen was collected.  Do not place the patient’s name or medical record number 
on the label.  The container will become very cold.  Do not handle with unprotected hands.  
Safety goggles should be use throughout the procedure. Snap freeze samples in liquid nitrogen.  
If not available, you may use an alcohol/dry ice bath.   Fill pan about 1-2 inches deep with 
methanol.  The depth should be enough to cover the height of the vial.  Slowly add crushed dry 
ice until the boiling stops.  The bath is now ready for use.  Drop the sealed vials directly into 
the liquid nitrogen (LN2) carefully.  Leave the vials in the liquid nitrogen for at least one 
minute.  Once frozen, transfer the samples using tongs or a large spoon to remove the vials 
from the liquid nitrogen and transfer to a –80 C freezer until shipped.   
 
D. Serum (microRNA, PK, M30) 
 
Blood samples for the assays will be taken at the times described in the protocol.  Serum will 
be obtained in s serum separator tubes and will be sent to: Dr. Yang’s Lab. 
 
Dr. Yang’s lab should be notified of these samples. The lab pager number is 2677.  The 
laboratory address is: 
 
The Hazelrig Salter Radiation Oncology Center 
176F 
Suite 2222G  
(Phone: 205-975-2881) 
 
E. Pharmacogenetic Sample Processing 
 
Blood samples for pharmacogenomic analyses will be collected on a first day before initiation of 
research agents. Blood will be collected into one 6 ml K2EDTA polypropylene blood collection 
tube (Becton-Dickinson) and into one PAX gene tube. The 6 mL polypropylene K2EDTA tube 
will be placed in an ice bath immediately following collection and stored upright in a freezer set 
at -20ºC (+/- 10ºC) until sending to the laboratory. It is important to collect a full tube of whole 
blood. The PAX gene tube should be stored upright at room temperature for a minimum of 2 hours 
or a maximum of 4 hours before processing or transferring to a freezer. They should be stored 
upright in a wire rack and stored at -20 degrees Celsius or colder until sending to the laboratory. 
  
Blood samples should be sent as soon as logistically possible following blood draws to: 
The University of Alabama at Birmingham  

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 71 
 
 
Attention: Center for Clinical Translation Science (CCTS) Laboratory, Jefferson Tower, 
Room 1531, 625 19th Street south, Birmingham, AL 35233 
 
 
F.  IATA Packing Instructions 
 
650 GENERAL REQUIREMENTS 
Shippers of diagnostic specimens where a relatively low probability exists that infectious 
substances are present must comply with Packaging Instruction 650 of these regulations. 
Diagnostic specimens being transported for the purpose of initial diagnosis may be considered 
to fall under this category where a low probability exists that infectious substances are present. 
The shipper must also ensure that shipments are prepared in such a manner that they arrive at 
their destination in good condition and that they present no hazard to persons or animals during 
shipment.  
Inner packaging contains: 
 A watertight primary receptacle(s)- for diagnostic specimens the maximum quantity must 
not exceed 500mL 
 A watertight secondary packaging -the maximum quantity per outer packaging for 
diagnostic specimens must not exceed 4L 
 An absorbent material- must be placed between the primary receptacle and the secondary 
packaging. No absorbent material is required when shipping solid substances. 
 
If multiple primary receptacles are placed in a single secondary packaging they must be 
wrapped individually or for those transported in liquid nitrogen, separated and supported to 
ensure that contact between them is prevented.  The absorbing material, for example cotton or 
wool, must be sufficient to absorb the entire contents of all primary receptacles. 
 
 An outer packaging of adequate strength for its capacity, weight and intended use. 
 
The primary receptacle or the secondary packaging used for liquid diagnostic specimens must 
be capable of withstanding, without leakage, an internal pressure which produces a pressure 
differential of not less than 95 kPa (0.95 bar, 13.8lb/in2) in the range of -40.oC to + 55.oC(-
40.oF to 130.oF). It is not necessary for the primary or secondary packaging to be capable of 
withstanding 95 kPa pressure differential when solid diagnostic specimens are being shipped. 
 
Packages consigned as freight must be at least 100 mm (4 in) in the smallest overall external 
dimension. 
 
An itemized list of contents must be enclosed between the secondary packaging and the outer 
packaging. Each package and the "Nature and Quantity of Goods" box of the airbill must show 
the text "DIAGNOSTIC SPECIMEN PACKED IN COMPLIANCE WITH IATA PACKING 
INSTRUCTION 650" (example below). A Shipper's Declaration for Dangerous Goods is not 
required. 
 
650 SPECIFIC REQUIREMENTS 
 
Substances shipped at ambient temperatures or higher- Primary receptacles include those of 
glass, metal or plastic.  Positive means of ensuring a leak-proof seal, such as heat seal, skirted 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 72 
 
 
stopper or metal crimp seal must be provided.  If screw caps are used these must be reinforced 
with adhesive tape or parafilm. 
 
Substances shipped on dry ice must be placed outside the secondary packaging(s) or 
alternatively in an overpack with one or more completed packaging.  Interior support must be 
provided to secure the secondary packaging(s) in the original position after the dry ice has 
dissipated.  The packaging must be leak-proof. The outer packaging must permit the release of 
carbon-dioxide gas. The primary receptacle must maintain its containment integrity at the 
temperature of the refrigerant as well as at the temperatures and pressure of air transport to 
which the receptacle could be subjected if refrigeration were to be lost. New shipping 
regulations effective January 1, 2005 (Package must have both the shipper and recipient’s 
name, address and phone number) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Package must have the new UN3373 symbol and the words “Diagnostic Specimen” adjacent 
to that symbol; keep the biohazard sticker in place as well. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Labeled box should be inserted into the FedEx Diagnostic Shipping Bag as usual for shipment 
via FedEx. 
 
904 GENERAL REQUIREMENTS 
 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 73 
 
 
Carbon dioxide, (dry ice, LN2), when offered for transport by air, must be in packaging 
designed and constructed to permit the release of carbon dioxide gas and to prevent a build-up 
of pressure that could rupture the packaging. 
 
The net weight of the Carbon dioxide, solid (dry ice) must be marked on the outside of the 
package. 
 
Arrangements between shipper and operators must be made for each shipment to ensure 
ventilation safety procedures are followed.  When a Shipper's Declaration is not required, the 
information as required by 8.2.3 for dry ice (LN2) must be contained in the "Nature and 
Quantity of Goods" box on the air bill, excluding the packing instruction number and packing 
group. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 74 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX F 
SOP for Investigator INDs Held by Physician 
Members of the UAB Comprehensive Cancer Center 
(available upon request) 
 
 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 75 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX G 
Prohibited Medications 
 
 
 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 76 
 
 
 
Drug Class 
Agent 
Washout1 
CYP3A4 Inducers 
Antibiotics  
All rifamycin class agents (e.g. rifampicin, 
rifabutin, rifapentine)  
14 days 
 
 
Anticonvulsants  
Phenytoin, carbamazepine, barbiturates (e.g. 
phenobarbital)  
Antiretrovirals  
Efavirenz, nevirapine, tipranivir, etravirine 
Glucocorticoids (oral)  
Cortisone (>50 mg), Hydrocortisone (>40 mg), 
prednisone (>10 mg), methylprednisolone or 
triamcinolone (>8 mg), betamethasone or 
dexamethasone (>1.5 mg)2 
Other  
St. John’s Wort, modafinil 
 
CYP3A4 Inhibitors 
Antibiotics  
Clarithromycin, erythromycin, troleandomycin  
7 days 
Antifungals  
Ketoconazole, itraconazole, fluconazole (>150 mg 
daily), voriconazole  
Antiretrovirals, Protease Inhibitors  
Delaviridine, nelfinavir, amprenavir, ritonavir, 
indinavir, saquinavir, lopinivir, atazanavir 
Calcium channel blockers  
Verapamil, diltiazem 
Antidepressants  
Nefazodone, fluvoxamine  
GI Agents  
Cimetidine, aprepitant  
Fruits/fruit juices  
Grapefruit, star fruit, and papaw 
Other  
Amiodarone  
6 months 
 
Miscellaneous 
Antacids  
Mylanta, Maalox, Tums, Rennies  
1 hr before/after dosing 
Herbal/dietary supplements3  
Ginkgo biloba, kava, grape seed, valerian, ginseng, 
echinacea, evening primrose oil  
14 days 
 
1. At the time of screening, if a subject is receiving any of the above listed 
medications/substances, the medication or substance must be discontinued (if clinically 
appropriate) for the period of time specified prior to administration of the first dose of lapatinib 
and throughout the study period in order for the subject to be eligible to participate in the study. 
 
2. Glucocorticoid daily doses (oral) ≤ 1.5 mg dexamethasone are allowed. Glucocorticoid 
conversions are provided in parentheses. 
 
3. Because the composition, pharmacokinetics, and metabolism of many herbal supplements are 
unknown, the concurrent use of all herbal supplements is strongly discouraged during the 
study. 
 
 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 77 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX H 
Suggested Management of Dermatological Toxicities 
 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 78 
 
 
For all patients: advise patients to use acne cleanser twice daily (face, chest, and neck), apply 
alcohol-free moisturizer twice daily (e.g. Cetaphil), and use sunscreen with SPF 15 or higher.  
 
Rash Severity 
 
1.  Mild: Generally localized, minimal symptoms, no impact on ADL 
      
 
Intervention:  
- Maintain dose & monitor for change in severity  
                             
- No Treatment OR topical Clindagel 1% BID  
 
     Reassess after 1-2 weeks; if symptoms worsen or fail to improve, proceed to next step 
 
2.  Moderate: Generalized, mild symptoms (e.g. pruritus/tenderness), minimal impact on ADL     
 
 
 
Intervention: 
- Maintain dose & monitor for change in severity 
 
- Topical Clindagel 1% BID plus minocycline 100 mg BID or Doxycycline     
100 mg BID 
 
 
Reassess after 1-2 weeks; if symptoms worsen or fail to improve, proceed to next step 
 
3.  Severe: Generalized, severe symptoms (e.g. pruritus, tenderness), significant impact on ADL 
 
 
 
 
Intervention:   
- Consider drug holiday; continue treating as below: 
 
- Topical Clindagel 1% BID plus minocycline 100 mg BID or doxycycline 
100     mg BID plus Medrol Dose-Pak 
 
 
Reassess after 1-2 weeks; if symptoms worsen or fail to improve, consider dose reduction 
 
 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 79 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX I 
Diarrhea Management Guidelines 
 
 
 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 80 
 
 
Diarrhea Management Guidelines 
 
Background 
 
Experience thus far suggests that when lapatinib is used as monotherapy 51% of patients 
experience diarrhea; most diarrhea presents as uncomplicated NCI CTCAE Grade 1 or 2 (G1 30%, 
G2 15%, G3 6%, G4<1%) (Crown, 2008). 
 
In rare cases, diarrhea can be debilitating, and potentially life threatening if accompanied by 
dehydration, renal insufficiency, and/or electrolyte imbalances. 
 
Standardized and universal guidelines have been developed by an American Society of Clinical 
Oncology (ASCO) panel for treating chemotherapy-induced diarrhea (Benson, 2004).  Presented 
in the sections below are the recommended guidelines for the management of diarrhea in subjects 
receiving lapatinib-based therapy; these guidelines were derived from the recommendations 
published by the ASCO panel (Benson, 2004). 
 
Early identification and intervention is critical for the optimal management of diarrhea.  A 
subject’s baseline bowel patterns should be established so that changes in patterns can be identified 
while subject is on treatment. 
 
It is strongly recommended to give subjects receiving lapatinib-based therapy a prescription 
of loperamide with instructions to start loperamide at the onset of diarrhea as per the 
recommendations outlined below. Subjects should be instructed to first notify their 
physician/healthcare provider at onset of diarrhea of any severity. 
 
An assessment of frequency, consistency and duration as well as knowledge of other symptoms 
such as fever, cramping, pain, nausea, vomiting, dizziness and thirst should be taken at baseline. 
Consequently subjects at high risk of diarrhea can be identified.  Subjects should be educated on 
signs and symptoms of diarrhea with instructions to report any changes in bowel patterns to the 
physician. 
 
It is recommended that subjects keep a diary and record the number of diarrhea episodes and its 
characteristics. They should also include information on any dietary changes or other observations 
that may be useful in the evaluation of their diarrhea history. 
 
If subjects present with diarrhea of any Grade, check they are taking lapatinib correctly, i.e. single 
daily dose, rather than splitting it through the day.  Obtain information on food (solid and liquid) 
and over the counter (OTC) medication, including herbal supplements, taken during the lapatinib 
treatment period. 
 
Definitions 
 
National Cancer Institute (NCI) guidelines define diarrhea compared to baseline (Table 1). 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 81 
 
 
Table 1:  NCI Common Terminology Criteria for Grading Diarrhea Adverse Events1 
Adverse 
Event Grade 
Diarrhea 
1 
Increase of <4 stools/day over baseline; mild increase in ostomy output compared to 
baseline 
2 
Increase of 4-6 stools/day over baseline; moderate increase in ostomy output 
compared to baseline; 
3 
Increase of ≥7 stools/day over baseline; incontinence; hospitalization indicated; severe 
increase in ostomy output compared to baseline; limiting self care activities of daily 
living (ADL) 
4 
Life-threatening consequences; urgent intervention indicated 
 
 
5 
Death 
1 National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 
Uncomplicated diarrhea is considered mild-to-moderate and defined as CTCAE Grade 1 or 2 
with no complicating signs or symptoms. 
Complicated diarrhea is severe and defined as any CTCAE Grade 3 or 4 diarrhea, or Grade 1 or 
2 with one or more of the following signs or symptoms: 
 Moderate to severe abdominal cramping  
 Nausea/vomiting ≥Grade2 
 Decreased performance status 
 Fever 
 Sepsis 
 Neutropenia 
 Frank bleeding (red blood in stool) 
 Dehydration 
 
 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 82 
 
 
Management Guidelines for Subjects Receiving Lapatinib Alone or as Combination 
 
A) 
Uncomplicated Diarrhea 
I. 
CTCAE Grade 1 
NOTE:  Subject should be instructed to: start supportive care immediately at the first 
episode of diarrhea (i.e., unformed stool) and call their physician. 
1. Administer loperamide*  
a. Initial dose 4mg followed by 2mg after every unformed stool. Re-evaluate after 24 
hours, if: 
i. 
Diarrhea is resolving: 
 Continue loperamide treatment at 2mg dose after every unformed stool until 
diarrhea free (i.e., <Grade 1/bowel patterns returned to baseline) for 12 hours. 
o If diarrhea recurs, re-initiate loperamide treatment as needed to maintain 
normal bowel patterns 
ii. 
Diarrhea is not resolving: 
 Administer loperamide at 2mg every 4 hours for the next 24 hour.  Re-evaluate 
after 24 hours.  If diarrhea is resolving, administer loperamide at 2mg after 
every unformed stool until diarrhea free (i.e., <Grade 1/bowel patterns returned 
to baseline) for 12 hours.  If diarrhea is not resolving continue loperamide 
treatment at 2mg every 4 hours and re-evaluate every 24 hours. 
 
b. If Grade 1 diarrhea persists for more than 1 week with loperamide treatment, consider 
treatment with second-line agents (i.e., octreotide, budesonide or tincture of opium). 
 
2. Dietary modifications which are essential in the management of diarrhea  include the 
following recommendations (American Cancer Society; National Cancer Institute): 
a. Stop all lactose containing products and eat small meals 
b. Avoid spicy, fried and fatty foods, raw vegetables and other foods high in fiber 
 Eat foods low in fiber (i.e., lean meat, rice, skinless chicken or turkey, fish, 
eggs, canned or cooked skinless fruits, cooked/pureed vegetables) 
c. Avoid caffeine and alcohol as they can irritate the bowel and increase motility 
d. Hydration:  Drink 8-10 large glasses of clear liquids a day (e.g., water, electrolyte 
drink). 
 Avoid acidic drinks such as tomato juice and fizzy soft drinks 
e. Supplement diet to include foods rich in potassium (e.g., bananas, potatoes, and 
apricots) , evaluate their impact on diarrhea due to the fiber content (e.g., apricots) 
3. Continue with study treatment (i.e., lapatinib-based treatment) 
 
 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 83 
 
 
Continue with supportive care until diarrhea has resolved (diarrhea free for 12 hours/bowel pattern 
return to baseline).  Once diarrhea has resolved, the subject can begin to gradually re-introduce 
foods from their normal diet. If diarrhea recurs following stopping of loperamide treatment, resume 
loperamide treatment at the dose and schedule recommended above and re-introduce diet 
modifications.  Continue with study treatment. If Grade 1 diarrhea persists for ≥2 weeks, refer to 
the management guidelines for Persistent Grade 2 Diarrhea. 
II. 
CTCAE Grade 2 
NOTE:  Subject should be instructed to call physician at first episode of diarrhea and start 
supportive care immediately 
1. Administer loperamide* 
a. Initial dose 4mg followed by 2mg every 4 hours or after every unformed stool.  Re-
evaluate after 24 hours.  If: 
i. 
Diarrhea is resolving, continue loperamide treatment at 2mg dose after every 
unformed stool until diarrhea free (i.e., <Grade 1/bowel patterns returned to 
baseline) for 12 hours 
o If diarrhea recurs, re-initiate loperamide treatment as needed to 
maintain normal bowel patterns 
ii. 
Diarrhea is not resolving, consider loperamide dose of 2mg every 2 hours for 24 
hours. If Grade 2 diarrhea persists after total of 48 hours of loperamide treatment, 
start second-line agents (i.e., octreotide, budesonide or tincture of opium). 
o Consider performing stool work-up, CBC, electrolytes and other tests as 
appropriate 
2. Dietary modifications which are essential in the management of diarrhea include the 
following recommendations (American Cancer Society; National Cancer Institute): 
a. Stop all lactose containing products and eat small meals 
b. Avoid spicy, fried and fatty foods, bran, raw vegetables and other foods high in fiber 
 Eat foods low in fiber (i.e., lean meat, rice, skinless chicken or turkey, 
fish, eggs, canned or cooked skinless fruits, cooked/pureed vegetables) 
c. Avoid caffeine and alcohol as they can irritate the bowel and increase motility 
d. Hydration:  Drink 8-10 large glasses of clear liquids a day (e.g., water, electrolyte 
drink). 
 Avoid acidic drinks such as tomato juice and fizzy soft drinks 
e. Supplement diet to include foods rich in potassium (e.g., bananas, potatoes, and 
apricots), evaluate their impact on diarrhea due to the fiber content (e.g., apricots) 
 
3. Continue with study treatment (i.e., lapatinib-based treatment) 
Continue with supportive care until diarrhea has resolved (diarrhea free for 12 hours/bowel 
pattern return to baseline).  Once diarrhea has resolved, the subject can begin to gradually re-
introduce foods from their normal diet.  Refer to Section IV “Recurrent Diarrhea” for study 
treatment guidelines. If diarrhea recurs following stopping of loperamide treatment, resume 
loperamide treatment at the dose and schedule recommended above and re-introduce diet 
modifications. 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 84 
 
 
III. 
Persistent (≥ 3days/72 hours) Grade 2 Diarrhea: hold lapatinib and chemotherapy (if 
applicable) until diarrhea resolves (<Grade 1/return to baseline bowel pattern). 
1. If supportive care measures and the interruption of study treatment (i.e., lapatinib and if 
applicable chemotherapy) are ineffective in treating persistent Grade 1 or Grade 2 
diarrhea, perform stool work-up, CBC, electrolytes and other tests as appropriate, 
consider consulting with a gastrointestinal (GI) specialist. 
a. After diarrhea resolves (<Grade 1/return to baseline bowel pattern), resume treatment 
with lapatinib and chemotherapy (if applicable). 
IV. 
Recurrent Diarrhea (more than 1 occurrence of Grade 2 diarrhea): once the 2nd 
occurrence of Grade 2 diarrhea resolves to ≤Grade 1, consider reducing the dose of lapatinib by 
250mg or 1 tablet, unless the lapatinib dose already had been reduced to 750mg.  No further dose 
reduction is recommended for subjects taking lapatinib at 750mg. 
2. Consider a dose reduction for chemotherapy (if applicable) 
B) 
Complicated Diarrhea 
I. CTCAE Grade 3 or Grade 1 or 2 with complicating features (severe cramping, severe 
nausea/vomiting, decreased performance status, fever, sepsis, Grade 3 or 4 neutropenia, 
frank bleeding, dehydration) 
1. Subject must call physician immediately for any complicated severe diarrhea event 
2. If loperamide has not been initiated, initiate loperamide immediately:  Initial dose 4mg 
followed by 2mg every 2 hours or after every unformed stool* 
3. Refer to the dietary modification recommendations for Grade 1 and Grade 2 uncomplicated 
diarrhea 
4. For dehydration use intravenous fluids as appropriate, if subject presents with severe 
dehydration administer octreotide 
5. Perform stool work-up, CBC, electrolytes and other tests as appropriate 
6. Administer antibiotics as needed (example fluoroquinolones), especially if diarrhea is 
persistent beyond 24 hours or there is fever or Grade 3-4 neutropenia 
Hold lapatinib and chemotherapy (if applicable) until symptoms resolve to ≤Grade 1 (without 
complicating features) and reintroduce lapatinib at a reduced dose (unless dose had been 
reduced to 750mg, contact medical monitor for further guidance): INFO: FOR ISS: remove 
the italicized guidance 
 
7. 
Supportive care and other interventions should be continued until diarrhea free (i.e., <Grade 
1/bowel patterns returned to baseline) for 24 hours 
8. 
Intervention may require hospitalization for subjects most at risk for life threatening 
complications 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 85 
 
 
II.CTCAE Grade 4 
1. Subject must call physician immediately for any Grade 4 diarrhea event 
2. Hold treatment with lapatinib, hold chemotherapy or other concurrent anticancer therapy (if 
applicable) 
o Contact the Medical Monitor to discuss the patient case history and the possibility of re-
initiation of study treatment, including dose modifications, following resolution of diarrhea 
(≤Grade 1) 
(INFO: NOTE: Can Modify Figure 1Grade 4 with this guidance; For Investigator 
sponsored studies substitute the above recommendation  with the following: Evaluate the 
patient case history when deciding on the re-initiation of study treatment, including dose 
modifications, following resolution of diarrhea (≤Grade 1) 
3. If loperamide has not been initiated, initiate loperamide immediately:  Initial dose 4mg 
followed by 2mg every 2 hours or after every unformed stool* 
4. For dehydration use intravenous fluids as appropriate, if subject presents with severe 
dehydration administer octreotide 
5. Perform stool work-up, CBC, electrolyte and other tests as appropriate 
6. Recommend consulting with GI specialist 
7. Administer antibiotics as needed (example fluoroquinolones), especially if diarrhea is 
persistent beyond 24 hours or there is fever or Grade 3/4 neutropenia 
8. Supportive care and other intervention should be continued until diarrhea free (i.e., <Grade 
1/bowel patterns returned to baseline) for 24 hours 
9. Intervention may require hospitalization for subjects most at risk for life threatening 
complications 
*It is recommended that the maximum cumulative daily dose of loperamide follows local guidance  
Refer to and follow the recommended supportive care guidelines in the previous sections and as 
depicted in Figure 1. 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 86 
 
 
Figure 1: Algorithm for the management of diarrhea in subjects treated with lapatinib-
based therapy 
 
1. For Grade 1 diarrhea that persists for 2 weeks or longer, refer to Section III 
2. For Grade 2 diarrhea that persists longer than 3 days/72 hours, refer to Uncomplicated Diarrhea Section III 
3. For recurrent diarrhea, refer to Uncomplicated Diarrhea Section IV for further management guidelines 
References 
American Cancer Society. Coping with physical and emotional changes: Diarrhea: what the 
subject can do.  Diahttp://www.cancer.org/docroot/MBC/content/MBC_2_3X_Diarrhea.asp 
Benson A, Jaffer AA, Catalano RB, et al. Recommended Guidelines for the Treatment of Cancer 
RECOMMENDATION 

Loperamide prescription with instructions on administration for all subjects receiving 
lapatinib 

Patient diary to record baseline bowel patterns and changes; dietary changes 
EVALUATION 

Obtain history of onset and duration of diarrhea 

Describe number of stools and stool composition (Refer to baseline) 

Assess subject for fever, dizziness, abdominal pain/cramping or weakness 

Medications (Prescription; OTC; herbal supplements) and dietary profile 
UNCOMPLICATED 
Grade 1 or Grade 2 with no complicating 
signs or symptoms 
ADDED RISK 
FACTORS 
COMPLICATED 
Grade 3 or 4 diarrhea or Grade 1 or 2 with 
≥ 1 of these signs or symptoms: 
•
Cramping (moderate/severe) 
•
Nausea/vomiting (≥ Grade 2) 
•
Decreased performance status 
•
Fever 
•
Sepsis 
•
Neutropenia 
•
Frank bleeding 
•
Dehydration 
 MANAGEMENT 
•
Subjects should be instructed to administer loperamide and notify physician 
•
Discontinue lactose products  
•
Drink 8-10 large glasses of clear liquids per day 
•
Eat frequent small meals  
•
Eat foods low in fiber  
•
Continue with lapatinib-based treatment  
Reassess 24 hours later 
Diarrhea Resolving 
•
Continue instructions for dietary 
modification 
•
Gradually add solid food to diet 
•
Discontinue standard anti-
diarrheal after 12-hour diarrhea-
free interval 
•
If applicable resume treatment 
with lapatinib and chemotherapy 
Diarrhea Unresolved 

Continue  loperamide 

Continue dietary modifications 

Evaluate for  possible infection 
(Grade 2) 
Reassess 24 hours later 
Diarrhea unresolved 

Continue loperamide (Grade 1) 

Start second line anti-diarrheal agents 
(Grade 2) 

Start second-line anti-diarrheal agents for 
Grade 1 diarrhea that does not improve after 
1 week of loperamide treatment 
 MANAGEMENT 
•
Subject must call physician immediately 
•
Grade 3: hold lapatinib and chemotherapy (if applicable) 
•
Grade 4:hold all study treatment (lapatinib + chemotherapy) 
•
Evaluate for possible infection  
•
Consider hospitalization   
SUGGESTED TREATMENT 
•
Administer loperamide  
•
Hydration (i.v. fluids as needed) 
•
Consider need for antibiotics and consider second line anti-
diarrheals  
•
Consider consulting with GI specialist  
Diarrhea Free for 24 hours 

Discontinue diarrhea intervention 
For Grade 3 

Reintroduce lapatinib at a reduced 
dose (if dose was >750mg) and 
chemotherapy (if applicable) 

Consider dose reduction for 
chemotherapy 
For Grade 4 
Refer to Section B, subsection II 

U A B  1 3 7 2 ;  V e r s i o n  1 2 1 2 1 8                                P a g e  | 87 
 
 
Treatment-Inducted Diarrhea.  Journal of Clinical Oncology 2004; 22:2918-2926. 
Charma R, Tobin P, Clarke SJ.  Management of chemotherapy-induced nausea, vomiting, oral 
mucositis, and diarrhea.  Lancet/Oncology 2005; 6:93-102 
Crown JP, Burstein HA, Boyle F, et al. Pooled analysis of diarrhea events in patients with cancer 
treated with lapatinib.  Breast Cancer Res Treat 2008; 112:317-325. 
Saltz LB.  Understanding and Managing Chemotherapy-Induced Diarrhea. Journal of Supportive 
Oncology 2003; 1:35-46.  
National Cancer Institute. Nutrition in cancer care (PDQ®). 
http://www.cancer.gov/cancertopics/pdq/supportivecare/nutrition/Subject