Drug Distribution and Pharmacodynamic Study of Pulsatile Lapatinib in Surgically Accessible EGFR-Amplified Recurrent High-Grade Glioma
Phase: PHASE1
Conditions: Anaplastic Astrocytoma, Anaplastic Ependymoma, Anaplastic Oligodendroglioma, Gliosarcoma, Mixed Glioma, Recurrent Adult Brain Neoplasm, Recurrent Glioblastoma
Sponsor: National Cancer Institute (NCI)

 
1 
 
 
 
 
 
 
 
 
 
 
     ABTC #: 1302 
  NCI #: ABTC-1302 
 
  
 
 
 
  
 
Version Date –03/27/19 
Previous Version Dates: 03/05/14, 10/22/15, 04/19/16, 08/25/16, 03/29/18 
 
 
Drug Distribution and Pharmacodynamic Study of Pulsatile Lapatinib in 
Surgically Accessible EGFR-Amplified Recurrent High-Grade Glioma 
 
 
A Protocol of the Adult Brain Tumor Consortium (ABTC)  
 
Coordinating Center: ABTC Central Operations Office, 
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins  
 
 
NCI-Supplied Agent: lapatinib 
NSC #727989; 
IND Sponsor: CTEP, DCTD, NCI
Study Chair 
Timothy Cloughesy, MD 
University of California, Los Angeles 
 
Phone: 310-825-5321  
Fax: 310-825-0644 
Email: tcloughesy@mednet.ucla.edu 
 
 
Pharmacology Laboratories 
Jeffrey G. Supko, PhD 
Massachusetts General Hospital 
Phone: 617-724-1970 
Email: jsupko@partners.org 
Study Co-Chair 
Ingo Mellinghoff, MD 
Memorial Sloan-Kettering Cancer Center 
 
Phone: 646-888-2766  
Fax: 646-422-0856  
Email: mellingi@mskcc.org 
 
 
Biostatistician 
Xiaobu Ye, MD, MS 
Johns Hopkins University 
Phone: 410-614-6261 
Email: xye3@jhmi.edu 
  
 

Drug Distribution and Pharmacodynamic Study of Pulsatile Lapatinib in Surgically Accessible EGFR-Amplified 
Recurrent High-Grade Glioma 
 
ABTC # 1302 
NCI # ABTC-1302 
PI: T. Cloughesy 
 
2 
 
 
Version 03/27/19 
 
 
PARTICIPATING INVESTIGATORS: Adult Brain Tumor Consortium participating members 
 
 
 
Adult Brain Tumor Consortium Member Institutions 
 
Cleveland Clinic Foundation/ 
University Hospitals 
 
Harvard Neuro-Oncology 
 
Henry Ford Health System 
 
Johns Hopkins University 
 
 
Pharmacy Contact 
Anne Delisa, PharmD, BCOP 
Sidney Kimmel 
Comprehensive Cancer 
Center at Johns Hopkins 
Phone: (410) 502-1036 
Email: adelisa@jhmi.edu 
Memorial Sloan-Kettering 
Cancer Center 
 
University of Alabama at 
Birmingham  
 
University of California, Los 
Angeles 
 
 
Nursing Contact  
Stacey Green, MSN, GNP-
BC 
 
Neuro-Oncology Program 
University of California, Los 
Angeles 
Phone: 310-825-5321 
Email: 
sdgreen@mednet.ucla.edu   
University of California, San 
Francisco 
 
University of Pennsylvania 
 
University of Pittsburgh 
 
Wake Forest University 
 
 
 
 
 
ABTC Manager 
Joy Fisher 
Johns Hopkins University 
Phone: 410-955-3657 
Email: jfisher@jhmi.edu 
ABTC Data Coordinator 
Serena Desideri, M.D. 
Johns Hopkins University 
Phone: 410-614-4400 
Email: sdeside1@jhmi.edu 
Protocol Development 
Coordinator 
Anita Nandekya, MHS  
Johns Hopkins University 
Phone: 410-502-5973 
Email: sosire1@jhmi.edu 
 
ABTC Database Coordinator 
Jason Zhao 
Johns Hopkins University 
Phone: 410-502-9997 
Email: jzhao8@jhmi.edu 
 
 
 
 

Drug Distribution and Pharmacodynamic Study of Pulsatile Lapatinib in Surgically Accessible EGFR-Amplified 
Recurrent High-Grade Glioma 
 
ABTC # 1302 
NCI # ABTC-1302 
PI: T. Cloughesy 
 
3 
 
 
Version 03/27/19 
 
Table of Contents 
1.0 
OBJECTIVES .................................................................................................................................................. 5 
2.0 
BACKGROUND AND RATIONALE ........................................................................................................... 6 
2.1 
STUDY DISEASE ............................................................................................................................................. 6 
2.2 
LAPATINIB ...................................................................................................................................................... 6 
2.3 
RATIONALE .................................................................................................................................................... 8 
2.4 
CORRELATIVE STUDIES BACKGROUND ........................................................................................................ 10 
3.0 
PATIENT ELIGIBILITY CRITERIA ........................................................................................................ 12 
3.1  
PATIENT SAMPLE ......................................................................................................................................... 12 
3.2 
ELIGIBILITY CRITERIA .................................................................................................................................. 12 
3.3 
INELIGIBILITY CRITERIA ............................................................................................................................... 14 
4.0 
TREATMENT PLAN .................................................................................................................................... 16 
4.1 
TREATMENT SCHEMA ................................................................................................................................... 16 
4.2 
TREATMENT REQUIREMENTS ....................................................................................................................... 20 
4.3 
DRUG ADMINISTRATION .............................................................................................................................. 20 
4.4 
GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES ............................................. 21 
5.0 
TOXICITY ..................................................................................................................................................... 23 
5.1 
TOXICITY MANAGEMENT AND DOSE DELAY/MODIFICATION FOR LAPATINIB ............................................. 23 
5.2 
DOSE MODIFICATION/REDUCTION FOR LAPATINIB ...................................................................................... 24 
5.2.1 
Severe Cutaneous Reactions ................................................................................................................ 24 
5.2.2 
Lapatinib dose modification for LVEF events ..................................................................................... 24 
5.2.3 
Lapatinib dose modification for non-cardiac AEs ............................................................................... 26 
5.3 
MAJOR EVENTS ............................................................................................................................................ 27 
5.4 
USE OF HEMATOLOGIC GROWTH FACTORS .................................................................................................. 28 
5.5 
TOXICITY CRITERIA ..................................................................................................................................... 28 
6.0 
PHARMACEUTICAL INFORMATION .................................................................................................... 28 
6.1 
LAPATINIB (GW572016, NSC 727989) ....................................................................................................... 28 
7.0 
REGISTRATION PROCEDURES / PATIENT ENROLLMENT ........................................................... 31 
7.1 
CTEP REGISTRATION ................................................................................................................................... 31 
7.2 
SITE REGISTRATION ..................................................................................................................................... 32 
7.3 
PATIENT REGISTRATION ............................................................................................................................... 33 
8.0 
SAFETY AND QUALITY ASSURANCE ................................................................................................... 34 
8.1 
CRITERIA FOR RESPONSE ASSESSMENT ........................................................................................................ 34 
8.2 
ASSESSMENT OF RESPONSE .......................................................................................................................... 36 
8.3 
SAFETY ASSESSMENTS .................................................................................................................................. 36 
8.4 
QUALITY ASSURANCE .................................................................................................................................. 36 
9.0 
MONITORING OF PATIENTS .................................................................................................................. 38 
9.1 
TABLES OF REQUIRED OBSERVATIONS ......................................................................................................... 38 
9.2 
ADVERSE EVENTS ........................................................................................................................................ 41 
9.2.1 
Comprehensive Adverse Events and Potential Risks list (CAEPR) ..................................................... 41 
9.3 
SERIOUS ADVERSE EVENTS AND EXPEDITED ADVERSE EVENT REPORTING................................................. 45 
9.3.1 
Definition – Serious Adverse Event (SAE) ........................................................................................... 45 
9.3.2 
CTEP Adverse Event Reporting System (CTEP-AERS) ....................................................................... 46 

Drug Distribution and Pharmacodynamic Study of Pulsatile Lapatinib in Surgically Accessible EGFR-Amplified 
Recurrent High-Grade Glioma 
 
ABTC # 1302 
NCI # ABTC-1302 
PI: T. Cloughesy 
 
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9.3.3 
Expedited Reporting Requirements ...................................................................................................... 47 
9.3.4 
Other Reporting ................................................................................................................................... 48 
9.4 
DATA REPORTING ........................................................................................................................................ 49 
9.5  
CORRELATIVE STUDIES ................................................................................................................................ 50 
9.5.1 
Tissue Requirements for Protocol Surgery: Group A and Reference Group ....................................... 51 
9.5.2 
Archived and Protocol Surgery Paraffin Tumor Tissue (Group A and Reference Group) .................. 52 
9.5.3 
Plasma Pharmacokinetics: Group A Participants ............................................................................... 52 
9.5.4 
Handling and Shipping of Frozen Tumor for tumor concentration and EGFR phosphorylation ........ 53 
9.5.5 
Tumor Samples for Intratumoral Drug Distribution: Group A ........................................................... 55 
9.5.6  
Tumor Samples for Determination of EGFR phosphorylation in Tumor Tissue: (Group A and 
Reference Group) ................................................................................................................................................ 55 
9.5.7 
Tumor Sphere Cultures ........................................................................................................................ 56 
10.0    OFF TREATMENT/OFF STUDY CRITERIA .......................................................................................... 58 
10.1 
OFF TREATMENT CRITERIA .......................................................................................................................... 58 
10.2 
OFF STUDY CRITERIA ................................................................................................................................... 59 
11.0   STATISTICAL CONSIDERATIONS ......................................................................................................... 59 
12.0   RECORDS TO BE KEPT ............................................................................................................................. 61 
13.0  REFERENCES .............................................................................................................................................. 63 
14.0 
COLLABORATIVE AGREEMENTS LANGUAGE ................................................................................. 67 
15.0  ETHICAL AND LEGAL CONSIDERATIONS ......................................................................................... 69 
APPENDIX I – PATIENT MEDICATION DIARY ............................................................................................... 70 
APPENDIX II – INFORMATION ON POSSIBLE DRUG INTERACTIONS ................................................... 73 
APPENDIX III – INFORMATION ON EGFR MESOSCALE ASSAY .............................................................. 75 
 
 
 
 

Drug Distribution and Pharmacodynamic Study of Pulsatile Lapatinib in Surgically Accessible EGFR-Amplified 
Recurrent High-Grade Glioma 
 
ABTC # 1302 
NCI # ABTC-1302 
PI: T. Cloughesy 
 
5 
 
 
Version 03/27/19 
 
1.0 
OBJECTIVES  
 
Primary Objectives 
 
Group A:  
 
1. To achieve an intratumoral lapatinib concentration of at least 1.5 µM in at least 70% 
of patients 3 hours after the last dose of pulsatile lapatinib. 
 
Group A and Reference Group: 
  
2. To determine the pharmacodynamic (PD) effect of pulsatile lapatinib (at pulsatile 
MTD) on EGFR phosphorylation (using Mesoscale Discovery ELISA assay for total 
and phospho-EGFR). The successful PD effect is defined by EGFR blockade if at 
least 70% of the patients have an 80% reduction of EGFR phosphorylation/total in 
Group A tumors compared to the Reference Group tumors.  
  
 
 
Secondary/Exploratory Objectives: 
 
Group A and Reference Group:  
 
1. To evaluate the safety profile of pulsatile lapatinib in pre-operative patients with 
EGFR amplified recurrent high-grade glioma; to evaluate acute and late toxicities 
associated with pulsatile lapatinib 
 
2. To determine the effect of lapatinib on tumor cell proliferation (KI-67 staining) 
(Group A compared to Reference Group) 
 
3. To determine the ex-vivo sensitivity of tumor sphere cultures to lapatinib 
 
4. To assess tumor objective response rate (ORR) 
 
5. To estimate overall survival (OS) 
 
6. To estimate progression-free survival 
 
 
 
 
 
 
 

Drug Distribution and Pharmacodynamic Study of Pulsatile Lapatinib in Surgically Accessible EGFR-Amplified 
Recurrent High-Grade Glioma 
 
ABTC # 1302 
NCI # ABTC-1302 
PI: T. Cloughesy 
 
6 
 
 
Version 03/27/19 
 
2.0 
BACKGROUND AND RATIONALE 
 
2.1 
Study Disease 
 
High-Grade Glioma 
 
Glioblastoma (WHO grade IV) and anaplastic glioma (WHO grade III) represent the 
most common malignant brain tumor in adults. These tumors are universally fatal with 
most patients succumbing to their disease within ten years, and there is a dire need for the 
development of novel therapeutics (Wen 2008). Inhibitors of deregulated signaling 
pathways are active agents in a variety of human cancers (Sawyers 2009, Sellers 2011) 
and represent a compelling area of drug development for high-grade glioma because 
many of these tumors harbor genetic alterations in growth factor-signaling pathways 
(Killela et al. 2013, Parsons et al. 2008).  
 
2.2 
Lapatinib 
 
Lapatinib (Tykerb) is a dual EGFR/erbB2 kinase inhibitor. It is currently approved for the 
treatment of patients with advanced breast cancer in combination with capecitabine. Its 
activity against EGFR has led to two trials exploring the use of lapatinib in recurrent 
glioblastoma (GBM).  
Lapatinib in clinical studies 
As of 05-Dec-2011, a total of 10 Phase I studies in healthy volunteers, 29 Phase I studies 
in subjects with cancer, and 55 Phase II or Phase III clinical efficacy studies in subjects 
with cancer have been completed or are active in the GlaxoSmithKline (GSK)-sponsored 
lapatinib program. For this investigator’s brochure (IB), the definition of the term 
“completed” refers to a study for which a final (End of Study) clinical report is available. 
 
All studies with subjects still on treatment are considered active. Once a study has met 
protocol-defined events or objectives, an analysis is usually performed; however, subjects 
may continue to receive study medication during or after the completion of this analysis. 
These subjects are followed per protocol, and a final safety analysis is performed once all 
subjects have withdrawn from study medication. 
 
A total of 385 healthy volunteers and over 1,100 subjects with cancer have been enrolled 
in Phase I studies. Over 30,000 subjects have been enrolled in Phase II, III and IV clinical 
monotherapy and combination therapy studies, of which over 27,000 subjects have been 
enrolled in breast cancer studies. Other subjects were enrolled in studies evaluating the 
use of lapatinib in the treatment of bladder, colorectal, head and neck, lung, renal, 
cervical, gastric, ovarian, and uterine cancer, relapsed adenocarcinoma of the esophagus, 
including tumors of the gastroesophageal junction and gastric cardia, and in the treatment 
of malignant gliomas. 
 

Drug Distribution and Pharmacodynamic Study of Pulsatile Lapatinib in Surgically Accessible EGFR-Amplified 
Recurrent High-Grade Glioma 
 
ABTC # 1302 
NCI # ABTC-1302 
PI: T. Cloughesy 
 
7 
 
 
Version 03/27/19 
 
Summary of lapatinib safety 
 
As of 05-Dec-2011 565 subjects have died due to events reported as serious adverse 
events (SAEs). One hundred and eleven of these deaths were assessed as related to 
investigational product (IP) by the investigator; 87 subjects received lapatinib, 13 
subjects received comparator, 10 subjects received placebo and 1 subject remained 
blinded. Based on current exposure, the estimated incidence rate of fatal outcomes related 
to lapatinib was 0.4% (87/20,586), compared with a rate of 0.3% (23/7421) for subjects 
who received placebo or comparator. Twenty-one of the lapatinib subjects received 
lapatinib monotherapy, the remaining 66 received lapatinib in combination with other 
chemotherapy (including capecitabine, paclitaxel, pazopanib, and trastuzumab).  The 
reported fatal events were all expected events for the cancer treatment regimens and/or 
the population under study. 
 
The most common adverse events (AEs) in clinical studies, regardless of relationship to 
study drug, were diarrhea, rash, and nausea. Majority of these AEs were of Grade 1 or 2 
severity, and resolved. These events are included in the core safety information (CSI) for 
lapatinib and are consistent with the safety profile of lapatinib as reported for the program 
as a whole. 
 
Lapatinib dosed at 750mg twice a day was used in a similar study to this with 
neoadjuvant delivery followed by craniotomy and tissue removal (NABTC 04-01).  There 
were no safety signals identified associated with wound healing or wound infections.  
There is no identified experience using pulsatile lapatinib in the setting of any surgery 
including craniotomy.  The safety concerns associated with wound healing or wound 
infection are unknown with the doses provided with this study. 
 
Summary of clinical pharmacology studies 
 
In healthy volunteer Phase I studies, most AEs reported were considered Grade 1 in 
severity and resolved spontaneously. Overall, the most frequently reported AEs were 
Grade 1 headache, GI-related events (diarrhea, loose stools, dyspepsia, gas, flatulence), 
and rash. There were no deaths or SAEs reported in the healthy volunteer studies while 
subjects were on study. There were no consistent lapatinib-related changes in physical 
examinations, hematology or clinical chemistry values, electrocardiogram (ECG), 
urinalyses, or ophthalmologic examinations. 
 
Of the over 1,100 subjects with cancer enrolled in Phase I lapatinib studies by 05-Dec-
2011, 357 subjects had received single-agent lapatinib in eight Phase I studies and over 
600 subjects had received lapatinib in combination with other agents including 
chemotherapeutic or hormonal anticancer treatments in 20 Phase I studies including one 
Phase I component of a Phase I/Phase II study and two Phase I continuation (rollover) 
studies. In the monotherapy lapatinib studies, lapatinib was administered at dosages 
ranging from 175 mg to 1800 mg once daily or 500 mg to 900 mg BID. In the lapatinib-

Drug Distribution and Pharmacodynamic Study of Pulsatile Lapatinib in Surgically Accessible EGFR-Amplified 
Recurrent High-Grade Glioma 
 
ABTC # 1302 
NCI # ABTC-1302 
PI: T. Cloughesy 
 
8 
 
 
Version 03/27/19 
 
based combination studies, lapatinib was administered at dosages ranging from 500 mg to 
1500 mg once daily. 
 
In completed lapatinib Phase I monotherapy studies in subjects with cancer, most AEs 
reported were Grade 1 or 2 in severity with the most frequently reported AEs being 
diarrhea, rash, nausea, anorexia, and fatigue. There were no consistent lapatinib-related 
changes in physical examinations, hematology or clinical chemistry values, ECG, 
urinalyses, or ophthalmologic examinations. 
 
Summary of clinical efficacy studies:  lapatinib monotherapy 
 
As of the clinical data cut-off date of 05-Dec-2011, over 5,000 subjects have been 
enrolled in 12 completed and 4 active Phase II or III lapatinib monotherapy studies. In the 
monotherapy studies, lapatinib was administered at dosages ranging from 1000 mg once 
daily to 1500 mg once daily or from 500 mg BID to 750 mg BID. Results from the data 
analyses performed for 15 lapatinib monotherapy studies suggest that lapatinib was 
generally well tolerated in subjects with cancer. The most common AEs regardless of 
relationship to drug were diarrhea, rash, and nausea. The majority of these AEs were of 
Grade 1 or Grade 2 severity. These events are included in the CSI for lapatinib and are 
consistent with the safety profile of lapatinib as reported for the program as a whole. 
 
Efficacy data from the 15 monotherapy studies with data analyses are summarized in 
Section 5.3.4.1 of the lapatinib Investigator’s Brochure. 
 
2.3 
Rationale  
 
The epidermal growth factor receptor (EGFR) is a member of the EGFR family of 
receptor tyrosine kinases, which also includes HER2 (ErbB2), HER3 (ErbB3), and HER4 
[ErbB4 (Yarden et al. 2001). EGFR has generated particular interest as a drug target in 
GBM because of the high frequency of EGFR alterations in this disease (Furnari et al. 
2007) and because ATP-site competitive EGFR kinase inhibitors are active agents in 
patients with EGFR mutant lung cancer (Pao 2010). EGFR kinase inhibitors that received 
regulatory approval for the treatment of lung cancer (erlotinib, gefitinib), however, have 
shown disappointing results in patients with GBM (Brandes 2008). Reasons for this lack 
of response in GBM remain poorly understood and may include redundancy in signaling 
pathways (Stommel 2007) and intratumoral heterogeneity (Inda 2010).  
 
One key difference between EGFR in GBM and lung cancer is the distribution of 
mutations within the EGFR coding sequence. EGFR mutations in lung cancer reside in 
the intracellular kinase domain (Sharma SV 2007). EGFR mutations in GBM cluster in 
the extracellular (EC) domain and include in-frame deletions (such as the common 
“variant III” [Furnari et al. 2007]) and missense mutations (Lee et al. 2006). In contrast to 
the most common EGFR kinase domain mutants in lung cancer which respond well to the 
first-generation EGFR kinase inhibitors erlotinib and gefitinib, we recently found that the 
most common oncogenic EGFR alterations in GBM are relatively insensitive to erlotinib 

Drug Distribution and Pharmacodynamic Study of Pulsatile Lapatinib in Surgically Accessible EGFR-Amplified 
Recurrent High-Grade Glioma 
 
ABTC # 1302 
NCI # ABTC-1302 
PI: T. Cloughesy 
 
9 
 
 
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(Vivanco et al. 2012). Instead, these mutants are preferentially inhibited by EGFR 
inhibitors that can only be accommodated by the inactive conformation of the EGFR 
catalytic pocket as the result of their bulky aniline substituents (lapatinib, HKI-272 
[Wood et al. 2004, Eck et al. 2010]). These results from Vivanco et al. are consistent with 
structural data (Park and Lemmon 2012) and argue for focused clinical development of 
type II EGFR kinase inhibitors such as lapatinib for EGFR-mutant GBM. 
A number of recent studies have shown that the level of kinase inhibition is a critical 
determinant of the biological effects of kinase inhibitors on cancer cells expressing 
oncogenic kinases. First, near complete inhibition of BCR-ABL, even for only minutes, 
irreversibly committed BCR-ABL mutant leukemia cells to cell death (Shah et al. 2008). 
Second, greater than 80% inhibition of ERK phosphorylation in the tumors of patients 
correlated with clinical response in BRAF mutant melanoma (Bollag et al. 2010). Third, 
intermittent, high-dose lapatinib was more effective than daily, lower dose lapatinib in 
xenograft models of two different ERB-driven cancers, namely HER2 amplified BT474 
breast cancer xenografts (Amin et al. 2010) and EGFR amplified GS676 glioblastoma 
xenografts (Vivanco et al. 2012). Titration experiments with multiple EGFR-shRNAs 
genetically confirmed the requirement of near complete EGFR inhibition for induction of 
cell death in EGFR mutant glioblastoma cells (Vivanco et al. 2012). Of note, we also found 
that near complete EGFR inhibition is able to overcome the effects of PTEN loss on EGFR 
kinase inhibitor resistance (Vivanco et al. 2010) and to induce cell death in EGFR mutant 
glioblastoma cells with endogenous loss of PTEN (Vivanco et al. 2012).  
A critical aspect of potent EGFR blockade is the “therapeutic window” of this strategy. 
While EGFR knockdown and lapatinib robustly induced death and blocked colony 
formation in GBM cells with EGFR gene amplification or EGFR mutation (Vivanco et al. 
2012), reflecting their “dependence” on EGFR signals for survival, neither EGFR 
knockdown nor pharmacological EGFR blockade induced cell death in immortalized 
human astrocytes or in GBM cells that were wildtype for EGFR. Furthermore, clinical 
studies at Memorial Sloan Kettering Cancer Center have shown that high-dose intermittent 
dosing of the type I EGFR kinase inhibitor erlotinib (weekly administration of 1200-2000 
mg) is well tolerated (Milton 2006, Clarke et al. 2010, Grommes et al. 2011).  
Unfortunately, current dosing schedules of lapatinib do not reach sufficiently high 
intratumoral drug concentrations to potently inhibit EGFR in GBM. When given at a dose 
of 750 mg twice daily (NABTC 04-01 in Vivanco et al. 2012), lapatinib only inhibited 
EGFR by about 50 % (based on ratio of phosphorylated to total EGFR using the MSD 
mesoscale assay [Vivanco et al. 2012]) and failed to prolong progression-free survival in 
patients with recurrent GBM in that study, and another recent phase I/II trial (Thiessen et 
al. 2010). Unfortunately, these trials did not restrict patient enrollment to EGFR-mutant 
GBMs. In the NABTC 04-01 study, for example, neither of the two GBM patients with 
intratumoral lapatinib concentrations shown to induce cell death in-vitro (>1,500 nM) and 
EGFR protein overexpression could be evaluated for therapeutic response.  
The current trial restricts enrollment to patients with EGFR amplified high grade glioma 
because glioma cells with amplification of wildtype EGFR gene are more sensitive to 
lapatinib than cells with non-amplified wildtype EGFR (Vivanco et al. 2012). Furthermore, 

Drug Distribution and Pharmacodynamic Study of Pulsatile Lapatinib in Surgically Accessible EGFR-Amplified 
Recurrent High-Grade Glioma 
 
ABTC # 1302 
NCI # ABTC-1302 
PI: T. Cloughesy 
 
10 
 
 
Version 03/27/19 
 
the EGFR VIII mutation in GBM occurs almost exclusively in the setting of EGFR gene 
amplification and EGFRvIII showed greater sensitivity to type II EGFR kinase inhibitors 
(such as lapatinib) than to the type I EGFR kinase inhibitor erlotinib. 
The pharmacokinetic (PK) goal of this study is to achieve intratumoral concentrations of 
lapatinib >1,500 nM. The pharmacodynamic (PD) goal is to achieve near complete 
inhibition of pEGFR, defined as 80% reduction of EGFR phosphorylation. Of note, the 
feasibility of such “pulsatile” lapatinib therapy has already been explored in advanced solid 
tumors and found to be well tolerated (Chien et al. 2009).  
 
2.4 
Correlative Studies Background 
 
EGFR gene amplification in tumor cells (Integral):  EGFR mutations in high-grade 
glioma include point mutations and a variety of structural alterations (Frederick et al. 
2000, Frattini et al. 2013, Brennan et al. 2013, Ciriello et al. 2013). Since these mutations 
are commonly accompanied by amplification of the EGFR gene, evidence of regional 
DNA amplification of EGFR will be used as an integral biomarker.  EGFR amplification 
will be determined centrally by fluorescence in-situ hybridization (FISH) (See Section 
9.5.2). 
 
Tumor lapatinib concentrations (Integrated):  See Section 2.3, above, regarding the 
rationale and selection of pharmacokinetic endpoints.  The concentration of lapatinib in 
tumor samples will be determined using a validated LC-MS/MS assay. Details of the 
sample collection, processing, storage and shipment procedures are provided in Section 
9.5.5. 
 
EGFR phosphorylation in tumor cells (Integrated): See Section 2.3, above, regarding 
the rationale and selection of pharmacodynamic endpoints. EGFR phosphorylation will 
be determined with the mesoscale electroluminescence platform which has shown greater 
sensitivity than other ELISA-based assays (Sharma J et al. 2012) and is widely used in 
the evaluation of signal transduction inhibitors (http://www.mesoscale.com). Details of 
the procedures for sample collection, sample batching, and assay performance 
characteristics are provided in Section 9.5.4., Section 9.5.6, and Appendix IV.   
 
Plasma lapatinib concentrations (Exploratory):  The concentration of lapatinib in 
plasma samples will be determined using a validated LC-MS/MS assay. Details of the PK 
sample collection, processing, storage and shipment procedures are provided in Section 
9.5.3. 
 
Tumor cell proliferation (KI-67 staining) (Exploratory): We will compare tumor cell 
proliferation in lapatinib-treated patients (group A) with tumor cell proliferation in 
lapatinib-naïve patients (reference group). We will also examine tumor cell proliferation 
in the archival sample from both groups of patients and compare it to the matched 
specimen from the current protocol surgery (matched pair comparison). Together, these 

Drug Distribution and Pharmacodynamic Study of Pulsatile Lapatinib in Surgically Accessible EGFR-Amplified 
Recurrent High-Grade Glioma 
 
ABTC # 1302 
NCI # ABTC-1302 
PI: T. Cloughesy 
 
11 
 
 
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analyses aim to determine the effect of lapatinib on tumor cell proliferation. Details of the 
procedures for sample collection and staining are provided in Section 9.5.2. 
 
Ex-vivo sensitivity of tumor sphere cultures to lapatinib (Exploratory): Compared to 
commercially available human glioblastoma cell lines grown under standard tissue 
culture conditions, freshly derived tumor sphere cultures grown under serum-free 
conditions (with exogenous FGF/EGF) more closely resemble the original human tumor 
sample  (Pandita et al. 2004, Lee J et al. 2006). We will therefore generate such cultures 
from all patients in the study (Group A and Reference Group) and examine their lapatinib 
sensitivity ex-vivo using a Trypan Blue exclusion Assay (Vivanco et al. 2012). Details of 
the sample collection and shipping procedures are provided in Section 9.5.7. 
 
 

Drug Distribution and Pharmacodynamic Study of Pulsatile Lapatinib in Surgically Accessible EGFR-Amplified 
Recurrent High-Grade Glioma 
 
ABTC # 1302 
NCI # ABTC-1302 
PI: T. Cloughesy 
 
12 
 
 
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3.0 
PATIENT ELIGIBILITY CRITERIA 
 
 
3.1  
Patient Sample 
 
Sample Size:  
Group A: 18 patients 
Reference Group: 15 patients  
 
Accrual Rate:  
3 patients per month 
 
Gender: 
Male and female 
 
Age: 
Patients must be at least 18 years of age.  
 
Race/Ethnicity: 
Minorities will be actively recruited.  No exclusion to this study will be based on race or 
ethnicity.  
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
2 
+ 
2 
= 
4 
Not Hispanic or Latino 
11 
+ 
18 
= 
29 
Ethnic Category: Total of all subjects 
13 
(A1) + 
20 
(B1) = 
33 
(C1) 
Racial Category 
 
American Indian or Alaskan Native 
0 
+ 
0 
= 
0 
Asian 
2 
+ 
2 
= 
4 
Black or African American 
2 
+ 
3 
= 
5 
Native Hawaiian or other Pacific Islander 
0 
+ 
0 
= 
0 
White 
9 
+ 
15 
= 
24 
Racial Category: Total of all subjects 
13 
(A2) + 
20 
(B2) = 
33 
(C2) 
 
(A1 = A2) 
 
(B1 = B2) 
 
(C1 = C2) 
 
 
3.2 
Eligibility Criteria 
 
1. 
Patients must have histologically proven WHO grade IV glioblastoma/ gliosarcoma 
or WHO grade III glioma (anaplastic astrocytoma, anaplastic oligodendroglioma, 
mixed anaplastic oligoastrocytoma, anaplastic ependymoma) which is progressive or 
recurrent following radiation therapy  chemotherapy. 

Drug Distribution and Pharmacodynamic Study of Pulsatile Lapatinib in Surgically Accessible EGFR-Amplified 
Recurrent High-Grade Glioma 
 
ABTC # 1302 
NCI # ABTC-1302 
PI: T. Cloughesy 
 
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2. 
Patients must have measurable, supratentorial contrast-enhancing progressive or 
recurrent high-grade glioma by MRI imaging within 21 days of starting treatment. 
Patient must be able to tolerate MRIs. 
 
3. 
Patients may have an unlimited number of prior therapy regimens. 
 
4. 
Patients must have recovered from severe toxicity of prior therapy. The following 
intervals from previous treatments are required to be eligible: 
 
• 12 weeks from the completion of radiation  
• 6 weeks from a nitrosourea chemotherapy 
• 3 weeks from a non-nitrosourea chemotherapy 
• 4 weeks from any investigational (not FDA-approved) agents 
• 4 weeks from the last treatment with bevacizumab 
• 2 weeks from administration of a non-cytotoxic, FDA-approved agent 
other than bevacizumab (e.g., hydroxychloroquine, etc.) 
 
5. 
Patients must be undergoing surgery that is clinically indicated as determined by their 
care providers. Patients must be eligible for surgical resection according to the 
following criteria: 
 
• Expectation that the surgeon is able to resect at least 500 mg of tumor from 
enhancing tumor and 100 mg from non-enhancing tumor with low risk of 
inducing neurological injury. 
 
6. 
Patient tumor sample must have evidence of EGFR gene amplification by FISH 
performed using a CLIA-certified laboratory assay. See Section 9.5.2 for details. 
 
7. 
Paraffin embedded tissue must be available from initial surgical resection at diagnosis 
(prior to any treatment). 
 
8. 
Patients must be 18 years of age or older.  
 
9.  
Patients must have a Karnofsky Performance Status  60% (i.e. the patient must be 
able to care for himself/herself with occasional help from others). 
 
10.  Patients must have the following organ and marrow function: 
 
Absolute neutrophil count 
>1,500/mcL 
Platelets 
>100,000/mcL 
Hemoglobin 
> 9 g/dL 
Total bilirubin                           institutional upper limit of normal 
AST (SGOT)/ALT (SGPT) 
 3 × institutional upper limit of normal 
Creatinine  
 
≤ institutional upper limit of normal 

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                    OR 
Creatinine clearance   
 
>60 ml/min/1.73m2 for patients with creatinine 
levels above institutional normal 
APTT/PTT  
 
≤ 1.5 x institutional upper limit of normal 
 
 
 
  
           
11. Patients must have left ventricular ejection fraction (LVEF) within normal 
institutional limits within 21 days of starting treatment. 
 
12. Patients must have a 12-lead electrocardiogram performed within 2 weeks of 
treatment start with QTC ≤470 msec. 
 
13. Patients must be able to provide written informed consent. 
 
14. Women of childbearing potential must have a negative serum pregnancy test prior to 
study entry. Women of childbearing potential and men must agree to use adequate 
contraception (hormonal or barrier method of birth control; abstinence) prior to study 
entry and for the duration of study participation.  Should a woman become pregnant 
or suspect she is pregnant while participating in this study, she should inform her 
treating physician immediately. Men treated or enrolled on this protocol must also 
agree to use adequate contraception prior to the study, for the duration of study 
participation, and for 4 months after completion of lapatinib administration.  
 
15. Patients must have no concurrent malignancy except curatively treated basal or 
squamous cell carcinoma of the skin or carcinoma in situ of the cervix, breast, or 
bladder.  Patients with prior malignancies must be disease-free for  five years. 
 
16. Patients must be able to swallow medication by mouth, either tablets or dispersed 
tablets in solution. 
 
 
3.3 
Ineligibility Criteria 
 
1. 
Patients may not be receiving any other investigational agents. 
 
2. 
Patients with a history of allergic reactions attributed to compounds of similar 
chemical or biologic composition to lapatinib are ineligible. The lapatinib 
Investigator Brochure can be referenced for more information. 
 
3. 
Patients with prior therapy with EGFR inhibitors are ineligible because treatment 
with EGFR kinase inhibitors or other EGFR-targeted agents has the potential to 
deplete the tumor of EGFR-amplified or EGFR mutant cell populations and confound 
the evaluation of lapatinib effects on EGFR phosphorylation. Patients with prior 
EGFRvIII vaccine are eligible if recurrent tumor is positive for EGFR gene 
amplification. 
 

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4. 
Patients on enzyme-inducing anti-epileptic drugs (EIAED) are not eligible for 
treatment on this protocol. Patients may be on non-enzyme inducing anti-epileptic 
drugs or not be taking any anti-epileptic drugs. Patients previously treated with 
EIAED may be enrolled if they have been off the EIAED for 10 days or more prior 
to the first dose of lapatinib. 
 
5. 
Patients must not have evidence of significant hematologic, renal, or hepatic 
dysfunction.  
 
6. 
Patients must not have evidence of significant intracranial hemorrhage. 
 
7. 
Patients with uncontrolled intercurrent illness including, but not limited to, 
hypertension, ongoing or active infection, symptomatic congestive heart failure, 
unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations 
that would limit compliance with study requirements, are ineligible.  
 
8. 
Pregnant women are excluded from this study because lapatinib has potential for 
teratogenic or abortifacients effects.  Because there is an unknown but potential risk 
for adverse events in nursing infants secondary to treatment of the mother with 
lapatinib, breastfeeding should be discontinued if the mother is treated with lapatinib. 
 
9. 
HIV-positive patients on strong CYP3A4 inducers or inhibitors are ineligible because 
of the potential for pharmacokinetic interactions with lapatinib.  
 
10. Patients who have acute or currently active/requiring anti-viral therapy hepatic or 
biliary disease are ineligible (with the exception of patients with Gilbert's syndrome, 
asymptomatic gallstones, liver metastases from the primary brain tumor, or stable 
chronic liver disease per investigator assessment). 
 
11. Patients receiving P-gp inhibitors are ineligible. See Section 4.4 for a list of P-gp 
inhibitors. 
 
12. Patients who are receiving a drug that has a risk of QTc prolongation if QTc is ≥ 460 
msec. are ineligible. 

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4.0 
TREATMENT PLAN 
 
This study will assess whether oral pulsatile lapatinib dosing at the established MTD 
(2500mg BID, for two days) provides adequate intratumoral drug concentrations and 
EGFR inhibition for future studies that utilize 2 days on/5 days off regimen in EGFR-
amplified high-grade glioma.  
 
Extent of EGFR inhibition will be determined through comparison of EGFR 
phosphorylation in tumor tissue from patients receiving preoperative lapatinib (Group A) 
compared to a Reference Group of patients who do not receive preoperative lapatinib.  
 
4.1 
Treatment Schema 
 
All patients must have recurrent EGFR-amplified high-grade glioma and be candidates 
for re-resection.  
 
The first 8 patients on the study will be enrolled into Group A and receive lapatinib pre-
operatively for 4 doses. Intratumoral drug levels will be analyzed following tissue sample 
collection during surgery. If adequate intratumoral drug concentration levels (1.5 µM or 
higher) are reached in at least 3 of the initial 8 patients, the study will proceed with 
further enrollment as follows. See Section 11.0, Primary Objectives and Sample Size for 
details. 
 
After the initial 8 patients are enrolled, subsequent patients will be sequentially assigned 
to either receive lapatinib pre-operatively for 4 doses (Group A) or to receive no drug 
prior to surgical resection (Reference Group): 20 patients will alternate enrollment into 
either Group A or the Reference Group (10 additional patients into Group A to complete 
the group, and 10 patients into the Reference Group); then 5 additional patients will 
enroll into the Reference Group to complete the group.  Fresh and paraffin embedded 
tissue from surgical resection will be utilized for correlative studies. 
 
Group A 
 
Patients with recurrent, EGFR-mutated high-grade glioma who require surgical resection 
will receive a pre-operative course of lapatinib at a dose of 2500mg BID for four doses 
prior to scheduled surgical resection for recurrent high-grade glioma. Patients may take 
one extra dose for a total of 5 doses if unexpected logistical problems delay the surgery. 
Patients will take the last dose of lapatinib ideally 3-5 hours before surgery to resect the 
tumor. Tumor tissue will be snap-frozen for determination of EGFR phosphorylation and 
intratumoral drug concentration. Plasma samples will be collected at selected time points 
to determine plasma levels of lapatinib during surgery.  
 
 
 
 

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Group A Treatment Plan 
 
Patients should begin presurgical treatment with lapatinib starting 2 days (Day -2) prior 
to the day of scheduled tumor resection (Day 0). Doses of lapatinib should be taken 12 
hours apart ± 2 hours.  The first dose should be taken in the evening on Day -2, the 
second dose should be taken in the morning on Day -1, the third dose should be taken in 
the evening on Day -1, and the fourth dose should be taken on the morning of surgery. 
One additional dose is permitted 12 hours after the fourth dose ± 2 hours if unexpected 
logistical problems delay the surgery.  
 
Patients who do not receive at least 4 doses of lapatinib prior to surgery will be replaced 
in the cohort; tissue from protocol surgery will no longer be required for these patients 
Group A:  
Pre-Surgery (Days -2 to 0) 
(EGFR-mutated, recurrent HGG: 
surgically eligible patients) 
 
Lapatinib: 2500 mg x 4 doses 
Surgery (Day 0) 
 
Surgical resection 3-5 hours 
after last dose of lapatinib 
Post-Surgery 
Upon recovery (within 30 days) patients will receive in 28-day cycles: 
 
Lapatinib: 2500 mg twice a day for 2 consecutive days, every 7 days 
 
(MRI performed within 21 days prior to re-starting lapatinib) 
 
MRI performed every 8 weeks 
until progression 

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but they may continue with post-surgical treatment provided any toxicity from pre-
surgical dosing resolves within protocol parameters. 
 
In order to accommodate biological sample collection and shipping, surgery must take 
place Monday-Thursday, with the exception of patients being treated at Memorial 
Sloan-Kettering Cancer Center: these patients may undergo surgery Monday- Friday 
(since tumor samples will be processed at MSKCC, these samples will not require 
overnight shipping).  
 
Surgery, during which tumor tissue samples will be acquired, should be performed 
ideally within 3 to 5 hours after taking the last dose of lapatinib. The time that the last 
dose is taken on the day of tumor resection must be recorded. Patients whose last dose of 
lapatinib is greater than 12 hours prior to surgery (the time tumor tissue is removed) will 
be replaced in the cohort; tissue from protocol surgery will no longer be required for 
these patients but they may continue with post-surgical treatment provided any toxicity 
from pre-surgical dosing resolves within protocol parameters. 
 
Research blood samples will be collected at baseline prior to the first presurgical dose 
and shortly before and after the time of surgery for determining the concentration of 
lapatinib in plasma. See Section 9.5.3 for details. 
 
Tumor specimens will be analyzed for drug levels and a portion will be snap frozen for 
determination of EGFR phosphorylation. Instructions for collecting and handling tumor 
specimens are in Sections 9.5.1, 9.5.4, and 9.5.5.  
 
Following surgery, patients will continue with standard post-operative management.  
 
After recovery from surgical resection, patients will receive lapatinib post-operatively 
twice a day for two consecutive days every 7 days (2 days on/5 days off) in 28-day 
cycles.  
 
Adequate recovery from surgical resection includes, but is not limited to, the following:  
• No signs or symptoms of infections related to the surgical wound (i.e., 
increasing erythema or cellulitis of the surrounding area, large amount of 
drainage, fever)  
• Wound edges have healed 
  
Post-operatively, patients must begin treatment within 30 days of surgical resection, and 
preferably within 3 weeks of the post-operative MRI; if more than 3 weeks elapse after 
the post-operative MRI, the patient will need a new MRI. 
 
Patients will be followed by routine blood work, general and neurological examination, 
and MR imaging. See Section 9.1 for schedule.  
 

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Patients may continue to receive cycles of lapatinib until tumor progression, development 
of unacceptable toxicity, or meeting other criteria for going off treatment (Section 10.1). 
Patients will be followed for adverse events for at least 30 days after the last dose of 
lapatinib. All patients will be followed for survival. 
 
Reference Group  
 
Patients with recurrent, EGFR-amplified high-grade glioma who require surgical 
resection will go to surgery to resect brain tumor. A portion of tumor tissue will be snap-
frozen for determination of EGFR phosphorylation. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reference Group Treatment Plan 
 
Patients in this group will receive no study medication pre-surgically.  
 
In order to accommodate biological sample collection, surgery must take place 
Monday-Thursday, with the exception of patients being treated at Memorial Sloan-
Kettering Cancer Center: these patients may undergo surgery Monday- Friday. 
 
Reference Group:  
 (EGFR-mutated, recurrent HGG: 
surgically eligible patients) 
 
No pre-surgical treatment  
Surgery (Day 0) 
 
Surgical resection: tumor tissue 
for EGFR phosphorylation  
Post-Surgery 
Upon recovery (within 30 days) patients will receive in 28-day cycles: 
 
Lapatinib: 2500 mg twice a day for 2 consecutive days, every 7 days 
 
(MRI performed within 21 days prior to re-starting lapatinib) 
MRI performed every 8 weeks 
until progression 

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Tumor tissue samples will be acquired during surgery to resect brain tumor. Tumor 
specimens will be snap frozen for determination of EGFR phosphorylation. Instructions 
for collecting and handling tumor specimens are in Sections 9.5.1 and 9.5.4.  
 
Following surgery, patients will continue with standard post-operative management.  
 
After recovery from surgical resection, patients will receive lapatinib post-operatively 
twice a day for two consecutive days every 7 days (2 days on/5 days off) in 28-day 
cycles.  
 
Adequate recovery from surgical resection includes, but is not limited to, the following:  
• No signs or symptoms of infections related to the surgical wound (i.e., 
increasing erythema or cellulitis of the surrounding area, large amount of 
drainage, fever)  
• Wound edges have healed 
  
Post-operatively, patients must begin treatment within 30 days of surgical resection, and 
preferably within 3 weeks of the post-operative MRI; if more than 3 weeks elapse after 
the post-operative MRI, the patient will need a new MRI. 
 
Patients will be followed by routine blood work, general and neurological examination, 
and MR imaging. See Section 9.1 for schedule. 
 
Patients may continue to receive cycles of lapatinib until tumor progression, development 
of unacceptable toxicity, or meeting other criteria for going off treatment (Section 10.1). 
Patients will be followed for adverse events for at least 30 days after the last dose of 
lapatinib. All patients will be followed for survival. 
 
4.2 
Treatment Requirements 
  
All eligible patients who consent to this study must have a baseline pre-treatment MRI 
within 21 days prior to the initiation of treatment, and a post-surgical MRI within 21 days 
prior to starting Cycle 1.    
 
Prior to every cycle patients must have: 
 
1) ANC  1500/µl and platelets   100,000 /µl. 
 
    AND 
2) All toxicities recovered to ≤ grade 1 or ≤ baseline  
 
4.3 
Drug Administration 
 
Lapatinib treatment will be administered on an outpatient basis. No investigational or 
commercial agents or therapies other than those described below may be administered with 
the intent to treat the patient's malignancy.  
 

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Patients will be provided with a medication diary and instructed in its use. Group A 
patients will be instructed to bring all unused pills and their medication diary to the 
hospital on the day of surgery for assessment of compliance. During post-surgical cycles 
of lapatinib, all patients will be instructed to bring all unused pills and their medication 
diaries to each study visit for assessment of compliance. 
 
4.3.1   Lapatinib Administration  
 
Lapatinib is an oral drug. Patients should take the lapatinib dose on an empty stomach, 
either 1 hour before or 1 hour after meals. Doses of lapatinib should be taken 12 hours 
apart ± 2 hours.  
 
If a patient misses or vomits a dose, he or she should be instructed not to take or make up 
that dose.  A dose will be considered missed, and should not be made up, if more than 2 
hours have passed from the time the dose is normally taken. 
 
Group A patients, pre-surgery: On the day of surgery the dose should be taken ideally 3-5 
hours before scheduled surgery but no more than 12 hours prior to surgery (the time 
tumor tissue is removed). One additional dose is permitted 12 hours after the fourth dose 
(± 2 hours) if unexpected logistical problems delay the surgery.  
 
Grapefruit and grapefruit juice are prohibited while on this protocol. 
 
4.4 
General Concomitant Medication and Supportive Care Guidelines 
 
  
Prohibited Concomitant Medication During Study 
 
There must be a period of at least 10 days from discontinuation of prohibited drugs and 
initiation of therapy unless otherwise specified in the protocol. Requests for specific 
exceptions to the required wait time can be submitted to the ABTC Central Office by 
providing a pharmacological rationale that the washout period for a particular drug 
should be less than 10 days (or as specified in the protocol); this must be approved by the 
ABTC Central Office. 
 
In vitro studies with human liver microsomes indicate that lapatinib is metabolized by 
CYP3A4 and CYP3A5, and to a lesser extent CYP2C19 and CYP2C8.  Co-
administration of lapatinib with potent or moderate CYP3A4 inhibitors (including 
grapefruit juice) and all CYP3A4 inducers is prohibited.  Assess risk/benefit before 
co-administering lapatinib with weak CYP3A4 inhibitors.  CYP3A4 inhibitors may 
decrease lapatinib metabolism (increasing levels); while CYP3A4 inducers may increase 
lapatinib metabolism (decreasing levels).   
In human subjects, lapatinib inhibited CYP3A4 and CYP2C8 at clinically relevant 
concentrations. Avoid co-administration of lapatinib with drugs that are substrates of 
CYP3A4 or CYP2C8 and have narrow therapeutic windows. 
 

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Pgp inhibitors: the following drugs are in vivo substrates of the P-gp transporter and 
may not be administered to patients receiving lapatinib:  aliskiren, ambrisentan, 
colchicine, dabigatran etexilate, digoxin, everolimus, fexofenadine, imatinib, lapatinib, 
maraviroc, nilotinib, posaconazole, ranolazine, saxagliptin, sirolimus, sitagliptin, 
talinolol, tolvaptan, topotecan; clinically significant interactions have been demonstrated 
for the following drugs: digoxin, loperamide, saquinovir, and ritonavir. 
 
Grapefruit and grapefruit juice are prohibited while on this protocol. 
 
Corticosteroids 
 
Postoperatively, corticosteroids should be tapered to a stable dose as determined by the 
clinical status of the patient.  Corticosteroid dose may, of course, be increased in the event 
of clinical deterioration or at the discretion of the attending physician. In the event of 
suspected clinical deterioration, repeat brain imaging is recommended. 
 
Antiemetics 
 
The use of any antiemetic deemed necessary for the care of the patient is allowed. 
 
Anticonvulsants 
 
For this study, patients may not be on enzyme-inducing anti-epileptic drugs (EIAED); 
patients who require anti-epileptic drugs (AED) may be on non-enzyme inducing anti-
epileptic drugs (NEIAED). If a patient on this study protocol needs to have an AED started 
or needs to have a second AED added then only NEIAED should be used.  There must be 
a ≥ 10 day period from discontinuation of an EIAED and initiation of therapy.  In the event 
that an enzyme-inducing anti-epileptic drug must be used for a patient on study the patient 
will be removed from the protocol. 
 
Antidiarrheal 
 
The use of any antidiarrheal is permitted.  Lapatinib-induced diarrhea is most commonly 
treated with loperamide. Patients should be educated about how to use loperamide. See 
also Supportive Care below for management of diarrhea.  
  
Herbal and Non-Traditional Medications 
 
No data exist regarding the interaction of lapatinib with commonly used herbal or non-
traditional medications. Patients should be instructed not to use such medications while 
receiving lapatinib therapy. 
 
Supportive Care 
 
Diarrhea 

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Early diarrhea management for patients taking lapatinib must be initiated as soon as the 
first episode of diarrhea has occurred.  Close monitoring and proactive management of 
diarrhea is essential.  At the time of starting lapatinib, all patients should be given a 
prescription for loperamide or analogue, and be advised to keep the 
prescription/medication with them at all times.  The patient should be clearly instructed to 
start loperamide promptly at the first signs of diarrhea.  A dose of 4 mg loperamide must 
be given after first episode of diarrhea, and 2 mg every 4 hours or after every episode of 
unformed stool, until the patient is free from diarrhea for 12 hours.  The maximum 
allowed daily dose of loperamide is 16 mg.  The patient must contact the investigator as 
soon as possible after diarrhea starts. 
 
For Grade 3 or 4 diarrhea or Grade 1 or 2 with complicating features (severe cramping, 
severe nausea/vomiting, decreased performance status, fever, sepsis, Grade 3 or 4 
neutropenia, frank bleeding, dehydration):  use intravenous fluids as appropriate, consider 
hospital administration and use prophylactic antibiotics as needed (example 
fluoroquinolones) especially if diarrhea is persistent beyond 24 hours or there is a fever 
or Grade 3-4 neutropenia. 
 
Rash 
There is no standard, known, or established treatment proven effective for drug-related 
skin rashes or changes due to lapatinib.  If the rash is severe (1-3% of cases) then most 
commonly, a papular/pustular rash has been observed, which frequently improves even 
though the same dose of lapatinib therapy is continued uninterrupted.  The need for oral 
or topical antibiotics is a clinical decision of the investigator and should be preceded by a 
culture of affected areas and, if indicated, a dermatology consultation.  Oral retinoids 
should not be given because of theoretical concerns about negatively affecting the 
lapatinib mechanism of action.  Oral steroids are also strongly discouraged.  Other 
options for treatment of significant rashes may be determined upon consultation with 
dermatologist.  
 
 
 
 
 
  
5.0 
TOXICITY 
 
5.1 
Toxicity Management and Dose Delay/Modification for Lapatinib 
 
Dose delays and dose modification requirements for clinically significant adverse events 
or abnormal laboratory values assessed as unrelated to disease progression, intercurrent 
illness, or concomitant medications are defined in the following sections. Toxicities must 
have an attribution of possible, probable, or definite to lapatinib (see Section 9.2.2). 
Adverse events (AEs) should be treated with the appropriate maximum supportive care 
and should be clearly documented on the case report form.  
 
Group A patients–pre-surgical treatment: Lapatinib is not dose-reduced for toxicities in 
the pre-surgical dosing period; if treatment is delayed for toxicity such that the patient 
cannot receive the four lapatinib doses according to the pre-surgical dosing schedule, or if 

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lapatinib is discontinued, the patient will be replaced in the cohort but may continue with 
post-surgical treatment provided toxicity from pre-surgical dosing resolves within 
protocol parameters. 
 
All adverse events will be monitored and collected throughout the trial and documented 
based on CTCAE version 5.0. If there are three or more delays of scheduled surgery due 
to lapatinib-related serious adverse events (SAE) among the initial 8 patients; or if there 
are any surgical complications and delayed wound healing SAEs grade ≥3 considered 
lapatinib-related among the first three patients, ABTC investigators will consult with 
CTEP investigators and the pharmaceutical sponsor about such events. See Section 9.3 
for SAE information. 
 
5.2 
Dose Modification/Reduction for Lapatinib 
 
The dose levels and the general approach to lapatinib dose modification on this trial are 
shown below. Adverse events (AEs) should be treated with the appropriate maximum 
supportive care, and dose reductions should be clearly documented on the case report form. 
 
If multiple toxicities occur, dose modification decisions should be based on the most severe 
toxicity. 
 
Dosing will be held until the toxicity has resolved as specified in Table 5.2.2, Dose 
interruption or discontinuation due to LVEF, and Table 5.2.3, Toxicity management / Dose 
discontinuation due to AEs. The maximum length of time that lapatinib can be held for 
treatment-related toxicity is 14 days. If treatment-related toxicity is not resolved in  14 
days, the patient will be removed from treatment. After resolution, when dose reduction is 
permitted, the dose of lapatinib will be modified as stipulated below, with a maximum of 
1 dose reduction.  If there is any question, the ABTC Central Office and the Study Chair 
should be contacted. 
 
Dose Reduction Table for Lapatinib 
Dose Level 
Lapatinib 
Starting dose 
2500 mg twice a day 
First dose reduction 
2000 mg twice a day 
 
5.2.1 Severe Cutaneous Reactions 
 
Severe cutaneous reactions have been reported with lapatinib. If life-threatening reactions 
such as erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis 
(e.g., progressive skin rash often with blisters or mucosal lesions) are suspected, 
discontinue treatment with lapatinib. 
 
5.2.2 Lapatinib dose modification for LVEF events 
 
General instructions for cardiac monitoring 

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• All patients must have an LVEF measurement of at least 50% by echocardiography or 
MUGA scan (preferably echocardiography), within 21 days prior to treatment start. 
• The method used for LVEF assessment in an individual patient should be the same 
throughout the trial. 
• Echocardiography must be performed under the supervision of an experienced 
cardiologist, preferably at the same high-volume laboratory for the duration of the 
trial.  The guidelines of the American Society of Echocardiography will be used.   
• Subsequent scheduled LVEF assessments can be performed every 12 weeks during 
treatment.  Follow up LVEF assessment after discontinuation of therapy should be 
obtained if the findings are abnormal.    
• In addition, any patient who develops clinical signs or symptoms of cardiac failure 
should undergo an LVEF assessment and an ECG. 
• If there are two dose interruptions for an ejection fraction decrease from baseline, 
discontinue lapatinib. 
 
Table 5.2.2: Dose interruption or discontinuation due to LVEF 
System Organ 
Class (SOC) in 
CTCAE 
CTCAE Term 
Instructions 
Cardiac 
Disorders 
 
If symptomatic, please 
utilize CTCAE term 
“Left ventricular 
systolic dysfunction 
(LVSD)” or “Heart 
failure,” as appropriate 
Permanently discontinue lapatinib. 
 
Investigations 
If asymptomatic, please 
utilize CTCAE term 
”Ejection fraction 
decreased” 
Refer to Figure below and instructions 
above.  
 
If there are two dose interruptions for an 
ejection fraction (EF) decrease from 
baseline, discontinue lapatinib. 
 
Algorithm for continuation and discontinuation of GW572016 (lapatinib) based on 
interval LVEF assessments for patients with New York Heart Association (NYHA) Class 

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I or II congestive heart failure. 
 
 
Notes:  
• Only one dose interruption for ejection fraction decrease will be allowed. 
• All assessments will be compared to baseline ejection fraction at the start of the trial. 
 
5.2.3 Lapatinib dose modification for non-cardiac AEs 
 
Table 5.2.3:  
Adverse Events 
Grade 
Action 
Pneumonitis, Pulmonary 
fibrosis, Adult Respiratory 
Distress Syndrome 
(ARDS), Pulmonary edema 
(non-cardiogenic) 
Grade 1 to 4 
Patients who develop symptoms or signs suggestive of 
pulmonary infiltrates or pneumonitis, should have lapatinib 
interrupted while a thorough evaluation is performed.  If 
pneumonitis is confirmed, permanently discontinue 
lapatinib.  If other parenchymal abnormalities are confirmed 
and the relationship to lapatinib cannot be excluded, 
lapatinib must be permanently discontinued. 
Rash 
Grade 1 
No dose modifications.  See “supportive care for rash.” 
 

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Adverse Events 
Grade 
Action 
Grade 2 
If toxicity is unacceptable to patient or medically concerning, 
hold lapatinib until recovery to ≤ Grade 1 for up to 14 days. 
Restart at the same dose. 
 
If dose has previously been held for grade 2 toxicity and 
grade 2 symptoms recur, OR if the patient finds the 
symptoms unacceptable, hold dose until recovery to ≤ Grade 
1. See “supportive care for rash.”  Resume at one dose 
reduction.. 
Grade 3 
Hold lapatinib until recovery to < Grade 1 for up to 14 days.  
See “supportive care for rash.” 
Resume at one dose reduction. 
Grade 4 rash or 
toxic epidermal 
necrolysis (e.g., 
Stevens-Johnson 
Syndrome, etc.)  
Permanently discontinue lapatinib. See “supportive care 
for rash.” 
Diarrhea 
Grade 1 
Continue lapatinib, but start loperamide (initial dose 4 mg 
followed by 2 mg every 4 hours or after every unformed 
stool).  It is suggested to continue loperamide until the 
subject is free from diarrhea for 12 hours.  See “supportive 
care for diarrhea.” 
Grade 2 to 4 
Hold lapatinib until grade 1 or lower (up to 14 days).  Start 
loperamide as above, and other measure.  See “supportive 
care for diarrhea.” 
Resume at one dose reduction. 
Abnormal liver function 
tests (ALT, bilirubin) 
Grade 1 or 2 
abnormal ALT / 
bilirubin   
Lapatinib must be discontinued permanently for patients 
with: 
1.  BOTH bilirubin and ALT abnormalities being of Grade 
2 
OR 
2.  EITHER bilirubin OR ALT abnormality is Grade 2 and 
accompanied by signs or symptoms which, in the opinion of 
the treating physician, are related to liver injury caused by 
lapatinib.  (Such signs and symptoms may include 
abdominal pain, fever, jaundice, rash, eosinophilia or a 
performance status (PS) drop of ≥1 point from baseline.) 
Grade 3 to 4 
abnormal ALT and 
/ or bilirubin 
Permanently discontinue lapatinib.  
Other Grade 3 to 4 AEs or 
intolerable Grade 2 AEs 
due to lapatinib 
 
Permanently discontinue lapatinib therapy.   
 
 
5.3 
Major Events 
 
Major Events are non-treatment-related grade 3 and 4 hematologic and non-hematologic 
toxicities. Treatment should be discontinued for major events if lapatinib may further 
complicate the non-treatment-related event.  If a major event requires a delay of treatment, 
treatment must be delayed until toxicity is resolved (≤ grade 1 [or tolerable grade 2 for non-
hematologic toxicity] or ≤ baseline). If non-treatment-related toxicity is not resolved in  

Drug Distribution and Pharmacodynamic Study of Pulsatile Lapatinib in Surgically Accessible EGFR-Amplified 
Recurrent High-Grade Glioma 
 
ABTC # 1302 
NCI # ABTC-1302 
PI: T. Cloughesy 
 
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28 days, the patient will be removed from treatment. The ABTC Central Office should be 
consulted if it is not clear whether to continue or stop treatment. 
 
5.4 
Use of Hematologic Growth Factors 
 
No growth factors (G-CSF or GM-CSF) are to be used prophylactically in this protocol.  
Clinicians caring for patients on this protocol are permitted to use these growth factors to 
provide optimal care for patients with severe neutropenia in accordance with the ASCO 
27guidelines (JCO, 12, 1994: pp2471-2508). If these growth factors are used in the acute 
setting of neutropenia and infection (documented or suspected), they will not be utilized 
prophylactically in subsequent cycles and they will not subsequently be used in lieu of dose 
reduction of lapatinib. 
 
5.5 
Toxicity Criteria 
 
All toxicities will be described and graded according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0.  All appropriate treatment areas should 
have access to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can 
be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). See also 
Section 9.2.4, Recording of Adverse Events. 
 
 
 
6.0 
PHARMACEUTICAL INFORMATION 
 
6.1 
Lapatinib (GW572016, NSC 727989)  
 
Chemical Name: N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-
(methylsulfonyl)ethyl]amino}methyl)-2 furyl]-4-quinazolinamine 
 
Other Names: GW572016F, lapatinib ditosylate, Tykerb® 
 
Molecular Formula: C29H26ClFN4O4S(C7H8O3S)2H2O 
 
 
Molecular Weight: 
943.48 
 
Approximate Solubility: 
0.007 mg/mL in water and 0.001 mg/mL in 0.1 N HCl at 
25°C. 
 
Mode of Action: 
Dual inhibitor of epidermal growth factor receptor (EGFR or ErbB1) 
and ErbB2 tyrosine kinases. 
 
How Supplied: 
GlaxoSmithKline supplies and the NCI/DCTD distributes lapatinib 
as 250 mg oval, biconvex, orange film-coated tablets with one side plain and the opposite 
side debossed with FG HLS. The tablets contain 405 mg of lapatinib ditosylate 

Drug Distribution and Pharmacodynamic Study of Pulsatile Lapatinib in Surgically Accessible EGFR-Amplified 
Recurrent High-Grade Glioma 
 
ABTC # 1302 
NCI # ABTC-1302 
PI: T. Cloughesy 
 
29 
 
 
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monohydrate, equivalent to 250 mg lapatinib free base per tablet. The tablets are packaged 
into HDPE bottles with child-resistant closures containing 90 tablets per container.  
 
Excipients present in the tablet include: Microcrystalline cellulose, povidone, sodium 
starch glycolate, and magnesium stearate. 
 
The film-coat contains:  Hypromellose methylcellulose, titanium dioxide, macrogol/PEG 
400, Polysorbate 80, FD&C Yellow No. 6, and FCF aluminum lake. 
  
Storage: 
Store intact bottles at controlled room temperature (15°C-30°C).   
 
Stability:         Shelf life surveillance studies of the intact bottle are on-going. 
 
Route of Administration: Oral on an empty stomach (either 1 hour before or 1 hour after 
meals). 
 
Method of Administration:   Whenever possible, administer whole tablets.  Lapatinib 
tablets have not been deliberately formulated to be dispersible tablets; however, in 
circumstances where dosing of whole tablets is not possible, see procedure below.  Tablet 
crushing is not recommended.  
 
For patients unable to swallow tablets, a suspension preparation in water or Kool-Aid can 
be made using the following procedure: 
 
1. Prepare Lemonade or Tropical Punch Kool-Aid as directed on package. 
2. Place 2 or 4 ounces of water or Kool-Aid in a glass container, then add the required 
number of lapatinib tablets for dose (up to six tablets per 2 to 4 ounces) to the container. 
3. Cover the container, let it stand for 5 minutes, and then stir the mixture intermittently for 
15 minutes or until it is fully dispersed. 
4. Stir the container for 5 seconds then administer. 
5. Rinse the container with 2 ounces of water or Kool-Aid and repeat the administration 
process.  
 
(The lemonade mixture appears somewhat like orange juice whereas the tropical punch 
mixture appears like carrot juice.) 
 
Potential Drug Interactions:   In vitro studies with human liver microsomes indicate that 
lapatinib is metabolized by CYP3A4 and CYP3A5, and to a lesser extent CYP2C19 and 
CYP2C8.  Co-administration of lapatinib with potent or moderate CYP3A4 inhibitors 
(including grapefruit juice) and all CYP3A4 inducers is prohibited.  Assess 
risk/benefit before co-administering lapatinib with weak CYP3A4 inhibitors.  CYP3A4 
inhibitors may decrease lapatinib metabolism (increasing levels); while CYP3A4 
inducers may increase lapatinib metabolism (decreasing levels).   

Drug Distribution and Pharmacodynamic Study of Pulsatile Lapatinib in Surgically Accessible EGFR-Amplified 
Recurrent High-Grade Glioma 
 
ABTC # 1302 
NCI # ABTC-1302 
PI: T. Cloughesy 
 
30 
 
 
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In human subjects, lapatinib inhibited CYP3A4 and CYP2C8 at clinically relevant 
concentrations. Avoid co-administration of lapatinib with drugs that are substrates of 
CYP3A4 or CYP2C8 and have narrow therapeutic windows. 
 
Pgp inhibitors: the following drugs are in vivo substrates of the P-gp transporter and 
may not be administered to patients receiving lapatinib:  aliskiren, ambrisentan, 
colchicine, dabigatran etexilate, digoxin, everolimus, fexofenadine, imatinib, lapatinib, 
maraviroc, nilotinib, posaconazole, ranolazine, saxagliptin, sirolimus, sitagliptin, 
talinolol, tolvaptan, topotecan; clinically significant interactions have been demonstrated 
for the following drugs: digoxin, loperamide, saquinovir, and ritonavir 
 
For Potential Risks of Lapatinib, see Section 9.2.1, Comprehensive Adverse Events and 
Potential Risks list (CAEPR) for lapatinib. 
 
6.1.1  Agent Ordering 
 
Lapatinib may be requested by the Principal Investigator (or their authorized designees) at 
each participating institution.  Pharmaceutical Management Branch (PMB) policy requires 
that the agent be shipped directly to the institution where the patient is to be treated.  PMB 
does not permit the transfer of agents between institutions (unless prior approval from PMB 
is obtained).  The CTEP-assigned protocol number must be used for ordering all CTEP-
supplied investigational agents.  The responsible investigator at each participating 
institution must be registered with CTEP, DCTD through an annual submission of FDA 
Form 1572 (Statement of Investigator), Curriculum Vitae, Supplemental Investigator Data 
Form (IDF), and Financial Disclosure Form (FDF).  If there are several participating 
investigators at one institution, CTEP-supplied investigational agents for the study should 
be ordered under the name of one lead investigator at that institution. 
 
Active CTEP-registered investigators and investigator-designated shipping designees and 
ordering designees can submit agent requests through the PMB Online Agent Order 
Processing (OAOP) application (https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx).  
Access to OAOP requires the establishment of a CTEP Identity and Access Management 
(IAM) account (https://eapps-ctep.nci.nih.gov/iam/) and the maintenance of an “active” 
account status and a “current” password.  For questions about drug orders, transfers, 
returns, or accountability, call (240) 276-6575 Monday through Friday between 8:30 am 
and 4:30 pm (ET) or email PMBAfterHours@mail.nih.gov anytime. 
 
6.1.2  Agent Accountability 
 
The investigator, or a responsible party designated by the investigator, must maintain a 
careful record of the inventory and disposition of all agents received from DCTD using the 
NCI Drug Accountability Record Form.  See the NCI Investigator’s Handbook on the 
CTEP web site for Procedures for Drug Accountability and Storage.). 
 
 

Drug Distribution and Pharmacodynamic Study of Pulsatile Lapatinib in Surgically Accessible EGFR-Amplified 
Recurrent High-Grade Glioma 
 
ABTC # 1302 
NCI # ABTC-1302 
PI: T. Cloughesy 
 
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7.0 
REGISTRATION PROCEDURES / PATIENT ENROLLMENT 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU) Regulatory 
Office and uses the Oncology Patient Enrollment Network (OPEN). 
 
7.1 
CTEP Registration  
 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all individuals contributing to NCI-sponsored trials to register and to renew 
their registration annually.  To register, all individuals must obtain a Cancer Therapy 
Evaluation Program (CTEP) Identity and Access Management (IAM) account 
(https://ctepcore.nci.nih.gov/iam).  In addition, persons with a registration type of 
Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., 
clinical site staff requiring write access to OPEN, RAVE, or TRIAD or acting as a primary 
site contact) must complete their annual registration using CTEP’s web-based Registration 
and Credential Repository (RCR) (https://ctepcore.nci.nih.gov/rcr).  Documentation 
requirements per registration type are outlined in the table below. 
 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI Biosketch (education, training, employment, 
license, and certification) 
 
 
 
HSP/GCP training 
 
 
 
Agent Shipment Form (if applicable) 
 
CV (optional) 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access 
all CTEP and CTSU (Cancer Trials Support Unit) websites and applications.  In addition, 
IVRs and NPIVRs must list all clinical practice sites and IRBs covering their practice sites 
on the FDA Form 1572 in RCR to allow the following: 
• Added to a site roster 
• Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in 
OPEN 
• Act as the site-protocol PI on the IRB approval 

Drug Distribution and Pharmacodynamic Study of Pulsatile Lapatinib in Surgically Accessible EGFR-Amplified 
Recurrent High-Grade Glioma 
 
ABTC # 1302 
NCI # ABTC-1302 
PI: T. Cloughesy 
 
32 
 
 
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• Assigned the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).     
 
Additional information can be found on the CTEP website at https://ctep.cancer.gov.  For 
questions, please contact the RCR Help Desk by email at RCRHelpDesk@nih.gov. 
 
7.2 
Site Registration 
 
Each investigator or group of investigators at a clinical site must obtain IRB approval for 
this protocol and submit IRB approval and supporting documentation to the CTSU 
Regulatory Office before they can enroll patients. Assignment of site registration status in 
the CTSU Regulatory Support System (RSS) uses extensive data to make a determination 
of whether a site has fulfilled all regulatory criteria including but not limited to the 
following: 
• An active Federal Wide Assurance (FWA) number 
• An active roster affiliation with the ABTC 
• A valid IRB approval 
• Compliance with all protocol-specific requirements. 
 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
• Active registration status 
• The IRB number of the site IRB of record listed on their Form FDA 1572 
• An active status on a participating roster at the registering site. 
 
Downloading Site Registration Documents:  
 
See ABTC website (www.abtconsortium.org). 
 
Requirements for Site Registration: 
 
• 
IRB approval (local IRB documentation, an IRB-signed CTSU IRB Certification 
Form, 
Protocol 
of 
Human 
Subjects 
Assurance 
Identification/IRB 
Certification/Declaration of Exemption Form, or combination is accepted)  
 
Submitting Regulatory Documents:  
 
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal, where they will be entered and tracked in the CTSU RSS.  
 
Regulatory Submission Portal: www.ctsu.org (members’ area) → Regulatory Tab 
→Regulatory Submission  
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction 
and support. 

Drug Distribution and Pharmacodynamic Study of Pulsatile Lapatinib in Surgically Accessible EGFR-Amplified 
Recurrent High-Grade Glioma 
 
ABTC # 1302 
NCI # ABTC-1302 
PI: T. Cloughesy 
 
33 
 
 
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Checking Your Site’s Registration Status: 
 
You can verify your site registration status on the members’ section of the CTSU 
website. 
▪ Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
▪ Click on the Regulatory tab 
▪ Click on the Site Registration tab 
▪ Enter your 5-character CTEP Institution Code and click on Go 
 
Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements outlined by the ABTC. It does not reflect 
compliance with protocol requirements for individuals participating on the protocol or the 
enrolling investigator’s status with the NCI or their affiliated networks. 
 
7.3 
Patient Registration 
 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN). OPEN is a web-based registration system available to users enrolling patients to 
ABTC studies from 9 a.m. to 4:30 p.m. Eastern Time. To access OPEN, the site user must 
have an active CTEP-IAM account (check at https://ctepcore.nci.nih.gov/iam) and a 
'Registrar' role in ABTC.  Registrars must hold a minimum of an AP registration type. 
 
All site staff will use OPEN to enroll patients to this study.  It is integrated with the CTSU 
Enterprise System for regulatory and roster data and, upon enrollment, initializes the 
patient in the Rave database.  OPEN can be accessed at https://open.ctsu.org or from the 
OPEN tab on the CTSU members’ side of the website at https://www.ctsu.org.  To assign 
an IVR or NPIVR as the treating, crediting, consenting, drug shipment (IVR only), or 
investigator receiving a transfer in OPEN, the IVR or NPIVR must list on their Form FDA 
1572 in RCR the IRB number used on the site’s IRB approval. 
 
Patient enrollment for this study will be facilitated using the Slot-Reservation System in 
conjunction with the Registration system in OPEN. Prior to discussing protocol entry with 
the patient, site staff must check the ABTC website (www.abtconsortium.org) for protocol 
status and slot availability. Site staff must also use the CTSU OPEN Slot Reservation 
System to insure that a slot on the protocol is available to the patient. Once a slot-
reservation confirmation is obtained, and the ABTC Central Office has notified the site of 
the randomization assignment, site staff may then proceed to enroll patients to this study.  
 
Prior to accessing OPEN, site staff should verify the following: 
  
• All eligibility criteria have been met within the protocol stated timeframes. Site staff 
should use the registration forms provided on the group web site as a tool to verify 
eligibility. 

Drug Distribution and Pharmacodynamic Study of Pulsatile Lapatinib in Surgically Accessible EGFR-Amplified 
Recurrent High-Grade Glioma 
 
ABTC # 1302 
NCI # ABTC-1302 
PI: T. Cloughesy 
 
34 
 
 
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• All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable).  
  
Access requirements for OPEN: 
  
• Site staff will need to be registered with CTEP and have a valid and active CTEP-
IAM account. This is the same account (user id and password) used for credentialing 
in the CTSU members' web site.  
• To perform registrations, the site user must have been assigned the 'Registrar' role on 
the relevant Group or CTSU roster.  
 
The OPEN system will provide the site with a printable confirmation of registration and 
treatment assignment information.   Please print this confirmation for your records. Upon 
completion of the registration process in OPEN, sites must contact the ABTC Central 
Office to obtain confirmation of the patient’s registration and treatment assignment. 
  
Further instructional information is provided on the CTSU members' web site OPEN tab 
or within the OPEN URL (https://open.ctsu.org). For any additional questions contact the 
CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com.   
 
 
8.0 
SAFETY AND QUALITY ASSURANCE 
 
8.1 
Criteria for Response Assessment 
 
Subjects with measurable disease will be assessed by the RANO (radiographic 
assessment in neuro-oncology) criteria (Wen et al. 2010).  For the purposes of this study, 
subjects should be re-evaluated at the end of every 2 cycles (approximately every 8 
weeks) with a contrast-enhanced cranial MRI scan. The response will be determined as 
outlined in the RANO criteria below. 
 
The MRI obtained prior to starting post-surgery treatment cycles of lapatinib will be used 
as the baseline MRI for purposes of determining radiographic response.   
 
Measurable disease. Bidimensionally, contrast-enhancing, measurable lesions with 
clearly defined margins by MRI scan, with a minimal diameter of 1 cm, and visible on 2 
axial slices which are at least 5 mm apart with 0 mm skip. Measurement of tumor around 
a cyst or surgical cavity, if necessary, requires a minimum thickness of 3 mm. If there are 
too many measurable lesions to measure at each evaluation, the investigator must choose 
the largest two to be followed before a participant is entered on study. The remaining 
lesions will be considered non-measureable for the purpose of objective response 
determination. Unless progression is observed, objective response can only be determined 
when all measurable and non-measurable lesions are assessed.  
 
Complete Response (requires all of the following): 
 

Drug Distribution and Pharmacodynamic Study of Pulsatile Lapatinib in Surgically Accessible EGFR-Amplified 
Recurrent High-Grade Glioma 
 
ABTC # 1302 
NCI # ABTC-1302 
PI: T. Cloughesy 
 
35 
 
 
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a)   Complete disappearance of all enhancing measurable and non-measurable disease 
sustained for at least 4 weeks. In the absence of a confirming scan 4 weeks later, this 
scan will be considered only stable disease. 
b)   No new lesions. 
c)   All measurable and non-measurable lesions must be assessed using the same 
techniques as baseline. 
d)   Subjects must be off corticosteroids (or on physiologic replacement doses only). 
e)   Stable or improved non-enhancing (T2/FLAIR) lesions. 
f)   Stable or improved clinically. 
 
Note: Subjects with non-measurable disease cannot have a complete response. The best 
response possible is stable disease. 
 
Partial Response (requires all of the following): 
 
a)   Greater than or equal to 50% decrease compared to baseline in the sum of products of 
perpendicular diameters of all measurable enhancing lesions sustained for at least 4 
weeks. In the absence of a confirming scan 4 weeks later, this scan will be considered 
only stable disease. 
b)   No progression of non-measurable disease. 
c)   No new lesions. 
d)   All measurable and non-measurable lesions must be assessed using the same 
techniques as baseline. 
e)   The corticosteroid dose at the time of the scan evaluation should be no greater than 
the dose at time of baseline scan. 
f)   Stable or improved non-enhancing (T2/FLAIR) lesions on same or lower dose of 
corticosteroids compared to baseline scan. 
g)   Stable or improved clinically. 
 
Note: Subjects with non-measurable disease cannot have a partial response. The best 
response possible is stable disease. 
 
Stable Disease (requires all of the following): 
 
a)   Does not qualify for CR, PR, or progression. 
b)   The designation of stable disease requires a minimum of 4-week duration. 
c)   All measurable and non-measurable sites must be assessed using the same techniques 
as baseline. 
d)   Stable non-enhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids 
compared to baseline scan. In the event that the corticosteroid dose was increased for 
new symptoms and signs without confirmation of disease progression on 
neuroimaging, and subsequent follow-up imaging shows that this increase in 
corticosteroids was required because of disease progression, the last scan considered 
to show stable disease will be the scan obtained when the corticosteroid dose was 
equivalent to the baseline dose. 

Drug Distribution and Pharmacodynamic Study of Pulsatile Lapatinib in Surgically Accessible EGFR-Amplified 
Recurrent High-Grade Glioma 
 
ABTC # 1302 
NCI # ABTC-1302 
PI: T. Cloughesy 
 
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e)   Stable clinically. 
 
Progressive Disease (defined by any of the following): 
 
a) ≥25% increase in sum of the products of perpendicular diameters of enhancing 
lesions compared to the smallest tumor measurement obtained either at baseline (if no 
decrease) or best response, on stable or increasing doses of corticosteroids.*  
b)  Significant increase in T2/FLAIR non-enhancing lesion on stable or increasing doses 
of corticosteroids compared to baseline scan or best response following initiation of 
therapy,* not due to co-morbid events (radiation therapy, demyelination, ischemic 
injury, infection, seizures, postoperative changes, or other treatment effects). 
c)   Any new lesion. 
d)  Clear clinical deterioration not attributable to other causes apart from the tumor (e.g., 
seizures, medication adverse effects, complications of therapy, cerebrovascular 
events, infection, etc.) or changes in corticosteroid dose. The definition of clinical 
deterioration is left to the discretion of the treating physician, but it is recommended 
that a decrease in 20% of KPS or from any baseline to 50% or less be considered, 
unless attributable to comorbid events. 
e)   Failure to return for evaluation due to death or deteriorating condition. 
f)   Clear progression of non-measurable disease. 
 
* Stable doses of corticosteroids include patients not on corticosteroids. 
 
8.2 
Assessment of Response 
 
Assessment of response will begin with the MRI performed just prior to every odd-
numbered treatment cycle post-surgery.   If during any scheduled MRI, the subject has a 
Complete Response or Partial Response, the MRI should be repeated prior to the next 
cycle.  All scans are to be compared to the smallest measurement scan to date.  The 
subject will then return to the every odd-numbered cycle schedule.  This is required to 
confirm the duration of response.  Subjects will be classified as responders if they have a 
minimum duration of response for 4 weeks at any time after the first post-surgery cycle 
of lapatinib. MRI scans of subjects showing tumor response will be centrally reviewed by 
a neuroradiologist who will independently assess tumor size and compute percent tumor 
regression. 
 
8.3 
Safety assessments 
 
Safety assessments will consist of monitoring and recording all adverse events and serious 
adverse events, the regular monitoring of hematology, blood chemistry and urine values, 
regular measurement of vital signs, and the performance of physical/neurological 
examinations, and ECGs. 
 
8.4 
Quality Assurance 
 

Drug Distribution and Pharmacodynamic Study of Pulsatile Lapatinib in Surgically Accessible EGFR-Amplified 
Recurrent High-Grade Glioma 
 
ABTC # 1302 
NCI # ABTC-1302 
PI: T. Cloughesy 
 
37 
 
 
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Neuropathology:  The neuropathologic diagnosis of (study disease) will be made at the 
respective institution.  If any question arises regarding the accuracy of the neuropathologic 
diagnosis, slides (and pathological blocks, if necessary) will be reviewed by the central 
review pathologist.  For protocols with “response” as an outcome, all patients with a 
documented complete response or partial response will have representative pathology 
slides undergo central review. 
 
Neuroradiology: MRI scans of patients showing tumor response will be centrally reviewed 
by a neuroradiologist who will independently assess tumor size and compute percent tumor 
regression.   
 
Neuro-oncology:  The local investigator at the participating institution will communicate 
to the ABTC Central Office any unexpected neurological effects such as change in seizure 
frequency, alteration in neuromuscular function, alteration in cognitive function, or 
fluctuations in serum anticonvulsant drug levels. 
 
Adherence to protocol therapy:  As a quality assurance measure for the treatment 
delivered on this protocol, primary patient records may be reviewed.  The records to be 
examined will be selected retrospectively and at random; complete records must therefore 
be maintained on each patient treated on the protocol.  These records should include 
primary documentation (e.g., laboratory report slips, X-ray reports, scan reports, pathology 
reports, physician notes, etc.), which confirm that: 
 
•  
The patient met each eligibility criterion. 
•  
Signed informed consent was obtained prior to treatment. 
• 
Treatment was given according to protocol (dated notes about doses given; any 
reasons for any dose modifications). 
•  
Toxicity was assessed according to protocol (laboratory report slips,  etc.). 
• 
Response was assessed according to protocol (MRI scan, lab reports, dated notes on 
measurements and clinical assessment, as appropriate). 
•  
NCI Drug Accountability Records were maintained for this protocol. 

Drug Distribution and Pharmacodynamic Study of Pulsatile Lapatinib in Surgically Accessible EGFR-Amplified 
Recurrent High-Grade Glioma 
 
ABTC # 1302 
NCI # ABTC-1302 
PI: T. Cloughesy 
 
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9.0 
MONITORING OF PATIENTS 
 
9.1 
Tables of Required Observations   
 
Group A 
 
 
Baseline 
 
Pre- 
Surgery 
 
Day of 
Surgery 
Post-
Surgery 
 
Post-
Surgery 
Cycles 
 
Pre- 
Odd 
Cycles 
 
Pre-
Even 
Cycles 
Every 3 
Cycles 
Off 
Treatment 
(within 7 
days) 
30-Day 
Follow-
Up  
Lapatinib 
 
6 
 
 
6 
 
 
 
 
 
Adverse Event Evaluations 
 
 
7 
10 
 
17 
17 
 
12 
13 
Glucocorticoids Dose  
1 
 
 
19 
 
17 
 
 
12 
 
MRI 
1 
 
 
19 
 
17,18 
 
 
12 
 
H&P/Neuro exam 
1 
 
 
 
 
17 
17 
 
12 
 
KPS 
1 
 
 
 
 
17 
17 
 
12 
 
Vital Signs 
1,2 
 
 
 
 
2,17 
2,17 
 
2,12 
 
CBC, platelets, Differential 
1 
 
11 
 
 
17 
17 
 
12 
 
Serum Chemistry 
1,3 
 
3,14 
 
 
3,17 
3,17 
 
3, 12 
 
APTT or PTT 
1 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Test 
1,4 
 
 
 
 
 
 
 
 
 
Echocardiogram 
1 
 
 
 
 
16 
 
16 
 
 
12-Lead Electrocardiogram 
15 
 
 
 
 
 
 
 
 
 
Plasma Pharmacokinetics 
8 
 
8 
 
 
 
 
 
 
 
Fresh Tumor Tissue 
 
 
9 
 
 
 
 
 
 
 
Archived Tumor Tissue 
5 
 
 
 
 
 
 
 
 
 
1 – All baseline measurements must be done within 21 calendar days prior to start of treatment, unless otherwise 
indicated. 
2 – Including blood pressure, respiratory rate, heart rate, temperature, weight, and height: height is required at 
baseline only. 
3 – Albumin, alkaline phosphatase, total bilirubin, calcium, creatinine, magnesium, phosphorus, potassium, 
SGOT, SGPT, sodium. 
4 – Females with child-bearing potential must have a negative serum pregnancy test. 
5 – Archived tumor tissue from initial surgery at diagnosis of high-grade glioma. See Section 9.5.2 
6 – Four doses of lapatinib will be administered pre-operatively starting 2 days prior to the day of surgery with the 
last pre-operative dose taken 3-5 hours prior to scheduled surgery: see Section 4.1 for schedule. One 
additional dose is permitted if unexpected logistical problems delay surgery.  
Post-operatively patients will receive lapatinib twice a day for two consecutive days every 7 days (2 days 
on/5 days off) in 28-day cycles. Patients are required to keep a pill diary. See Section 4.3.1. 
7 – Patient should be seen on the day of surgery (prior to the the time of surgery) to evaluate for AEs. 
8 – Plasma specimens for pharmacokinetics will be obtained at baseline and pre- and post-surgical resection. See 
Section 9.5.3 for details. 
9 – Fresh tumor tissue for correlative studies will be collected day of surgery. See Section 9.5.1, 9.5.2, and 9.5.4 
for details. 
10 – Within 3 days post-surgery. 
11 – Within minus 1 day 
12 – Evaluations done within +7 days of off-treatment date unless indicated; do not repeat: if MRI within 14 days 
of off-treatment date; if H&P /neuro-exam, KPS, labs within minus 5 days of off-treatment date. 
13 – Adverse Events must be followed for at least 30 days from the last dose of lapatinib, until resolution, within 
+14 days. 

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14 – After last dose of study drug, prior to surgery 
15 – 12-lead electrocardiogram (ECG) must be performed within 2 weeks prior to start of treatment, with QTc 
≤470 msec. 
16 – LVEF must be monitored every 12 weeks (3 cycles), including pre-Cycle 1, to ensure that LVEF does not 
decline below the institutional lower limit of normal. See Section 5.2.2. 
17 – Within minus 5 calendar days of starting cycle 
18 – For Cycle 1 only, perform scan only if patient will start cycle >21 days from post-operative scan (patient must 
have scan within ≤21 days of Cycle 1 start). Record glucocorticoid dose at time of MRI. 
19 – Perform MRI 1-3 days post-operatively. Record glucocorticoid dose at time of MRI   
 

Drug Distribution and Pharmacodynamic Study of Pulsatile Lapatinib in Surgically Accessible EGFR-Amplified 
Recurrent High-Grade Glioma 
 
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40 
 
 
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Reference Group 
 
Baseline 
Day of 
Surgery 
Post-
Surgery 
 
Post-
Surgery 
Cycles 
 
Pre- 
Odd 
Cycles 
 
Pre-
Even 
Cycles 
Every 3 
Cycles 
Off 
Treatment 
(within 7 
days) 
30-Day 
Follow-
Up  
Lapatinib 
 
 
 
9 
 
 
 
 
 
Adverse Event Evaluations 
 
 
7 
 
10 
10 
 
12 
13 
Glucocorticoids Dose  
1 
 
8 
 
10 
 
 
12 
 
MRI 
1 
 
8 
 
10,14 
 
 
12 
 
H&P/Neuro exam 
1 
 
 
 
10 
10 
 
12 
 
KPS 
1 
 
 
 
10 
10 
 
12 
 
Vital Signs 
1,2 
 
 
 
2,10 
2,10 
 
2,12 
 
CBC, platelets, Differential 
1 
 
 
 
10 
10 
 
12 
 
Serum Chemistry 
1,3 
 
 
 
3,10 
3,10 
 
3,12 
 
APTT or PTT 
1 
 
 
 
 
 
 
 
 
Serum Pregnancy Test 
1,4 
 
 
 
 
 
 
 
 
Echocardiogram 
1 
 
 
 
11 
 
11 
 
 
12-Lead Electrocardiogram 
15 
 
 
 
 
 
 
 
 
Fresh Tumor Tissue 
 
6 
 
 
 
 
 
 
 
Archived Tumor Tissue  
5 
 
 
 
 
 
 
 
 
1 – All baseline measurements must be done within 21 calendar days prior to start of treatment, unless 
otherwise indicated. 
2 – Including blood pressure, respiratory rate, heart rate, temperature, weight, and height: height is required at 
baseline only. 
3 – Albumin, alkaline phosphatase, total bilirubin, calcium, creatinine, magnesium, phosphorus, potassium, 
SGOT, SGPT, sodium. 
4 – Females with child-bearing potential must have a negative serum pregnancy test. 
5 – Archived tumor tissue from initial surgery at diagnosis of high-grade glioma. See Section 9.5.2 
6 – Fresh tumor tissue for correlative studies will be collected day of surgery. See Section 9.5.1, 9.5.2, and 9.5.4 
for details. 
7 – Within 3 days post-surgery. 
8 – Perform MRI 1-3 days post-operatively. Record glucocorticoid dose at time of MRI. 
9 – Post-operatively patients will receive lapatinib twice a day for two consecutive days every 7 days (2 days 
on/5 days off) in 28-day cycles. Patients are required to keep a pill diary. See Section 4.3.1. 
10 – Within minus 5 calendar days of starting cycle 
11 – LVEF must be monitored every 12 weeks (3 cycles), including pre-Cycle 1, to ensure that LVEF does not 
decline below the institutional lower limit of normal. See Section 5.2.2. 
12 – Evaluations done within +7 days of off-treatment date unless indicated; do not repeat: if MRI within 14 
days of off-treatment date; if H&P /neuro-exam, KPS, labs within minus 5 days of off-treatment date. 
13 – Adverse Events must be followed for at least 30 days from the last dose of lapatinib, until resolution, within 
+14 days. 
14 – For Cycle 1 only, perform scan only if patient will start cycle >21 days from post-operative scan (patient 
must have scan within ≤21 days of Cycle 1 start). Record glucocorticoid dose at time of MRI. 
15 – 12-lead electrocardiogram (ECG) must be performed within 2 weeks prior to start of treatment, with QTc 
≤470 msec. 
 
 
 

Drug Distribution and Pharmacodynamic Study of Pulsatile Lapatinib in Surgically Accessible EGFR-Amplified 
Recurrent High-Grade Glioma 
 
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9.2 
Adverse Events  
 
Patients will be evaluated for toxicity if they have received at least one dose of lapatinib. 
    
The timely reporting of adverse events (including toxic deaths) is required by the Food and 
Drug Administration.  The reporting of toxicities is part of the data reporting for this study. 
 
The following Adverse Events must be reported to the ABTC Central Office and the NCI 
in the manner described in addition to the Institution’s Institutional Review Board. 
 
All adverse events will be mailed/emailed to the ABTC Central Office by the investigative 
site in a timely manner.  See Section 12.0 – Records to be Kept. 
 
All CTEP/NCI Adverse Drug Reactions will be reported to the ABTC Central Office and 
CTEP/NCI within 24 hours of known event (unless otherwise specified). 
 
9.2.1 Comprehensive Adverse Events and Potential Risks list (CAEPR) 
For Lapatinib (GW572016, NSC 727989) 
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single 
list of reported and/or potential adverse events (AE) associated with an agent using a 
uniform presentation of events by body system. In addition to the comprehensive list, a 
subset, the Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a 
separate column and is identified with bold and italicized text. This subset of AEs 
(SPEER) is a list of events that are protocol specific exceptions to expedited reporting to 
NCI (except as noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event 
Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pd
f for further clarification. Frequency is provided based on 6120 patients. Below is the 
CAEPR for Lapatinib (GW572016). 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses 
next to the AE in the SPEER.  If this CAEPR is part of a combination protocol using 
multiple investigational agents and has an AE listed on different SPEERs, use the lower 
of the grades to determine if expedited reporting is required. 
 
 
 
 
 
 
 
 
 
 
 

Drug Distribution and Pharmacodynamic Study of Pulsatile Lapatinib in Surgically Accessible EGFR-Amplified 
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Version 03/27/19 
 
Version 2.8, February 4, 20191  
 
 Adverse Events with Possible  
 Relationship to Lapatinib (GW572016) 
 (CTCAE 5.0 Term) 
[n= 6120] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
  
CARDIAC DISORDERS 
  
 
 
Left ventricular systolic 
dysfunction 
 Left ventricular systolic dysfunction 
(Gr 2) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal distension 
 
 Abdominal distension (Gr 2) 
 
Abdominal pain 
 
 Abdominal pain (Gr 2) 
 
Anal mucositis 
 
 Anal mucositis (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Dyspepsia 
 
 Dyspepsia (Gr 2) 
 
Flatulence 
 
 Flatulence (Gr 2) 
 
Mucositis oral 
 
 Mucositis oral (Gr 2) 
 
Nausea 
 
 Nausea (Gr 2) 
 
Rectal mucositis 
 
 Rectal mucositis (Gr 2) 
 
Small intestinal mucositis 
 
 Small intestinal mucositis (Gr 2) 
 
Vomiting 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Fatigue 
 
 Fatigue (Gr 2) 
 
Flu like symptoms 
 
 Flu like symptoms (Gr 2) 
HEPATOBILIARY DISORDERS 
  
 
 
Hepatic failure 
 Hepatic failure (Gr 2) 
IMMUNE SYSTEM DISORDERS 
  
 
 
Allergic reaction 
  
INFECTIONS AND INFESTATIONS 
  
 
Infection2 
 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase increased  
 Alanine aminotransferase increased 
(Gr 2) 
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase 
increased (Gr 3) 
 
Blood bilirubin increased 
 
 Blood bilirubin increased (Gr 2) 
 
 
Ejection fraction decreased 
  
 
 
Electrocardiogram QT corrected 
interval prolonged 
 Electrocardiogram QT corrected 
interval prolonged (Gr 2) 
 
Neutrophil count decreased 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 2) 
 
Dehydration 
 
 Dehydration (Gr 2) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
Myalgia 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dysgeusia 
 
 Dysgeusia (Gr 2) 

Drug Distribution and Pharmacodynamic Study of Pulsatile Lapatinib in Surgically Accessible EGFR-Amplified 
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Version 03/27/19 
 
 
 Adverse Events with Possible  
 Relationship to Lapatinib (GW572016) 
 (CTCAE 5.0 Term) 
[n= 6120] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
Headache 
 
 Headache (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
  
 
Epistaxis 
 
  
 
Laryngeal mucositis 
 
 Laryngeal mucositis (Gr 2) 
 
Pharyngeal mucositis 
 
 Pharyngeal mucositis (Gr 2) 
 
 
Pneumonitis 
  
 
Tracheal mucositis 
 
 Tracheal mucositis (Gr 2) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
  
 
Dry skin 
 
  
 
 
Erythema multiforme 
  
 
Nail changes 
 
  
 
 
Palmar-plantar erythrodysesthesia 
syndrome 
  
 
Pruritus 
 
 Pruritus (Gr 2) 
 
Rash acneiform 
 
 Rash acneiform (Gr 2)  
Rash maculo-papular 
 
 
 Rash maculo-papular (Gr 2) 
 
 
Stevens-Johnson syndrome 
  
 
 
Toxic epidermal necrolysis 
  
VASCULAR DISORDERS 
  
 
Flushing 
 
 Flushing (Gr 2) 
 
Hot flashes 
 
  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all Principal 
Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should be 
included in the e-mail 
 
2Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
Adverse events reported on lapatinib (GW572016) trials, but for which there is insufficient evidence to 
suggest that there was a reasonable possibility that lapatinib (GW572016) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Febrile neutropenia 
CARDIAC DISORDERS - Atrial fibrillation; Chest pain - cardiac; Pericarditis; Sinus tachycardia 
EYE DISORDERS - Blurred vision 
GASTROINTESTINAL DISORDERS - Ascites; Constipation; Dysphagia; Gastritis; Hemorrhoids; Ileus; 
Pancreatitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema limbs; Fever; Non-cardiac 
chest pain; Pain 
IMMUNE SYSTEM DISORDERS - Anaphylaxis 
INVESTIGATIONS - Alkaline phosphatase increased; Creatinine increased; GGT increased; INR increased; 
Lymphocyte count decreased; Platelet count decreased; Weight loss; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Hyperglycemia; Hyperphosphatemia; Hypoalbuminemia; 
Hypoglycemia; Hypokalemia; Hyponatremia; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Bone pain; Flank pain 

Drug Distribution and Pharmacodynamic Study of Pulsatile Lapatinib in Surgically Accessible EGFR-Amplified 
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Version 03/27/19 
 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Tumor 
hemorrhage 
NERVOUS SYSTEM DISORDERS - Cerebrospinal fluid leakage; Depressed level of consciousness; Dizziness; 
Intracranial hemorrhage; Nervous system disorders - Other (altered dream pattern); Nervous system disorders - 
Other (sleep walking); Paresthesia; Peripheral motor neuropathy; Peripheral sensory neuropathy; Syncope 
PREGNANCY, PUERPERIUM AND PERINATAL CONDITIONS - Pregnancy loss 
PSYCHIATRIC DISORDERS - Insomnia 
RENAL AND URINARY DISORDERS - Acute kidney injury 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Dyspnea; Hypoxia; Oropharyngeal pain; 
Pleural effusion; Pulmonary edema; Pulmonary fibrosis 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Nail loss; Pain of skin; Skin and subcutaneous tissue 
disorders - Other (onychocryptosis); Skin and subcutaneous tissue disorders - Other (seborrheic dermatitis); Skin 
ulceration; Urticaria 
VASCULAR DISORDERS - Hematoma; Hypertension; Hypotension; Thromboembolic event; Vascular disorders 
- Other (hypovolemia) 
 
 
Note: Lapatinib (GW572016) in combination with other agents could cause an exacerbation of any adverse event 
currently known to be caused by the other agent, or the combination may result in events never previously 
associated with either agent. 
 
 
9.2.2 Definition - Adverse Event (AE) 
 
Adverse event is defined as any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom or disease temporally associated with the use of a medical 
treatment or procedure regardless of whether it is considered related to the medical 
treatment or procedure (attribution of unrelated, unlikely, possible, probable, or definite). 
 
9.2.3    Relationship 
 
The Investigator will be asked to document his/her opinion of the relationship of the event 
to study medication as follows: 
 
 
• Unrelated 
 
The adverse event is clearly not related to the investigational agent(s). 
 
• Unlikely 
The adverse event is doubtfully related to the investigational agent(s). 
 
• Possible 
The adverse event may be related to the investigational agent(s). 
 
•     Probable 
The adverse event is most likely related to the investigational agent(s). 
 
• Definite 
The adverse event is clearly related to the investigational agent(s). 

Drug Distribution and Pharmacodynamic Study of Pulsatile Lapatinib in Surgically Accessible EGFR-Amplified 
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ABTC # 1302 
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Version 03/27/19 
 
 
 
9.2.4 Recording of Adverse Events - ABTC AE Form  
 
•  Document on ABTC Adverse Event Data Form  
 
▪ The Investigator will monitor each patient closely for the development of 
adverse events and record all such events on the ABTC AE Case Report 
Form.  Each single sign or symptom must be reported separately.  
 
▪ CTCAE term (AE description) and grade:  The descriptions and 
grading scales found in the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting.  
All appropriate treatment areas should have access to a copy of the 
CTCAE version 5.0. A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.h
tm). You must use one of the CTCAE criteria to define your event. 
 
▪ Adverse events not included in the CTCAE should be reported under 
“Other” within the appropriate category and graded 1 to 5 according to the 
general grade definitions - mild, moderate, severe, life-threatening, fatal or 
disabling - as provided in the CTCAE or the CTCAE Manual.  New adverse 
events 
may 
be 
submitted 
to 
the 
CTEP 
Help 
Desk 
at 
ncictcaehelp@mail.nih.gov for annual evaluation by the CTCAE Change 
Management Committee. 
 
▪ Abnormal lab results which are graded by NCI CTCAE will be recorded on 
the ABTC Laboratory Cover Sheet along with documented attribution, not 
on the AE form.   However, if an action was taken due to this abnormality 
(e.g. RBC transfusion due to low Hgb) this would be recorded on the AE 
form also.    
 
All adverse events should be followed up in accordance with good medical practice.  
Abnormalities of laboratory events which, in the opinion of the investigator, constitute 
adverse events (even if not serious) should be followed. 
 
9.3 
Serious Adverse Events and Expedited Adverse Event Reporting 
 
9.3.1 Definition – Serious Adverse Event (SAE) 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
 
1) Death 
2) A life-threatening adverse event  

Drug Distribution and Pharmacodynamic Study of Pulsatile Lapatinib in Surgically Accessible EGFR-Amplified 
Recurrent High-Grade Glioma 
 
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46 
 
 
Version 03/27/19 
 
3) An adverse event that results in inpatient hospitalization or prolongation of 
existing hospitalization for ≥ 24 hours 
4) A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions  
5) A congenital anomaly/birth defect 
6) Important Medical Events (IME) that may not result in death, be life threatening, 
or require hospitalization may be considered serious when, based upon medical 
judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 
 
9.3.2 CTEP Adverse Event Reporting System (CTEP-AERS) 
 
•  Use CTEP-AERS Web Application and Document on ABTC AE Form  
 
▪ Expedited AE reporting for this study must use CTEP-AERS (CTEP 
Adverse Event Reporting System), accessed via the CTEP Web site 
(http://ctep.cancer.gov).  The reporting procedures to be followed are 
presented in the “NCI Guidelines for Investigators: Adverse Event 
Reporting Requirements” which can be downloaded from the CTEP Web 
site (http://ctep.cancer.gov). 
 
▪ This study will utilize the descriptions and grading found in the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 
for toxicity and Serious Adverse Event Reporting.  A copy of the CTCAE 
version 
5.0 
can 
be 
downloaded 
from 
the 
CTEP 
web 
site 
(http://ctep.cancer.gov). All appropriate treatment areas should have access 
to a copy of the CTCAE version 5.0. You must use one of the CTCAE 
criteria to define your event. 
 
Serious Adverse Events not included in the CTCAE should be reported 
under “Other” within the appropriate category and graded 1 to 5 according 
to the general grade definitions - mild, moderate, severe, life-threatening, 
fatal or disabling - as provided in the CTCAE or the CTCAE Manual.  
 
▪ Use the NCI protocol number and the protocol-specific patient ID provided 
during trial registration on all reports. 
 
▪ In the rare occurrence when Internet connectivity is lost, a 24-hour 
notification is to be made to CTEP by telephone at 301-897-7497.  Once 
Internet connectivity is restored, the 24-hour notification phoned in must be 
entered electronically into CTEP-AERS by the original submitter at the site.  
 
▪ CTEP-AERS is programmed for automatic electronic distribution of reports 
to the following individuals:  Study Coordinator of the Lead Organization, 

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Principal Investigator, and the local treating physician.  CTEP-AERS 
provides a copy feature for other e-mail recipients. 
 
Secondary Malignancy:  
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A 
secondary malignancy is not considered a metastasis of the initial neoplasm.  
CTEP requires all secondary malignancies that occur following treatment with an agent 
under an NCI IND/IDE be reported via CTEP-AERS. Three options are available to 
describe the event: 
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML]) 
• Myelodysplastic syndrome (MDS)  
• Treatment-related secondary malignancy  
Any malignancy possibly related to cancer treatment (including AML/MDS) should also 
be reported via the routine reporting mechanisms outlined in each protocol. 
 
Second Malignancy: 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT 
a metastasis from the initial malignancy).  Second malignancies require ONLY routine 
reporting via CDUS unless otherwise specified. 
 
9.3.3 Expedited Reporting Requirements 
 
Note:  A death on study requires both routine and expedited reporting regardless of 
causality, unless as noted below.  Attribution to treatment or other cause must be 
provided. 
 
Death due to progressive disease should be reported as Grade 5 “Disease Progression” in 
the system organ class (SOC) “General disorders and administration site conditions”.  
Evidence that the death was a manifestation of underlying disease (e.g., radiological 
changes suggesting tumor growth or progression: clinical deterioration associated with a 
disease process) should be submitted. 
 
Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse Events that 
Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent/Intervention 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   

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1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 
21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-
AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization       
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization       
≥ 24 hrs 
Not required 
NOTE:   Protocol-specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-
hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar 
days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
9.3.4 Other Reporting 
 
Any Serious Adverse Event, as described in Section 9.3.1, including death due to any 
cause, which occurs during this study must be reported immediately (within 24 hours) to 
the ABTC Central Office.   
 
 
 A phone call must be made to: 
 
SERENA DESIDERI 
ABTC DATA COORDINATOR 
OFFICE: 410-614-4400 

Drug Distribution and Pharmacodynamic Study of Pulsatile Lapatinib in Surgically Accessible EGFR-Amplified 
Recurrent High-Grade Glioma 
 
ABTC # 1302 
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49 
 
 
Version 03/27/19 
 
FAX: 410-614-9335 
(OR JOY FISHER, ABTC MANAGER: 410-955-3657 / 410-599-4610) 
 
  
 
 
 
 These events also must be reported by the Investigator to the appropriate Institutional 
Review Board (IRB). 
 
Patients who are removed from study due to adverse events should be followed until the 
adverse event has resolved or stabilized.  Copies of relevant documentation, such as 
laboratory reports, should be kept with the patient's study records. 
 
9.4 
Data Reporting 
 
This study will be monitored by the Clinical Data Update System (CDUS).  The ABTC 
Central Office is responsible for compiling and submitting CDUS data to CTEP for all 
participants and for providing the data to the Principal Investigator for review.   
Cumulative CDUS data will be submitted quarterly to CTEP by electronic means.  
Reports are due January 31, April 30, July 31 and October 31. 
     
 
 

Drug Distribution and Pharmacodynamic Study of Pulsatile Lapatinib in Surgically Accessible EGFR-Amplified 
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9.5  
Correlative Studies 
 
Table 9.5: Synopsis of Correlative Studies  
 
Measurement 
Technique 
Participants 
Timing of 
collection 
Collection 
requirements 
More 
Information  
EGFR gene 
amplification in 
Tumor: (Integral 
Biomarker) 
Fluorescence In-
Situ Hybridization 
(FISH) on FFPE 
Group A and 
Reference Group 
Archived 
sample 
5 UNSTAINED 
SLIDES (4 micron 
thick) from most 
recent surgery 
 Section 
9.5.2 
Ki67 and other 
IHC 
measurements 
(Exploratory) 
 
 
IHC of FFPE 
tumor tissue  
Group A and 
Reference Group 
Archived 
and 
protocol 
surgery 
20 UNSTAINED 
SLIDES each from 
archived tumor block 
and protocol surgery 
tumor block:  5 
micron thick  
Section 9.5.2 
Lapatinib  
blood 
concentrations 
(Exploratory) 
 
LC-MS/MS  
analysis  
of plasma samples 
Group A 
Before and 
During 
Protocol 
surgery 
Three BLOOD 
SAMPLES: one 
sample  collected 
before starting 
lapatinib and two 
samples collected 
during tumor 
resection 
Section 9.5.3 
Lapatinib  
tumor 
concentration 
(Integrated) 
 
 
LC-MS/MS 
analysis of fresh 
frozen tissue  
Group A 
Protocol 
Surgery 
Combined Total 
Tumor Tissue 
Required for both 
tumor concentration 
and EGFR 
phosphorylation 
(FROZEN TUMOR 
SPECIMEN WILL 
BE SPLIT INTO 
ALIQUOTS AT 
CENTRAL SITE):  
 
At least 500mg from 
contrast enhancing 
region. When 
possible, also at least 
100 mg from non-
contrast enhancing 
region 
Section 9.5.5 
EGFR 
phosphorylation 
in Tumor 
(Integrated)  
 
 
 Electro-
chemiluminescence
of fresh frozen 
tissue 
Group A and 
Reference Group 
Protocol 
surgery 
Section 9.5.6  
Ex-vivo 
sensitivity of 
tumor sphere 
cultures 
(Exploratory)  
 
 
Trypan Blue Assay 
Group A and 
Reference Group 
Protocol 
Surgery 
When possible, 500 
mg or more of 
additional Tumor 
Tissue for Tumor 
Sphere Culture 
Section 9.5.7 
 
 
 
 

Drug Distribution and Pharmacodynamic Study of Pulsatile Lapatinib in Surgically Accessible EGFR-Amplified 
Recurrent High-Grade Glioma 
 
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Biospecimen Criteria for Patient Replacement: patients on protocol will be replaced if any 
of the following tissue factors apply: 
 
Surgical sample: 
• Less than 500 mg of frozen tissue obtained from the contrast enhancing 
portion of the tumor 
• Frozen tissue does not contain tumor 
• Time from tumor removal to freezing greater than 5 minutes 
• No paraffin tumor block or fewer than 20 unstained slides available. 
 
Archived surgical sample: 
• Fewer than 20 unstained slides available 
 
Blood PK (applies to Group A only): 
• Blood samples not obtained at time of surgery 
 
9.5.1 Tissue Requirements for Protocol Surgery: Group A and Reference Group 
 
Every effort should be made to collect adequate amounts of tissue.  
 
The minimum tissue requirements to be collected from participants at the time of 
surgery include: 
 
• 500 mg of fresh frozen tissue from the contrast enhancing portion of the tumor. 
This sample will be used for the determination of the primary objectives of the 
study for both the tumor drug distribution endpoints (Section 9.5.5)  and EGFR 
phosphorylation endpoints ( Section 9.5.6) 
  
• 100 mg of fresh frozen tissue from the non-contrast enhancing portion of the 
tumor (if low risk of inducing neurological injury). This sample will be used in an 
exploratory fashion regarding tumor drug distribution and EGFR phosphorylation. 
 
• If sufficient tissue is available, 500 mg or more of additional enhancing tissue (for 
tumor sphere cultures) 
 
The remainder of the sample should be fixed in formalin and processed for routine 
paraffin embedding and sectioning at the site, per usual site protocols in pathology.  
 
The precise location in the tumor from which these specimens were obtained and the 
precise time should be recorded. Depending on local site’s capabilities, if a common 
navigation system is used for surgical localization, segmentation of the tumor using 3D 
visualization software is recommended for accurate sampling localization. Using this 

Drug Distribution and Pharmacodynamic Study of Pulsatile Lapatinib in Surgically Accessible EGFR-Amplified 
Recurrent High-Grade Glioma 
 
ABTC # 1302 
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reconstructed model, a representative screenshot is requested demonstrating the location 
of the resected tissue. If not possible, then a screenshot of the MRI showing the location 
of the resected tissue should be included.  
 
9.5.2 Archived and Protocol Surgery Paraffin Tumor Tissue (Group A and Reference 
Group) 
 
Prior to registration (Integral Biomarker): Archived tumor tissue from the most recent 
prior resection of high-grade glioma (pre-treatment) will be collected from all patients 
who are being screened for enrollment. Evidence of EGFR amplification from this 
analysis will be considered a necessary inclusion criteria for enrollment. EGFR gene 
amplification must be determined through a CLIA-certified FISH assay. Results of the 
EGFR-FISH assay must be sent to the ABTC Central Office to confirm patient eligibility. 
Determination of EGFR gene dosage through next-generation sequencing assay will not 
suffice for patient eligibility. 
 
After completion of protocol surgery: 20 consecutively cut unstained slides each  from 
the archived sample and the protocol surgery will be requested for exploratory IHC 
analysis including KI67 Analysis. These can be shipped together in separate containers 
along with the associated pathology report from the institution of collection. Notification 
of the delivery must be made by e-mail to both Dr. Ingo K. Mellinghoff (email: 
mellingi@mskcc.org) and Carl Campos (e-mail: camposc@mskcc.org). Include the name 
of the courier and the tracking no. in the email.   
 
Please ship to:  
Dr. Ingo Mellinghoff 
Memorial Sloan Kettering Cancer Center 
Zuckerman Research Building, Room Z-703 
408 East 69th Street 
New York, NY. 10021 
Telephone: + 1 (646) 888-2766 
Fax: + 1 (646) 422-0856 
 
9.5.3 Plasma Pharmacokinetics: Group A Participants 
 
Obtaining single plasma samples before and after the surgical procedure will allow the 
average drug concentration in plasma during the surgical procedure to be calculated.  The 
pretreatment baseline plasma sample is needed to document that there are no potential 
compounds that could interfere with the detection of the drug in plasma or tumor 
samples.  Obtaining these plasma samples is an important component of the drug 
distribution study and it does not have an additional objective per se.  Samples are not 
being collected to characterize the pharmacokinetic behavior of the drug. 
 

Drug Distribution and Pharmacodynamic Study of Pulsatile Lapatinib in Surgically Accessible EGFR-Amplified 
Recurrent High-Grade Glioma 
 
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A single blood sample will be obtained at baseline, prior to the first dose of lapatinib. In 
addition, single blood samples will be obtained on the day of surgery at convenient times, 
both shortly before and shortly after the tumor resection. 
 
For all pharmacokinetic plasma samples, draw 3 mL of blood into a plastic plasma 
collection tube with spray-coated sodium heparin at each of the time points specified. 
Promptly mix the specimen by gently inverting the collection tube several times and then 
place it on wet ice. Centrifuge the sample at 1,100-1,300 x g for 10 min at 4°C within 5-
10 min after collection. Remove the plasma from the blood cells using a pipette and 
distribute it in equal volumes into two self-standing polypropylene cryogenic tubes with 
external threads. Affix a computer-printed label (protocol no., patient no., sample no., 
scheduled sample time) to each cryotube. Completely cover the label with protective 
cryogenic freezer tape (Fisher catalog no. 11-867B). Place the tubes on crushed dry ice 
until stored in a freezer maintained at -70°C.  
 
The concentration of lapatinib in study samples will be determined by the ABTC 
Pharmacokinetics Center using an LC-MS/MS assay.  The analytical method will be 
validated and applied to the analysis of study samples as recommended by the FDA 
Guidance for Industry: Bioanalytical Method Validation, May 2001 
(http://www.fda.gov/downloads/Drugs/Guidances/ucm070107.pdf). 
 
Send complete sets of plasma samples from each patient by overnight courier to the 
address listed below. Place the sample tubes within a zip lock plastic bag. Fill a seamless 
styrofoam container with at least 3 inches of dry ice, place the plastic bag containing the 
samples on top of the dry ice, and completely cover the bag with an additional 3 inches or 
more of dry ice. Seal the styrofoam container within a tight-fitting cardboard shipping 
box. Seal a copy of the sample collection time form for each set of samples within a zip-
lock plastic bag and place the bag on top of the styrofoam container before the external 
shipping box is sealed.  Send the samples on a Monday, Tuesday, or Wednesday by 
overnight courier for delivery by 10:00 AM on the following day. Notification of the 
delivery must be made by e-mail to both Dr. Jeffrey G. Supko (email: 
jsupko@partners.org) and Sarah Hilderbrand (e-mail: slhilderbrand@partners.org). 
Include the name of the courier and the tracking no. in the email.   
 
Please ship to: 
Dr. Jeffrey G. Supko 
Massachusetts General Hospital 
55 Fruit St., GRJ 1025 
Boston, MA 02114 
Tel: 617-724-1970 
 
9.5.4 Handling and Shipping of Frozen Tumor for tumor concentration and EGFR 
phosphorylation 
 

Drug Distribution and Pharmacodynamic Study of Pulsatile Lapatinib in Surgically Accessible EGFR-Amplified 
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Neurosurgeons at all participating sites are trained in the collection of biospecimens for 
pharmacokinetic and pharmacodynamic analyses. Tumor samples will be frozen within 5 
min of collection.  
 
The research nurse will notify the laboratory of scheduled sample collections, preferably 
giving at least 24-h notice, to allow sufficient time to set up laboratory supplies, collect 
relevant clinical information, and ensure rapid transport of specimens to the laboratory 
for placement at -80ºC (or lower) after collection.  
 
Promptly after excision, rinse the tissue with ice-cold phosphate buffered saline and 
gently blot on Whatman filter paper to remove surface fluid.  Place the tissue into pre-
chilled 2.0 mL cryogenic tubes (Fisher catalogue no. 12-565-291). The label must contain 
the patient ID no. and information identifying the region from which the tissue was 
excised. Snap freeze the specimen by placing the tube in liquid nitrogen or a dry 
ice/ethanol bath and record the time of freezing in the Batch Record. Calculate the total 
time elapsed from biopsy collection to biopsy freezing and record the total number of 
minutes and seconds elapsed in the Batch Record. Samples will be transferred to a -80°C 
freezer or liquid nitrogen tank for storage until shipment to the PD processing laboratory. 
Record the date and time specimens are placed at -80ºC.  
 
Just prior to shipment, specimen tubes will be placed into an 81-place freezer box and 
then in a shipping container with sufficient dry ice to maintain the samples at -20°C for at 
least 72 hours. Specimens will be shipped via FedEx for delivery by 10 AM the next day 
(FedEx First Overnight).  Seal the box and print and attach the shipping address onto the 
outside of the shipping container and label the contained as containing biohazardous 
specimens. Record the shipping date, time, tracking number, and shipping information in 
the Batch Record. Notification of the delivery must be made by e-mail to both Dr. Ingo 
K. Mellinghoff (email: mellingi@mskcc.org) and Carl Campos (e-mail: 
camposc@mskcc.org). Include the name of the courier and the tracking no. in the email.     
 
Ship all frozen tumor samples to:  
Ingo Mellinghoff, MD 
Memorial Sloan Kettering Cancer Center 
Zuckerman Research Building, Room Z-703 
408 East 69th Street 
New York, NY. 10021 
Telephone: + 1 (646) 888-2766 
Fax: + 1 (646) 422-0856 
 
Once specimens arrive at the Mellinghoff laboratory, they will be immediately placed at -
80ºC (or lower). Dr. Mellinghoff’s group will collect all samples, cut a 5 µM section 
from each specimen and then perform H&E staining. Histopathological review of the 
H&E stain will be performed by a board-certified neuropathologist at Memorial Sloan-
Kettering Cancer Center. Only samples with a tumor cell content > 80 % as determined 
by a pathologist will be used for further analyses. Each frozen tumor specimen that 

Drug Distribution and Pharmacodynamic Study of Pulsatile Lapatinib in Surgically Accessible EGFR-Amplified 
Recurrent High-Grade Glioma 
 
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NCI # ABTC-1302 
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passes histopathological Q/C will be split into two samples, one for the determination of 
intratumoral lapatinib concentrations (Section 9.5.5) and one for the determination of 
EGFR phosphorylation (Section 9.5.6).  
 
9.5.5 Tumor Samples for Intratumoral Drug Distribution: Group A  
 
The specimens for the determination of intratumoral lapatinib concentration will be 
shipped to the ABTC Pharmacokinetics Center by the Mellinghoff Laboratory following 
the shipping guidelines in Section 9.5.3. The concentration of lapatinib in study samples 
will be determined by the ABTC Pharmacokinetics Center using an LC-MS/MS assay, 
also described in Section 9.5.3.  
Biopsy specimens selected for drug concentration measurement should be at least 0.05 
cm3 (50 mg) intact sections of tumor tissue. To the extent possible, at least one biopsy 
sample should be resected from a contrast enhancing region of the tumor and another 
from a non-contrast enhancing region for drug level analysis. These samples must be 
clearly identified accordingly.  
Intratumoral lapatinib concentrations will be measured in fresh frozen tumor aliquots in 
two batches.  
• the first batch of samples (patients # 1-8) will be used for the interim futility 
analysis and will be run after the initial eight patients. Study enrollment will 
continue if three or more of these eight tumor samples show an intratumoral 
lapatinib concentration of > 1.5 µM.  
• the second batch of tumor samples (patient # 9-18) will be performed after 
enrollment has been completed.  
 
Lapatinib concentrations in plasma at the time of tumor resection will also be determined 
(Section 9.5.3) and this data will be used to calculate a lapatinib tumor/plasma ratio. 
  
9.5.6  Tumor Samples for Determination of EGFR phosphorylation in Tumor Tissue: 
(Group A and Reference Group) 
  
Determination of EGFR protein levels and EGFR phosphorylation will be performed in 
the Mellinghoff Laboratory. Samples will be lysed in sample buffer with protease and 
phosphatase inhibitors which has been optimized by MesoScale Discovery to minimize 
decay of the protein and phosphosignal (http://www.mesoscale.com). All clinical trial 
samples will be run through the mesoscale electrochemiluminescent assay in a single 
batch. Residual samples will be aliquoted and frozen. All specimens will be handled and 
stored to minimize decay of the phospho-signal. Further Details regarding the EGFR 
Mesoscale Assay are provided in Appendix IV. Performance characteristics of this 
pharmacodynamic assay will be validated in additional laboratory experiments and 
presented for CTEP review before the specimens from the trial are analyzed. 
 

Drug Distribution and Pharmacodynamic Study of Pulsatile Lapatinib in Surgically Accessible EGFR-Amplified 
Recurrent High-Grade Glioma 
 
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NCI # ABTC-1302 
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9.5.7 Tumor Sphere Cultures 
 
Glioma Tumor Sphere Lines will be prepared from fresh tumor samples whenever 
possible (i.e., if there is 500 mg or more of additional enhancing tissue) at each 
participating ABTC site. The consortium has successfully derived glioma tumor sphere 
cultures in the context of a prior clinical trial (ABTC 0906).  
 
Whenever possible, at least 500 mg grams of viable tissue will be processed for 
neurosphere studies.  The sterility of the specimen should be preserved while it is minced 
gently into 0.5 cm cubes in the operating room which optimizes conditions for cellular 
survival, prevents tube breakage/leakage, and maintains cells at low temperature while 
avoiding freezing of cells.  In brief, a pre-labeled 25cc tube should be filled to the top 
with a low-glucose, serum-free, buffered transport medium and placed immediately on 
wet ice in the operating room. The specimen should then be inserted into a protective 
tube to prevent breakage, sealed in a Ziploc bag, and packed on wet ice in a pre-labeled 
styrofoam container with relevant identifying information.  The starting and ending times 
of resection should be noted by personnel at the institution and included in the specimen 
identification form.  
 
Specimens for tumor sphere cultures must be shipped immediately from the 
participating ABTC site to the Mellinghoff Laboratory. Specimens will be shipped 
via FedEx on the same day for delivery by 10 AM the next day (FedEx First Overnight).  
Seal the box and print and attach the shipping address onto the outside of the shipping 
container and label the container as containing biohazardous specimens. Record the 
shipping date, time, tracking number, and shipping information in the Batch Record.  
 
Notification of the delivery must be made by e-mail to both Dr. Ingo K. Mellinghoff 
(email: mellingi@mskcc.org) and Carl Campos (e-mail: camposc@mskcc.org). Include 
the name of the courier and the tracking no. in the email.     
 
Ship all tumor samples to:  
Ingo Mellinghoff, MD 
Memorial Sloan Kettering Cancer Center 
Zuckerman Research Building, Room Z-703 
408 East 69th Street 
New York, NY. 10021 
Telephone: + 1 (646) 888-2766 
Fax: + 1 (646) 422-0856 
 
Upon receipt, the specimen will be immediately logged into the Oncore database and 
transported to the Mellinghoff laboratory. Within 20 minutes of arrival at the 
Mellinghoff Laboratory, sterile, refrigerated specimens will be processed into 
neurosphere cultures. Tumor specimen samples are washed in cold PBS twice, then 
manually dissociated and placed in Accumax (Innovative Cell Technologies) for 15 min 
under sterile conditions. Cells are subsequently washed and filtered through a 100-μm 

Drug Distribution and Pharmacodynamic Study of Pulsatile Lapatinib in Surgically Accessible EGFR-Amplified 
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strainer and plated in NeuroCult NS-A proliferation media (Stemcell Technologies) 
supplemented with 10 ng/mL rhbFGF for all experimental conditions in the study. Initial 
cultures are also supplemented with 20 ng/mL rhEGF. Cells are incubated at normal 
oxygen levels at a temperature 37.0 °C and 5% CO2 (Szerlip et al. 2012).  
 
Lapatinib sensitivity will be determined in the Mellinghoff Lab using a Trypan Blue 
Exclusion Assay (Vivanco et al. 2012).  
 
 
 
 

Drug Distribution and Pharmacodynamic Study of Pulsatile Lapatinib in Surgically Accessible EGFR-Amplified 
Recurrent High-Grade Glioma 
 
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10.0    OFF TREATMENT/OFF STUDY CRITERIA 
 
Each subject has the right to withdraw from the study at any time without prejudice.  The 
investigator may discontinue any subject’s participation for any reason, including adverse 
event or failure to comply with the protocol (as judged by the investigator such as 
compliance below 80%, failure to maintain appointments, etc.). 
Should a subject withdraw from the study, the reason(s) must be stated on the case report 
form, and a final evaluation of the subject should be performed.  
 
Patients who go off treatment must be followed for adverse events (AEs) for at least 30 
days from the last dose of lapatinib. 
 
 
10.1 
Off Treatment Criteria 
 
1. Disease Progression:  Remove patient from protocol therapy at the time progressive 
disease is documented. Disease progression is defined as:  Progressive neurologic 
abnormalities not explained by causes unrelated to tumor progression (e.g. 
anticonvulsant or  corticosteroid toxicity, electrolyte abnormalities, hyperglycemia, 
etc.) or a greater than 25% increase in the measurement of the tumor by MRI scan.  If 
neurologic status deteriorates, on a stable or increasing dose of steroids, or if new 
lesions appear on serial MRI, further study treatment will be discontinued 
 
2. Adverse Event: 
• Intercurrent illness that prevents further administration of treatment 
• Patients who experience unacceptable toxicity. Patients removed from study for 
unacceptable adverse events will be followed until resolution or stabilization of 
the adverse event. 
 
3. Patient Withdrawal: Patient’s refusal to continue treatment: in this event, document the 
reason(s) for withdrawal. 
 
4. Non Compliance: Failure to comply with protocol (as judged by the investigator such 
as compliance below 80%, failure to maintain appointments, etc.) 
 
5. Physician Decision: If at any time the treating physician feels constraints of this 
protocol are detrimental to the patient’s health remove the patient from protocol 
therapy. 
 
6. Protocol Defined Delay:  
• Patients who experience a treatment-related toxicity causing a delay in treatment > 
14 days 
• Delay in protocol > 28  days for major events or other non-treatment related delays 
 
7. Death 
 

Drug Distribution and Pharmacodynamic Study of Pulsatile Lapatinib in Surgically Accessible EGFR-Amplified 
Recurrent High-Grade Glioma 
 
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10.2 
Off Study Criteria 
 
Patients will only be off study at the time of death. All patients will be followed for survival 
every 2 months for the first two years from the off treatment date; after 2 years, patients 
will be followed every 6 months until death. Survival status may be obtained by phone call, 
clinic visit, or medical records (e.g. physician notes/laboratory results of clinic or hospital 
visit). 
 
 
11.0   STATISTICAL CONSIDERATIONS 
 
This is an open-label, multicenter, early phase clinical trial to evaluate whether lapatinib, 
when given on a pulsatile dosing schedule, will reach an intratumoral concentration of 
1.5 µM or higher in 70% of patients with recurrent and surgically accessible EGFR-
amplified high-grade glioma. It will also determine whether this lapatinib dosing regimen 
will achieve 80% reduction in ratio of phosphorylated to total EGFR in tumor tissue in 
70% of patients with recurrent and surgically accessible EGFR-amplified high-grade 
glioma. 
 
Primary Endpoints:  
 
• Lapatinib intratumoral concentration (PK)  
 
• Ratio of pEGFR/total EGFR (PD) in tumor tissue 
 
Primary Objectives and Sample Size: 
 
The first primary objective is to evaluate whether pulsatile lapatinib, when given on the 
pulsatile dosing schedule, can reach an intratumoral concentration of 1.5 µM or higher in 
70% of patients with recurrent and surgically accessible EGFR-amplified high-grade 
glioma.  
 
Initially eight patients will be treated with pulsatile lapatinib and the intratumoral 
concentration of lapatinib will be analyzed.    
 
• if no more than 2 patients achieve adequate tumor lapatinib concentration of 1.5 
µM or higher, the trial will be stopped early for futility. The probability of early 
stopping for futility is 68% with a true null of 25% while maintaining only 1.1% 
probability of early termination for a true rate of 70% (the target). 
 
• if 3 or more of the initial 8 patients reach an intratumoral drug concentration level 
of 1.5 µM or higher, 10 additional patients will be enrolled into the study.  
 
• if 8 or more of the 18 patients treated with pulsatile lapatinib achieve intratumoral 
lapatinib concentrations of at least 1.5 µM, the PK objective will be met. This 

Drug Distribution and Pharmacodynamic Study of Pulsatile Lapatinib in Surgically Accessible EGFR-Amplified 
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design has 98% power to detect a true rate of 70% from a null of 25% in 
achieving lapatinib intratumoral concentration level of 1.5 µM with a false 
positive rate of 0.05.  
 
The PD study will be pursued after the initial 8 patients’ PK objective is met. 
 
The primary PD objective is to test the hypothesis that 70% of patients will achieve 80% 
reduction in ratio of phosphorylated to total EGFR after pulsatile lapatinib treatment 
assuming a null of 25% patients. A ratio of pEGFR/total EGFR at 80% reduction from a 
median value from the untreated reference group will be considered as the putative 
threshold to qualify a near complete inhibition of EGFR (at 80%). If at least 9 (50%) of 
the 18 treated patients demonstrate a pEGFR/total EGFR ratio which corresponds to at 
least an 80% reduction compared to the median pEGFR/total EGFR ratio for the 15 
patients enrolled on the reference arm, the PD objective will be met.  This design yields 
98% power to detect a true 70% rate of near complete (80%) EGFR inhibition and it 
yields a false positive rate of 2% for a true 25% rate of such EGFR inhibition.   
 
Initial safety monitoring: All adverse events will be monitored and collected throughout 
the trial and documented based on CTCAE version 5.0. If there are three or more delays 
of scheduled surgery due to lapatinib-related Serious Adverse Events among the initial 8 
patients; or if there are any surgical complications and delayed wound healing SAEs 
grade ≥3 considered lapatinib-related among the first three patients, ABTC investigators 
will consult with CTEP investigators and the pharmaceutical sponsor about such events. 
An internal safety monitoring evaluation will be conducted after the first three patients 
complete their first follow-up visit after surgery.  
 
Reference Group (for primary PD study): 
 
15 lapatinib-naïve patients with recurrent and surgically accessible EGFR-amplified 
high-grade glioma will be enrolled as a reference group for the PD evaluation to establish 
the threshold of 80% reduction in the ratio of pEGFR/total EGFR. After the initial 8 
patients are enrolled into Group A, eligible patients will be sequentially assigned to either 
treatment group or reference group. The sample size of 15 patients on the reference arm 
yields 90% confidence that the observed median falls between the true 30th and 70th 
percentiles of the pEGFR/total EGFR distribution for untreated patients. 
 
To avoid batch effect and other variations through tumor sample processing, all tumor 
samples will be processed at the same time at the Mellinghoff Lab, Memorial Sloan-
Kettering Cancer Center. 
 
Secondary and Exploratory Objectives: 
 
1. All treatment or surgically related AEs will be reported descriptively. A proportion of 
toxicity grade >=3 will be estimated using binomial distribution. 

Drug Distribution and Pharmacodynamic Study of Pulsatile Lapatinib in Surgically Accessible EGFR-Amplified 
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2. To estimate inhibition of tumor cell proliferation (KI-67), descriptive statistics will be 
used for summarizes results and Box plots could be used to present the difference 
between the treated and untreated groups.  
3. To characterize ex-vivo sensitivity of tumor sphere cultures to lapatinib, the ex-vivo 
sensitivity of tumor sphere cultures established from surgical specimens to pulsatile 
lapatinib is defined by a minimum of 20% reduction in cell proliferation as measured 
by cell titer glow in the pulsatile lapatinib group compared to the untreated group. 
Fisher’s exact test will be used for testing a difference in the proportion between the 
two groups. 
4.   To estimate tumor objective response rate as the evidence of biological activity 
among patients with recurrent GBM treated by lapatinib, the proportion of patients 
who had objective PR or CR during the course of the treatment will be estimated 
along with 95% confidence intervals using the exact binomial method. 
5. To estimate overall survival (OS), the survival time is defined from the date of 
treatment start to the date of death. Patients who have not expired by the data analysis 
cutoff date will be censored at their last date known to be alive. The Kaplan-Meier 
method will be used to estimate overall survival probability and median time of 
survival along with a 95% confidence interval. 
6. To estimate progression-free survival,  The progression is defined a radiographic 
tumor progression, a >=25% increasing from baseline scan with a confirmatory scan 
at least 8 weeks apart from the initial scan that tumor progression was observed. The 
date of progression is defined as the date of initial scan deemed tumor progression. 
The Kaplan-Meier method will be used to estimate progression-free survival 
probability and median time of survival along with a 95% confidence interval. The 
progression-free survival at 6-month is defined as: patient, who started treatment, is 
alive and progression free at the time of 6 month follow-up. The probability of 6-
month progression-free survival will be estimated using binomial distribution. 
 
 
12.0   RECORDS TO BE KEPT   
  
  
  
 
 
Data collection for this study will be done exclusively through CTEP’s Medidata 
Rave.   
 
Access to the trial in Rave is granted through the iMedidata application to all persons 
with the appropriate roles in the Regulatory Support System (RSS).  To access 
iMedidata/Rave the site user must have an active CTEP IAM account (https://eapps-
ctep.nci.nih.gov/iam).  In addition, site users that are a member of the ABTC must have 
the Rave CRA role in RSS at the enrolling site. 
 
Upon initial site registration approval for the study in RSS, all persons with Rave roles 
assigned on the appropriate roster will be sent a study invitation e-mail from 
iMedidata.   Please note, site users will not be able to access the study in Rave until all 
required Medidata and study specific trainings are completed.  Trainings will be listed in 
the upper right pane of the iMedidata screen.   

Drug Distribution and Pharmacodynamic Study of Pulsatile Lapatinib in Surgically Accessible EGFR-Amplified 
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Users that have not previously activated their iMedidata/Rave accounts will also receive an 
invitation from iMedidata to activate their account.  If you have any questions please contact 
the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com.  
 
• All data are due within 14 days of evaluation time point.  Please see Section 9.1 
for evaluation time points. 
• Serious Adverse Events, PHONE IMMEDIATELY, SEE SECTION 9.3 
 
 

Drug Distribution and Pharmacodynamic Study of Pulsatile Lapatinib in Surgically Accessible EGFR-Amplified 
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Amin DN, Sergina N, Ahuja D, McMahon M, Blair JA, Wang D, Hann B, Koch KM, 
Shokat KM, Moasser MM. Resiliency and vulnerability in the HER2-HER3 tumorigenic  
driver. Sci Transl Med. 2010 Jan 27;2(16):16ra7. PMID: 20371474; PubMed Central PMCID: 
PMC3033659 
 
Bollag G, Hirth P, Tsai J, Zhang J, Ibrahim PN, Cho H, Spevak W, Zhang C, Zhang Y, Habets 
G, Burton EA, Wong B, Tsang G, West BL, Powell B, Shellooe R, Marimuthu A, Nguyen H, 
Zhang KY, Artis DR, Schlessinger J, Su F, Higgins B, Iyer R, D'Andrea K, Koehler A, Stumm 
M, Lin PS, Lee RJ, Grippo J, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, 
Chapman PB, Flaherty KT, Xu X, Nathanson KL, Nolop K.  Clinical efficacy of a RAF inhibitor 
needs broad target blockade in BRAF-mutant melanoma.  Nature. 2010 Sep 30;467(7315):596-9. 
PMID: 20823850; PMCID: PMC2948082 
 
Brandes AA, Franceschi E, Tosoni A, Hegi ME, Stupp R. Epidermal growth factor receptor 
inhibitors in neuro-oncology: hopes and disappointments. Clin Cancer Res 2008;14:957–60.  
PMID: 18281526 
 
Brennan CW, Verhaak RG, McKenna A, Campos B, Noushmehr H, Salama SR, Zheng S, 
Chakravarty D, Sanborn JZ, Berman SH, Beroukhim R, Bernard B, Wu CJ, Genovese G, 
Shmulevich I, Barnholtz-Sloan J, Zou L, Vegesna R, Shukla SA, Ciriello G, Yung WK, Zhang 
W, Sougnez C, Mikkelsen T, Aldape K, Bigner DD, Van Meir EG, Prados M, Sloan A, Black 
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14.0 
COLLABORATIVE AGREEMENTS LANGUAGE 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the 
NCI under a Collaborative Agreement (CRADA, CTA, CSA) between the 
Pharmaceutical Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI 
Division of Cancer Treatment and Diagnosis.  Therefore, the following 
obligations/guidelines, in addition to the provisions in the “Intellectual Property Option 
to Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained 
within the terms of award, apply to the use of the Agent(s) in this study: 
 
1.   Agent(s) may not be used for any purpose outside the scope of this protocol, nor 
can Agent(s) be transferred or licensed to any party not participating in the 
clinical study.  Collaborator(s) data for Agent(s) are confidential and proprietary 
to Collaborator(s) and shall be maintained as such by the investigators. The 
protocol documents for studies utilizing Agents contain confidential information 
and should not be shared or distributed without the permission of the NCI.  If a 
copy of this protocol is requested by a patient or patient’s family member 
participating on the study, the individual should sign a confidentiality agreement. 
A suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2.   For a clinical protocol where there is an investigational Agent used in 
combination with (an)other Agent(s), each the subject of different Collaborative 
Agreements, the access to and use of data by each Collaborator shall be as follows 
(data pertaining to such combination use shall hereinafter be referred to as "Multi-
Party Data”): 
 
a.   NCI will provide all Collaborators with prior written notice regarding the 
existence and nature of any agreements governing their collaboration with 
NCI, the design of the proposed combination protocol, and the existence of 
any obligations that would tend to restrict NCI's participation in the proposed 
combination protocol. 
 
b.   Each Collaborator shall agree to permit use of the Multi-Party Data from the 
clinical trial by any other Collaborator solely to the extent necessary to allow 
said other Collaborator to develop, obtain regulatory approval or 
commercialize its own Agent. 
 
c.   Any Collaborator having the right to use the Multi-Party Data from these trials 
must agree in writing prior to the commencement of the trials that it will use 
the Multi-Party Data solely for development, regulatory approval, and 
commercialization of its own Agent. 
 
3.   Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available to Collaborator(s), the NCI, and the FDA, as 

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appropriate and unless additional disclosure is required by law or court order as 
described in the IP Option to Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). 
Additionally, all Clinical Data and Results and Raw Data will be collected, used 
and disclosed consistent with all applicable federal statutes and regulations for the 
protection of human subjects, including, if applicable, the Standards for Privacy 
of Individually Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4.   When a Collaborator wishes to initiate a data request, the request should first be 
sent to the NCI, who will then notify the appropriate investigators (Group Chair 
for Cooperative Group studies, or PI for other studies) of Collaborator's wish to 
contact them. 
 
5.   Any data provided to Collaborator(s) for Phase 3 studies must be in accordance 
with the guidelines and policies of the responsible Data Monitoring Committee 
(DMC), if there is a DMC for this clinical trial. 
 
6.   Any manuscripts reporting the results of this clinical trial must be provided to 
CTEP by the Group office for Cooperative Group studies or by the principal 
investigator for non-Cooperative Group studies for immediate delivery to 
Collaborator(s) for advisory review and comment prior to submission for 
publication.  Collaborator(s) will have 30 days from the date of receipt for review.  
Collaborator shall have the right to request that publication be delayed for up to 
an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are 
protected.  Copies of abstracts must be provided to CTEP for forwarding to 
Collaborator(s) for courtesy review as soon as possible and preferably at least 
three (3) days prior to submission, but in any case, prior to presentation at the 
meeting or publication in the proceedings. Press releases and other media 
presentations must also be forwarded to CTEP prior to release. Copies of any 
manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Email: ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No 
publication, manuscript or other form of public disclosure shall contain any of 
Collaborator’s confidential/ proprietary information. 
 
 

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15.0  ETHICAL AND LEGAL CONSIDERATIONS 
 
 
This study will be conducted in accordance with the Declaration of Helsinki and in 
compliance with all applicable laws and regulations of the locale where the study is 
conducted. 
 
It is the responsibility of the investigator that the patient is made aware and consent is given 
that personal information may be scrutinized during audits by competent authorities and 
properly authorized persons, but that personal information will be treated as strictly 
confidential and not be publicly available.  The investigator is responsible for the retention 
of the patient log and patient records. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Drug Distribution and Pharmacodynamic Study of Pulsatile Lapatinib in Surgically Accessible EGFR-Amplified 
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APPENDIX I – PATIENT MEDICATION DIARY 
 
 
Pre-Surgical Treatment (Group A patients): Lapatinib 2500 mg, 12 hours apart, during the 2 
days prior to surgery and on the day of surgery 
 
 
 
Patient Name____________________________ (initials acceptable)   Patient Study ID ___________________   
 
 
INSTRUCTIONS TO THE PATIENT: 
1. You will take 4 doses of lapatinib 2500 mg, 12 hours apart (±2 hrs.), starting 2 days prior to surgery 
and on the morning of surgery. If surgery is delayed you may take one additional dose of lapatinib.  
Dose:  take ___ 250 mg tablets. 
2. Take on an empty stomach, either 1 hour before or 1 hour after meals. 
3. Do not consume grapefruit or grapefruit juice during participation on this study. 
4. Record the date, the time you took the tablets, and the number of tablets that you took.   
Record missed or skipped dose(s). 
5. Bring this form and any remaining lapatinib tablets when you return for surgery. 
Day 
Timeframe 
Date 
Time 
# of 250mg 
tablets 
Comments 
2 days prior to surgery 
Evening 
 
 
 
 
1 day prior to surgery 
Morning 
 
 
 
 
Evening 
 
 
 
 
Day of Surgery: 3-5 hrs. 
prior to surgery 
Morning 
 
 
 
 
(additional dose if surgery 
delayed) 
 
 
 
 
 
 
 
Patient’s Signature _________________________________________________________________________ 
 
Date ____________________ 
 

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Post-Surgical Treatment: Lapatinib 2500 mg twice a day for 2 consecutive days, every 7 days 
during 28-day cycles 
 
Patient Name____________________________ (initials acceptable)   Patient Study ID ___________________   
 
Cycle # _______ 
 
INSTRUCTIONS TO THE PATIENT: 
1. You will take lapatinib _______ mg twice a day, 12 hours apart (±2 hrs.), for 2 days in a row every week (7 days), 
during each 4-week cycle.  
Dose:  take _____ 250 mg tablets. 
2. Take on an empty stomach, either 1 hour before or 1 hour after meals. 
3. Do not consume grapefruit or grapefruit juice during participation on this study. 
4. Record the date, the time you took the tablets, and the number of tablets that you took.   
Record missed or skipped dose(s). Vomited doses should not be replaced/repeated. 
5. Bring this form and your bottles of lapatinib tablets when you return for each appointment. 
 
Week 
Day 
Date 
Time of 
morning dose 
Time of 
evening dose 
# of 250 mg 
tablets taken 
Comments 
1 
1 
 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
No dose 
No dose 
- 
 
 
4 
 
No dose 
No dose 
- 
 
 
5 
 
No dose 
No dose 
- 
 
 
6 
 
No dose 
No dose 
- 
 
 
7 
 
No dose 
No dose 
- 
 
2 
8 
 
 
 
 
 
 
9 
 
 
 
 
 
 
10 
 
No dose 
No dose 
- 
 
 
11 
 
No dose 
No dose 
- 
 
 
12 
 
No dose 
No dose 
- 
 
 
13 
 
No dose 
No dose 
- 
 
 
14 
 
No dose 
No dose 
- 
 
3 
15 
 
 
 
 
 
 
16 
 
 
 
 
 
 
17 
 
No dose 
No dose 
- 
 
 
18 
 
No dose 
No dose 
- 
 
 
19 
 
No dose 
No dose 
- 
 
 
20 
 
No dose 
No dose 
- 
 
 
21 
 
No dose 
No dose 
- 
 
4 
22 
 
 
 
 
 
 
23 
 
 
 
 
 
 
24 
 
No dose 
No dose 
- 
 
 
25 
 
No dose 
No dose 
- 
 
 
26 
 
No dose 
No dose 
- 
 

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27 
 
No dose 
No dose 
- 
 
 
28 
 
No dose 
No dose 
- 
 
 
Patient’s signature _________________________________________________________________________ 

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APPENDIX II – INFORMATION ON POSSIBLE DRUG INTERACTIONS 
 
Information on Possible Interactions with Other Agents for Patients and Their Caregivers and Non-Study 
Healthcare Team 
 
[Note to investigators:  This appendix consists of an “information sheet” to be handed to the patient at the time of 
enrollment.  Use or modify the text as appropriate for the study agent, so that the patient is aware of the risks and 
can communicate with their regular prescriber(s) and pharmacist.  A convenient wallet-sized information card is 
also included for the patient to clip out and retain at all times.] 
 
The patient ____________________________ is enrolled on a clinical trial using the experimental agent lapatinib.  
This clinical trial is sponsored by the National Cancer Institute.  This form is addressed to the patient, but includes 
important information for others who care for this patient.  
 
Lapatinib interacts with many drugs that are processed by your liver.  Because of this, it is very important to tell 
your study doctors about all of your medicine before you start this study.  It is also very important to tell them if you 
stop taking any regular medicine, or if you start taking a new medicine while you take part in this study.  When you 
talk about your medicine with your study doctor, include medicine you buy without a prescription at the drug store 
(over-the-counter remedy), or herbal supplements such as St. John’s wort.  
 
Many health care prescribers can write prescriptions.  You must also tell your other prescribers (doctors, physicians’ 
assistants or nurse practitioners) that you are taking part in a clinical trial. Bring this paper with you and keep the 
attached information card in your wallet.  These are the things that you and they need to know:  
 
 Lapatinib interacts with (a) certain specific enzyme(s) in your liver.  
• The enzyme in question is CYP3A4 and certain agents are considered “inducers” which when taken will 
more rapidly clear lapatinib and make it less effective and agents are considered “inhibitors” which when 
taken slow down the clearance of lapatinib and make it more likely to cause side effects.   
• Lapatinib must be used very carefully with other medicines that need these liver enzymes to be effective or to 
be cleared from your system.   
• You and healthcare providers who prescribe drugs for you must be careful about adding or removing any 
drug in this category.  
• Before you start the study, your study doctor will work with your regular prescriber to switch any prescribed 
medicines over-the-counter medications or supplements that are considered “strong inducers/inhibitors or 
substrates of CYP3A4 
• Your prescribers should look at this web site http://medicine.iupui.edu/clinpharm/ddis/table.aspx or consult a 
medical reference to see if any medicine they want to prescribe is on a list of drugs to avoid.   
• Please be very careful!  Over-the-counter drugs have a brand name on the label—it’s usually big and catches 
your eye.  They also have a generic name—it’s usually small and located above or below the brand name, 
and printed in the ingredient list.  Find the generic name and determine, with the pharmacist’s help, 
whether there could be an adverse interaction.   
 
 
Other medicines can be a problem with your study drugs.  
 
• 
You should check with your doctor or pharmacist whenever you need to use an over-the-
counter medicine or herbal supplement.  
 
• 
Your regular prescriber should check a medical reference or call your study doctor before 
prescribing any new medicine for you.  Your study doctor’s name is  
 
_____________________________________  
 

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and he or she can be contacted at  
 
_____________________________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
INFORMATION ON POSSIBLE DRUG INTERACTIONS  
You are enrolled on a clinical trial using the experimental agent 
lapatinib.  This clinical trial is sponsored by the NCI.  Lapatinib 
interacts with drugs that are processed by your liver.  Because of this, 
it is very important to: 
➢ Tell your doctors if you stop taking regular medicine or if you start 
taking a new medicine. 
➢ Tell all of your prescribers (doctor, physicians’ assistant, nurse 
practitioner, pharmacist) that you are taking part in a clinical trial. 
➢ Check with your doctor or pharmacist whenever you need to use 
an over-the-counter medicine or herbal supplement. 
Lapatinib interacts with a specific liver enzyme called CYP3A4, and 
must be used very carefully with other medicines that interact with 
this enzyme.  
➢ Before you start the study, your study doctor will work with your 
regular prescriber to switch any medicines that are considered 
“strong inducers/inhibitors or substrates of CYP3A4.” 
➢ Before prescribing new medicines, your regular prescribers should 
go to http://medicine.iupui.edu/clinpharm/ddis/table.aspx for a 
list of drugs to avoid, or contact your study doctor.   
➢ Your study doctor’s name is _____________________________ 
and can be contacted at _________________________________.  

Drug Distribution and Pharmacodynamic Study of Pulsatile Lapatinib in Surgically Accessible EGFR-Amplified 
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APPENDIX III – INFORMATION ON EGFR MESOSCALE ASSAY 
 
Sample Collection and Shipping: All patient samples will be collected at member institutions of 
the Adult Brain Tumor Consortium (ABTC). Neurosurgeons at all participating sites are trained 
in the collection of biospecimens for pharmacokinetic and pharmacodynamic analyses. The 
clinical trial protocol specifies detailed Standard Operating Procedures (SOP) for the Frozen 
Tumor collection and handling. Tumor samples will be frozen within 5 min of collection. 
Samples will be transferred to a -80°C freezer or liquid nitrogen tank for storage until shipment 
to the Mellinghoff Laboratory.  
 
Sample Processing and Batching: Dr. Mellinghoff’s group will collect all samples, cut a 5 µM 
section from each specimen using a cryotome housed in the Mellinghoff Laboratory, and then 
perform H&E staining and histopathological review of each specimen. Only samples with a 
tumor cell content > 80 % as determined by a pathologist will be used for further analyses. 
Samples will be lysed in sample buffer with protease and phosphatase inhibitors which has been 
optimized by MesoScale Discovery to minimize decay of the protein and phosphosignal 
(http://www.mesoscale.com).  
 
In preliminary experiments, we have confirmed the stability of the analyte in EGFR amplified 
human glioblastoma xenograft tumor samples processed under similar conditions as the primary 
human tumor samples.  
 
EGFR amplified GBM xenografts and lysates from several human cancer cell lines, were used to 
establish the dilution linearity and robustness of the MSD assay. Lysates from multiple cancer 
cell lines (A431, COS-7, SKOV3) were included as MSD Assay Controls. Lysates were tested at 
4-fold dilutions to provide an assortment of various assay signal levels. Prior to lysis, cells were 
treated to induce tyrosine phosphorylation (positive control) or inhibit phosphorylation (negative 
control). 
 
Samples will be run on 96 well plates which have been pre-coated with antibodies against total 
EGFR and phosphorylated EGFR (tyrosine 1173), respectively. In our previous study (PMID: 
22588883), we used mesoscale plates which were coated with antibodies against EGFR and 
phospho-EGFR in two different quadrants of the same well. Because this approach can result in 
substrate competition which could jeopardize linearity and matrix tolerance, our future study will 
separate this assay into two plates, one plate coated with an antibody against total EGFR and one 
plate coated with an antibody against phospho-tyrosine 1173-EGFR. Each well will be loaded 
with 20 µg of total protein. 
 
All clinical trial samples will be run through the mesoscale electrochemiluminescent assay in a 
single batch. Residual samples will be aliquoted and frozen. All specimens will be handled and 
stored to minimize decay of the phospho-signal. Each well on the 96-well plate will be loaded 
with 20 µg of protein from tumor or cell line lysate. Samples from EGFR amplified GBM 
xenografts, that were used during assay development, will be included in the analysis.