MATCH Treatment Subprotocol Q: Ado-trastuzumab Emtansine in Patients With Tumors With HER2 Amplification (Except Breast and Gastric/Gastro-Esophageal Junction (GEJ) Adenocarcinomas)
Phase: PHASE2
Conditions: Advanced Lymphoma, Advanced Malignant Solid Neoplasm, Hematopoietic and Lymphoid Cell Neoplasm, Refractory Lymphoma, Refractory Malignant Solid Neoplasm, Refractory Multiple Myeloma
Sponsor: National Cancer Institute (NCI)

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EAY131-Q 
1 
Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol Q: Ado-trastuzumab 
Emtansine in Patients with Tumors with HER2 
Amplification (Except Breast and Gastric/Gastro-
Esophageal Junction (GEJ) Adenocarcinomas) 
ADO-TRASTUZUMAB EMTANSINE TREATMENT 
SUBPROTOCOL CHAIR: 
, MD, FACP 
ADO-TRASTUZUMAB EMTANSINE TREATMENT 
SUBPROTOCOL CO-CHAIR: 
, MD 
ADO-TRASTUZUMAB EMTANSINE 
TRANSLATIONAL CHAIR: 
, MD 
Version Date:  February 28, 2020 
NCI Update Date:  August 12, 2015 
NOTE: This subprotocol (EAY131-Q) should be 
used in conjunction with the MATCH 
Master Protocol (EAY131). 
NOTE: As of 11/17, all protocol changes will be 
noted by addendum number. Please 
reference the activation memo for the 
addendum activation date 
SUBPROTOCOL ACTIVATION DATE 
August 12, 2015 (Incorporated in Addendum #1) 
Update #2 – 8/15 
Addendum #2 – 2/16 
Addendum #3 – 5/16 
Addendum #5 – 12/16 
Addendum #6 – 1/17 
Addendum #7 – 3/17 
Addendum #16 
Addendum #17 
Addendum #24 
Agent 
NSC# 
Supply 
Ado-trastuzumab emtansine 
780263 
NCI Supplied 
Rev. Add16 
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2 
Table of Contents 
Molecular Analysis for Therapy Choice (MATCH) ...................................................... i 
MATCH Treatment Subprotocol Q: Ado-trastuzumab Emtansine in Patients with 
Tumors with HER2 Amplification (Except Breast and Gastric/Gastro-
Esophageal Junction (GEJ) Adenocarcinomas) ................................................... 1 
Table of Contents ...................................................................................................... 2 
Schema ...................................................................................................................... 4 
1. Introduction ........................................................................................................ 5 
1.1 Supporting Preliminary Data ..................................................................... 7 
1.2 Ado-trastuzumab emtansine .................................................................... 7 
2. Selection of Patients ......................................................................................... 16 
2.1 Eligibility Criteria ..................................................................................... 16 
3. Ado-trastuzumab emtansine Treatment Plan .................................................. 18 
3.1 Administration Schedule ......................................................................... 18 
3.2 Adverse Event Reporting Requirements ................................................. 18 
3.3 Comprehensive Adverse Events and Potential Risks List (CAEPR) for Ado-
Trastuzumab Emtansine (NSC 780263) ................................................... 21 
3.4 Dose Modifications ................................................................................. 25 
3.5 Supportive Care ....................................................................................... 27 
3.6 Duration of Agent-specific treatment ..................................................... 28 
3.7 Duration of Follow-Up ............................................................................. 28 
4. Study Parameters .............................................................................................. 29 
4.1 Therapeutic Parameters for Ado-trastuzumab emtansine Treatment ... 29 
5. Drug Formulation and Procurement ................................................................. 31 
5.1 Ado-trastuzumab Emtansine (NSC 780263) ............................................ 32 
6. Translational Studies ......................................................................................... 34 
7. References ........................................................................................................ 34 
Appendix I  Actionable Mutations for Sub-Protocol EAY131-Q .............................. 38 
Appendix II  Patient Drug Information Handout and Wallet Card .......................... 39 
Appendix III  CS-MATCH-0012 ................................................................................. 41 
 
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Schema 
 
Long-Term Follow-Up
Ado-trastuzumab Emtansine 
administered at 3.6mg/kg 
intravenously every 3 weeks (+ 3 
days) until toxicity* or progerssion
Cycle = 21  days
Accrual Goal: 70
*Please refer to sections 3.4 and 3.6
 
Rev. 3/17 
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5 
1. 
Introduction 
The National Cancer Institute (NCI) - Molecular Analysis for Therapy Choice (MATCH) is 
a broad-based genetic pre-screening study to assign patients whose tumors harbor 
specific molecular abnormalities to relevant targeted therapies, regardless of tumor type. 
This trial aims to establish whether patients with tumor mutations, amplifications or 
translocations in one of the genetic pathways of interest are likely to derive clinical 
benefit (defined as objective response) if treated with agents targeting that specific 
pathway in a single-arm design.  It will also investigate whether agents proven or likely to 
have activity against a molecular alteration in one disease will exhibit similar activity in 
other diseases that have the same molecular alterations. This subprotocol focuses on 
evaluating ado-trastuzumab emtansine for patients with non-breast, non-gastric/gastro-
esophageal junction (GEJ) adenocarcinomas with HER2 amplification. 
The human epidermal growth factor receptor 2 (HER2) is a member of the HER or ErbB 
family of tyrosine kinases that consists of four members HER1 (ErbB1/EGFR), HER2 
(ErbB2), HER3 (ErbB3) and HER4 (ErbB4).  The HER receptors are transmembrane 
proteins with an extracellular domain, a hydrophobic membrane spanning region (except 
for HER3) and an intracellular tyrosine kinase domain1. Ligand binding to the receptor 
leads to conformational changes and dimerization thus activating the tyrosine kinase 
part of the receptor and stimulation of the downstream signaling pathways such as the 
Ras/Raf/mitogen-activated protein kinase (Ras/Raf/MAPK) and phosphatidylinositol-3 
kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathways 
which ultimately leads to cell proliferation and survival2. In the case of HER2, activation 
is thought to occur predominantly in a ligand-independent manner, particularly when the 
receptor is found to be mutated or overexpressed.  Of note, in normal cells there are 2 
copies of the ERbB2 gene but in HER2 amplified cells, there may be as many as 100 
gene copies per tumor cell2-4. This gene amplification leads to HER2 overexpression 
both at the mRNA and protein level enabling homo (HER2:HER2) and 
heterodimerization (HER2:HER3) finally causing constitutive activation of growth factor 
signaling pathways.  In fact, HER2, the preferred partner for heterodimerization, has the 
strongest catalytic kinase activity among all four members and serves as an oncogenic 
driver1. HER2 therefore serves as a key target for HER2-directed therapy. 
Around 20% of breast cancers exhibit HER2 amplification and/or overexpression, 
presenting with an aggressive breast cancer phenotype and prior to the introduction of 
trastuzumab (a humanized monoclonal anti-HER2 antibody), a poor prognosis5,6. 
Similarly, HER2 amplification has also been linked with chemoresistance and overall 
poor survival in cervical, endometrial and ovarian cancers7. On the contrary, while 20% 
of gastric cancers and cancers of the GEJ also exhibit HER2 amplification and/or 
overexpression, studies have yielded inconsistent results regarding the prognostic role 
of HER2 amplification/overexpression in gastric cancer8,9. 
HER2 is also overexpressed in several other human solid tumors including and not 
limited to, ovarian, endometrial, colon, bladder, prostate, colon, cervical and non-small 
cell lung cancer  (Figure 1 and Table 1)20. Inhibition of this pathway can therefore have a 
potential therapeutic value in these tumors compared to tumors that lack HER2 
amplification. It is therefore hoped that ado-trastuzumab emtansine, a novel antibody 
drug-conjugate will be active for this group of patients and is being investigated in this 
subprotocol of the NCI-MATCH trial. 
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Figure 1: ERBB2 Alteration Frequency in Solid Tumors (www.cBioPortal.org) 
Table 1: HER2 aberrations in cancer 20. 
Cancer 
Incidence of HER2 positivity 
(3+ immunohistochemistry 
and/or amplification) 
Bladder 
5–15% 
Breast 
∼20% 
Cervix 
1–21% 
Cholangio-carcinoma 
1–8% 
Colorectal 
2–3% 
Endometrium 
8–35% 
Esophagus 
4–22% 
Gastric 
22% 
Germ Cell 
5–8% 
Glioblastoma 
7–15% 
Head and neck 
3% 
Liver 
2.40% 
Melanoma 
0–5% 
Lung (NSCLC) 
1–6% 
Osteosarcoma 
Uncommon 
Ovary 
6–7% 
Pancreas 
2–29% 
Prostate 
Uncommon 
Renal cell carcinoma 
Uncommon 
Salivary duct 
15–37% 
Soft tissue sarcoma 
Uncommon 
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1.1 
Supporting Preliminary Data  
Four HER2-directed therapies have been approved to date for HER2 amplified 
breast cancer. Trastuzumab was the first anti-HER2 directed therapy to be 
approved by the Food and Drug Administration (FDA) in the late 1990’s based on 
improved clinical benefit and overall survival in patients with metastatic breast 
cancer. Later, in 2005 trastuzumab in combination with chemotherapy was 
approved in the adjuvant setting for early stage HER2-positive breast cancer. 
Despite these significant advances, both de novo and acquired trastuzumab 
resistance occurs. Approximately 15 percent of women develop metastatic breast 
cancer (MBC) despite trastuzumab-based adjuvant therapy10. This has led to the 
development of other HER2 directed therapies. Lapatinib, a potent small 
molecule dual tyrosine kinase inhibitor of HER2 and epidermal growth factor 
receptor (EGFR), was approved by the United States Food and Drug 
Administration (FDA) in 2007 either in combination with capecitabine or 
trastuzumab for patients with HER2 positive MBC following disease progression 
on trastuzumab11-14.  In 2012, pertuzumab, a monoclonal antibody that binds sub-
domain II of the HER2 extracellular domain and blocks HER2 dimerization and 
signaling, was approved in combination with trastuzumab and docetaxel in the 
first-line setting for HER2-positive MBC15,16. 
One novel approach in the development of new HER2 targeted therapies has 
been the development of HER2-directed antibody-drug conjugates (ADCs)17. 
ADCs are cytotoxic drugs that are connected by chemical linkers to monoclonal 
antibodies specific for a tumor-associated antigen. ADCs are designed to 
preferentially deliver a cytotoxic drug to cancer cells while minimizing exposure to 
normal tissues, thus improving the therapeutic index18. Ado-trastuzumab 
emtansine is an ADC that was approved by the FDA in 2013 based on the pivotal 
results of the phase III, second-line EMILIA trial that demonstrated a survival 
benefit in favor of ado-trastuzumab emtansine compared to FDA-approved 
comparator of capecitabine plus lapatinib19. 
1.2 
Ado-trastuzumab emtansine 
Ado-trastuzumab emtansine consists of trastuzumab covalently bound via a 
thioether linker, [N-maleimidomethyl] cyclohexane-1-carboxylate (MCC), to the 
cytotoxic agent, DM1, a derivative of maytansine. DM1 is a highly potent 
antimitotic drug that binds to microtubules in a similar way to that of vinca 
alkaloids 17,21,22. Vinca alkaloids have demonstrated synergy with trastuzumab 23. 
Ado-trastuzumab emtansine binds to the extracellular domain of HER2 and the 
complex is then internalized into the cell. The antibody is degraded by proteases 
and the active metabolite, lysine-Nε –MCC-DM1 is released into the cytoplasm 21. 
This metabolite is a charged molecule and is relatively membrane impermeable. 
This reduces the chance that DM1 can enter a neighboring cell and limits the 
possibility of non-specific toxicity 21. Ado-trastuzumab emtansine also retains the 
effector functions of trastuzumab: inhibition of HER2-mediated signal transfusion 
and activation of antibody dependent cellular cytotoxicity 21,24. 
1.2.1 
Preclinical Studies 
Preclinical trials initially demonstrated synergistic or additive 
interactions of trastuzumab with a variety of antimicrotubulin agents, 
including maytansines. Because initial trials with maytansine proved 
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to be associated with intolerable side effects such as nausea and 
peripheral neuropathy, cell culture and animal work were geared 
towards developing an ADC with trastuzumab and maytansinoids25. 
Maytansinoids, derivatives of maytansine, bind directly to 
microtubules in a manner similar to the vinca alkaloids. Trastuzumab 
linked to DM1 through a nonreducible thioether linkage (MCC), 
displayed superior activity compared with unconjugated trastuzumab 
or trastuzumab linked to other maytansinoids through disulfide linkers. 
Serum concentrations of trastuzumab-MCC-DM1 remained elevated 
compared with other conjugates, and toxicity in rats was negligible 
compared with free DM1 or trastuzumab linked to DM1 through a 
reducible linker. Potent activity was observed on all HER2-
overexpressing tumor cells, whereas nontransformed cells and tumor 
cell lines with normal HER2 expression were unaffected. In addition, 
ado-trastuzumab emtansine was active in HER2-overexpressing, 
trastuzumab-refractory and lapatinib-refractory cell lines and tumors24. 
In vitro studies showed that ado-trastuzumab emtansine and 
trastuzumab have similar binding affinities for HER2. After binding, it 
is postulated that the ado-trastuzumab emtansine –HER2 complex is 
endocytosed and degraded in lysosomes, resulting in the release of 
an active metabolite, Lys-MCC-DM1 and induces a direct cytotoxic 
effect via direct release of adenylate kinase, PARP cleavage, and 
caspase 3/7 activation. ado-trastuzumab emtansine has also been 
shown to retain the same mechanisms of action of unconjugated 
trastuzumab. These include inhibition of the HER3/phosphoinositide 
3-kinases (PI3K)/AKT signaling pathway, inhibition of HER2 shedding, 
and Fcy receptor-mediated engagement of immune cells, which may 
result in antibody-dependent cellular cytotoxicity24,25. 
In conclusion, because trastuzumab linked to DM1 through a 
nonreducible linker offered improved efficacy and pharmacokinetics 
and reduced toxicity over the reducible disulfide linkers evaluated, T-
MCC-DM1 (ado-trastuzumab emtansine) was selected for clinical 
development. 
1.2.2 
Clinical Pharmacology of Ado-trastuzumab emtansine 
The half-life of ado-trastuzumab emtansine is approximately 3.5-4 
days and there is no significant accumulation of ado-trastuzumab 
emtansine when given every 3 weeks. The level of free DM1 in the 
plasma is very low (average of approximately 5 ng/mL) throughout the 
treatment cycle, which is likely related to the favorable toxicity profile 
of ado-trastuzumab emtansine. Pre-treatment residual levels of 
trastuzumab have not been shown to influence the pharmacokinetics 
(PK) or clinical efficacy of ado-trastuzumab emtansine 26,27. 
Maximum distributions (Cmax) of the ado-trastuzumab emtansine and 
DM1 have been observed close to the end of the infusion. In vitro 
studies have indicated that DM1 undergoes metabolism by CYP 
3A4/5. DM1 does not inhibit or induce major CYP450 enzymes in 
vitro. In human plasma, ado-trastuzumab emtansine catabolites MCC-
DM1, Lys-MCC-DM1 and DM1 have been detected at low levels 28.  
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A population PK analysis on 671 patients revealed that body weight, 
sum of longest diameter of target lesions by RECIST, HER2 
extracellular domain (ECD) concentrations, AST, albumin and 
baseline trastuzumab concentrations were identified as statistically 
significant covariates for ado-trastuzumab emtansine clearance. 
However, the magnitude of effect of these covariates on ado-
trastuzumab emtansine exposure suggests that, with the exception of 
body weight, these covariates are unlikely to have a clinically 
meaningful effect on KADCYLA exposure. Therefore, the body weight 
based dose of 3.6 mg/kg every 3 weeks without correction for other 
covariates is considered appropriate 28. The PK of ado-trastuzumab 
emtansine are not affected by mild to moderate renal impairment.  
The effect of multiple doses of ado-trastuzumab emtansine (3.6 mg/kg 
every 3 weeks) on the QTc interval was evaluated in an open-label, 
single-arm study of 51 patients with HER2-positive MBC. No large 
changes in the mean QT interval (>20 msec) were observed in this 
study 28. 
1.2.3 
Clinical trials of ado-trastuzumab emtansine in the metastatic setting 
1.2.3.1 
Phase I Studies of ado-trastuzumab emtansine 
Ado-trastuzumab emtansine was initially evaluated as a 
single agent in a phase I dose escalation study in 24 
patients with trastuzumab-refractory HER2+ MBC 
(TDM3569g) 22. Weekly and every-3-week dosing 
schedules were tested. The maximum tolerated dose 
(MTD) for the 3-week regimen was determined to be 3.6 
mg/ kg. Ado-trastuzumab emtansine was well tolerated 
and the most common adverse events (AEs) were 
thrombocytopenia, elevated transaminases, fatigue, 
anemia, and nausea 22. In the 3-week regimen, the 
objective response rate (ORR) was 44% in patients treated 
at the MTD and was comparable to patients treated on the 
weekly regimen (40%). Subsequently, the every-3-week 
schedule has been utilized in the majority of subsequent 
studies, largely due to the convenience for patients 22,26. 
1.2.3.2 
Phase II Studies of ado-trastuzumab emtansine 
Ado-trastuzumab emtansine monotherapy has been 
studied in two single arm phase II trials (TDM4258g and 
TDM4374g). TDM4258g evaluated ado-trastuzumab 
emtansine at 3.6 mg/kg every 3 weeks for patients with 
HER2-positive MBC who had progressed on at least one 
line of HER2-directed therapy. A total of 112 patients with 
a median of 8 (range 2-19) prior anticancer agents in all 
settings were enrolled. The primary endpoint, ORR, was 
25.9% (95% confidence interval [CI], 18.4% to 34.4%). 
Median PFS was 4.6 months (95% CI, 3.9 to 8.6 months), 
and median duration of response (DOR) was not reached. 
In a post hoc exploratory analysis, the ORR in patients 
who had received prior lapatinib and trastuzumab was not 
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significantly different than the overall ORR, suggesting that 
ado-trastuzumab emtansine has activity after progression 
on prior HER2-directed therapies 29. 
TDM4374g enrolled 110 patients who had previously 
received trastuzumab, lapatinib, capecitabine, a taxane, 
and an anthracycline for HER2-positive breast cancer and 
had progressed on at least two HER2-directed agents in 
the metastatic or locally advanced setting30. This was in 
contrast to TDM4258g, which only required that patients 
had received and progressed on at least one prior HER2-
directed therapy and had received at least one 
chemotherapy regimen in the metastatic setting 29. In 
TDM4374g, all patients were heavily pretreated with a 
median of 7 (range 3-17) anticancer agents in the 
metastatic setting. The ORR was 34.5% (95% CI, 26.1% to 
43.9%) with a median PFS of 6.9 months (95% CI, 4.2 to 
8.4 months) and a CBR of 48.2% (95% CI, 38.8% to 
57.9%). This confirmed the single agent activity of ado-
trastuzumab emtansine in the metastatic setting 30 . 
The TDM4450g study was a phase II trial in which 137 
patients with previously untreated HER2-positive 
metastatic or locally advanced breast cancer were 
randomized to ado-trastuzumab emtansine or trastuzumab 
plus docetaxel. The primary endpoints were PFS and 
safety. PFS was significantly longer in patients receiving 
ado-trastuzumab emtansine compared with those receiving 
trastuzumab plus docetaxel (14.2 months vs 9.2 months, 
HR 0.59; 95% CI, 0.36 to 0.97; P=.035). Patients receiving 
ado-trastuzumab emtansine had fewer grade ≥3 AEs 
compared with the trastuzumab plus docetaxel group 
(46.4% vs 90%). Of note, only 27.1% of the patients in the 
trastuzumab plus docetaxel group and 17.9% of the 
patients in the ado-trastuzumab emtansine group had 
received trastuzumab in the neoadjuvant or adjuvant 
setting 31. 
Encouraged by the synergistic activity noted in xenograft 
models, the combination of ado-trastuzumab emtansine 
plus pertuzumab was evaluated in a phase Ib/II clinical trial 
(TDM4373g). The safety and efficacy of ado-trastuzumab 
emtansine plus pertuzumab in 64 patients with HER2-
positive locally advanced or MBC was assessed. Patients 
received the combination either in the first-line or relapsed 
setting (defined as progression on prior HER2 therapy for 
MBC). Patients with advanced MBC had received 
trastuzumab and a median of 6 prior nonhormonal 
treatments for MBC. 86% of patients receiving ado-
trastuzumab emtansine in the first line MBC setting had 
receiving trastuzumab in the neoadjuvant or adjuvant 
setting. The ORR was 41% overall: 33% in patients with 
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advanced MBC and 57% in first line patients. Median OS 
was 6.6 months, 5.5 months and 7.7 months in the overall, 
advanced MBC and first line MBC settings, respectively. 
The combination was deemed to be safe and tolerable. 
The most common adverse events (AEs) were fatigue, 
nausea and diarrhea. The most frequent grade ≥3 AEs 
were thrombocytopenia, fatigue and liver enzyme 
elevations. One patient had a left ventricular ejection 
fraction (LVEF) of less than 40% after study drug 
discontinuation 32. 
1.2.3.3 
Phase III Studies of ado-trastuzumab emtansine 
Ado-trastuzumab emtansine was subsequently evaluated 
in two large, randomized studies. The pivotal EMILIA study 
was a phase III, international trial in patients with locally 
advanced or metastatic, centrally confirmed, HER2-
positive breast cancer. Patients had previously received a 
taxane and trastuzumab and had progressed on their most 
recent treatment in the locally advanced or metastatic 
setting or within 6 months of completion of adjuvant 
trastuzumab for early-stage disease. A total of 991 patients 
were randomized 1:1 to ado-trastuzumab emtansine (3.6 
mg/kg every 3 weeks) or to lapatinib (1250 mg daily) and 
capecitabine (2000 mg/m2 days 1-14). The primary 
endpoints were PFS and OS. Treatment with ado-
trastuzumab emtansine significantly improved median PFS 
compared with lapatinib plus capecitabine (9.6 vs 6.4 
months; hazard ratio [HR] 0.65; 95% CI, 0.55 to 0.77; 
P<.001). OS also favored ado-trastuzumab emtansine 
(30.9 vs 25.1 months, HR 0.68; 95% CI, 0.55 to 0.85; 
P<.001). ORR and DOR were superior in patients treated 
with ado-trastuzumab emtansine. Serious AEs were 
reported for 18% of patients in the lapatinib-capecitabine 
group versus 15.5% in the ado-trastuzumab emtansine 
group. There were more grade ≥3 AEs in the lapatinib-
capecitabine group versus in the ado-trastuzumab 
emtansine group (57% vs 40.8%). The most commonly 
reported grade 3 or 4 AEs were diarrhea and palmar-
plantar erythrodysesthesia in the lapatinib-capecitabine 
group and thrombocytopenia and elevated transaminases 
in the ado-trastuzumab emtansine group 33. The results of 
the EMILIA study led to the FDA approval of ado-
trastuzumab emtansine in February 2013 for patients with 
HER2-positive MBC 22. 
The TH3RESA trial evaluated the efficacy and safety of 
ado-trastuzumab emtansine in comparison with treatment 
of physician’s choice (TPC) in 602 patients with MBC or 
unresectable locally advanced/recurrent HER2-positive 
breast cancer who had received at least two prior HER2-
directed therapies, including trastuzumab and lapatinib. 
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602 patients were randomly assigned in a 2:1 ratio to ado-
trastuzumab emtansine versus TPC. The PFS was 
significantly improved with ado-trastuzumab emtansine 
compared with TPC (6.2 months versus 3.3, months, 
stratified HR 0.528 [0.422-0.661], P<0.0001). Interim 
overall survival showed a trend favoring ado-trastuzumab 
emtansine (stratified HR 0.552 [95% CI 0.369-0.836], 
P=0.0034) but stopping boundary was not crossed. There 
was a lower incidence of grade ≥ 3 adverse events 
reported with ado-trastuzumab emtansine compared to 
TPC. Neutropenia, diarrhea and febrile neutropenia were 
more common in the TPC arm and thrombocytopenia was 
more common in the ado-trastuzumab emtansine arm 34.   
1.2.3.4 
Other Studies of ado-trastuzumab emtansine 
Multiple trials of ado-trastuzumab emtansine in various 
combinations are ongoing. After the promising results of 
the TDM4373g study, the MARIANNE study is a 
randomized, 3-arm, multicenter, phase III study that is 
evaluating the efficacy and safety of ado-trastuzumab 
emtansine with pertuzumab in patients with HER2-positive 
progressive or recurrent locally advanced or previously 
untreated MBC (NCT01120184). Patients were 
randomized to one of the three cohorts: ado-trastuzumab 
emtansine with pertuzumab, ado-trastuzumab emtansine 
with pertuzumab-placebo (blinded for pertuzumab), or 
trastuzumab combined with a taxane. This trial has 
completed enrollment 35.   
The KATHERINE Trial is a phase III trial evaluating 
adjuvant ado-trastuzumab emtansine versus trastuzumab 
in HER2+ breast cancer with residual tumor in breast or 
axillary lymph nodes following neoadjuvant therapy, with 
the primary endpoint being disease-free survival (DFS). 
The trial is currently recruiting 36. 
1.2.4 
Ado-trastuzumab emtansine in gastric cancer 
National clinical trials of ado-trastuzumab emtansine in gastric cancer 
are available (NCT01641939, NCT01702558). 
1.2.5 
Safety of ado-trastuzumab emtansine 
Overall, ado-trastuzumab emtansine is well tolerated with a relatively 
low rate of clinically significant AEs 26,37. A pooled analysis of toxicity 
data from 884 patients treated in seven studies (six clinical ‘parent’ 
studies and one extension study) with single agent ado-trastuzumab 
emtansine at 3.6 mg/kg every 3 weeks found that the most commonly 
reported all-grade AEs were fatigue (46.4%), nausea (43.0%), 
thrombocytopenia (32.2%), headache (29.4%), and constipation 
(26.5%) 38,39. The most common grade 3 to 4 AEs were the laboratory 
abnormalities of thrombocytopenia (11.9%) and increased AST serum 
concentration (4.3%). These were manageable and not generally 
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associated with clinical symptoms. Other grade ≥ 3 AEs occurring in  
≥ 2% of patients included fatigue (3.2%), hypokalemia (3.3%), 
increased ALT (3.1%) and anemia (2.9%). There were 12 AE-related 
deaths (hepatic failure; hepatic failure and encephalopathy; hepatic 
function abnormal; bacterial sepsis; neutropenic sepsis; pneumonia 
(n=2); metabolic encephalopathy; respiratory failure (n=2); interstitial 
lung disease (ILD); and sudden death). AEs resulted in dose 
reductions in 17.2% of patients and drug discontinuations in 7.0% 
38,39. It is important to note that up to two dose modifications (3.0 
mg/kg and 2.4 mg/kg) are allowed with ado-trastuzumab emtansine 
treatment. After two dose reductions, any further requirements for 
dose reductions should result in discontinuation of ado-trastuzumab 
emtansine 28,38,39. 
Table 2: Most common AEs (> 20% incidence in single agent trials) reported in clinical 
trials of ado-trastuzumab emtansine.  
 
a. 
Patients were treated with 0.3-4.8 mg/kg every 3 weeks. This trial also included a separate cohort 
of a weekly regimen, which is not reported here.  
b. 
TDM4450g compared ado-trastuzumab emtansine (n=67) versus trastuzumab plus docetaxel (HT) 
(n=70). Only the ado-trastuzumab emtansine arm is reported here. 67 patients were enrolled in the 
ado-trastuzumab emtansine arm but two patients in the HT arm mistakenly received a dose of 
ado-trastuzumab emtansine and were included in the ado-trastuzumab emtansine safety analyses.  
c. 
TDM4373g compared ado-trastuzumab emtansine with pertuzumab. The AEs reported here are of 
the combination regimen. This trial consisted of a dose escalation (n=9) and dose expansion 
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(n=58) phase. Data reported for the 6 out of 9 patients treated in dose escalation phase (3.0 mg/kg 
dose not included). Study only reports Grade ≥2 AEs and higher.  
d. 
EMILIA compared ado-trastuzumab emtansine (n=490) versus lapatinib plus capecitabine 
(n=488). Only the ado-trastuzumab emtansine arm is reported here. 
e. 
TH3RESA compared ado-trastuzumab emtansine (n=404) to treatment of physician’s choice 
(N=198). Safety data for 403 patients provided. Only the ado-trastuzumab emtansine arm is 
reported here. 
f. 
One patient required a dose reduction for neuropathy but exact grade is not known. 
NR: Not reported 
1.2.6 
Adverse Events of Special Interest 
AEs of Special Interest are defined as a potential safety problem, 
identified as a result of safety monitoring of ado-trastuzumab 
emtansine. 
The trastuzumab emtansine Events of Special Interest are: 
• 
Cardiac events (LVEF < 40% or symptomatic CHF, Grade ≥ 3 left 
ventricular systolic dysfunction._ 
Cardiotoxicity has been carefully studied in patients receiving ado-
trastuzumab emtansine because of the cardiac toxicity of 
trastuzumab, and a boxed warning for left ventricular dysfunction 
exists for ado-trastuzumab emtansine [26, 40]. In the pooled 
safety analysis, four patients (0.5%) had a baseline LVEF < 40%, 
and 16 patients (1.8%) had LVEF decline ≥ 15 percentage points 
from baseline to below 50%. A total of 4 patients discontinued 
ado-trastuzumab emtansine because of cardiac disorders (atrial 
fibrillation, n=1; left ventricular dysfunction, n=1; and decreased 
EF, n=2) [26, 38, 39]. The incidence of cardiac dysfunction may be 
underestimated as patients with cardiac toxicity secondary to 
trastuzumab or severe cardiac disease were excluded from 
enrollment [39]. The effect of multiple doses of ado-trastuzumab 
emtansine (3.6 mg/kg every 3 weeks) on the QTc interval was 
evaluated in an open label, single arm study in 51 patients with 
HER2-positive MBC. No large changes in the mean QT interval 
(i.e. > 20 msec) were detected in the study [28]. 
• 
Thrombocytopenia (Grade ≥ 3) 
Thrombocytopenia is typically grade 1 or 2 and rapidly reversible, 
and has generally not been associated with clinically significant 
bleeding [22, 26]. Platelet counts can start to decline as soon as 
24 hours after dosing, nadir around day 8, and recover by day 15 
[22]. In approximately 20% of patients, platelet counts do not 
completely recover to baseline after repeated dosing [26, 38]. 
• 
Hepatic events  
Serious hepatobiliary disorders, including fatal cases of severe 
drug-induced liver injury and associated hepatic encephalopathy, 
have been reported; as such, the prescribing information for ado-
trastuzumab emtansine includes a boxed warning for 
hepatotoxicity [40, 41]. Rare cases of nodular regenerative 
hyperplasia (NRH) have also been described [26, 40]. NRH is a 
rare liver disorder characterized by a widespread transformation of 
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the hepatic parenchyma into small regenerative nodules and can 
result in noncirrhotic portal hypertension [42]. NRH can only be 
diagnosed by a liver biopsy and should be considered in any 
patient receiving ado-trastuzumab emtansine who develops signs 
and/or symptoms of portal hypertension but with normal 
transaminases and no manifestations of cirrhosis. [42]. Ado-
trastuzumab emtansine should be discontinued if NRH develops 
[26, 42]. 
• 
Infusion Associated Reactions, Hypersensitivity 
• 
Embryofetal Toxicity or Birth Defects 
• 
Pregnancies 
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2. 
Selection of Patients 
Each of the criteria in the checklist that follows must be met, along with the eligibility in 
the MATCH Master Protocol, in order for a patient to be considered eligible for this 
study. Use the checklist to confirm a patient’s eligibility. For each patient, this checklist 
must be photocopied, completed and maintained in the patient’s chart.  
In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0. Therefore, if a test is done on a Monday, the Monday 
four weeks later would be considered Day 28.  
ECOG-ACRIN Patient No. ____________________________ 
Patient’s Initials (L, F, M) _______________________ 
Physician Signature and Date ___________________ 
NOTE: 
Policy does not allow for the issuance of waivers to any protocol specified 
criteria (http://ctep.cancer.gov/protocolDevelopment/policies deviations.htm). 
Therefore, all eligibility criteria listed in Section 2 must be met, without 
exception. The registration of individuals who do not meet all criteria listed in 
Section 2 can result in the participant being censored from the analysis of the 
study, and the citation of a major protocol violation during an audit. All 
questions regarding clarification of eligibility criteria must be directed to the 
Group's Executive Officer (EA.Execofficer@jimmy.harvard.edu) or the 
Group's Regulatory Officer (EA.RegOfficer@jimmy.harvard.edu). 
NOTE: 
Institutions may use the eligibility checklist as source documentation if it has 
been reviewed, signed, and dated prior to registration/randomization by the 
treating physician. 
NOTE: 
All patients must have signed the relevant treatment consent form 
2.1 
Eligibility Criteria  
2.1.1 
Patients must fulfill all eligibility criteria outlined in Section 3.1 of 
MATCH Master Protocol. (excluding Section 3.1.6) at the time of 
registration to treatment step (Step 1, 3, 5, 7). 
2.1.2 
Patients’ tumor sample must have HER2 amplification > 7 based on 
targeted custom Ampliseq panel on the Ion Torrent PGM. See 
Appendix I for a list of the ERBB2 amplifications and corresponding 
Levels of Evidence. 
2.1.3 
Adequate hematologic function as defined by:  
• 
Hemoglobin ≥ 9.0g/dL (which may be reached by transfusion) 
Hemoglobin level _________ 
Date of Test: ___________ 
2.1.4 
Patients will be allowed if on anticoagulation (except warfarin and 
other coumarin derivatives) or on aspirin 81 mg by mouth daily. 
Additional monitoring while on anticoagulation will be based on 
institutional guidelines and/or physician discretion. However, patients 
will not be allowed if on long acting anti-platelet agents such as 
clopidogrel. 
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2.1.5 
Patients must have an electrocardiogram (ECG) within 4 weeks prior 
to treatment assignment and must have no clinically important 
abnormalities in rhythm, conduction or morphology of resting ECG 
(e.g. complete left bundle branch block, third degree heart block). 
Date:  _______________ 
2.1.6 
Patients must have ECHO or nuclear study (MUGA or First Pass) 
within 4 weeks prior to registration to treatment and must not have a 
left ventricular ejection fraction (LVEF) < 50% to be eligible. 
Date of ECHO/nuclear study:  _______________ 
2.1.7 
Patients with a diagnosis of Breast cancer or gastric/GEJ cancer will 
be excluded. 
2.1.8 
Patients must not have known hypersensitivity to ado-trastuzumab 
emtansine or compounds of similar chemical or biologic composition. 
2.1.9 
Patients with current peripheral neuropathy of Grade 3 or greater 
(NCI-CTC, version 4.0) will be excluded. 
Neuropathy assessment and grade assignment will be based on 
history (location, duration, balance and gait, effect on activity of daily 
living (ADLs)) and physical exam. 
2.1.10 
Patient must not have had any of the prior therapies: 
• 
FDA approved: 
Trastuzumab 
Pertuzumab 
Ado-trastuzumab emtansine 
• 
Investigational: 
Margetuximab 
PF-05280014 (Pfizer, Trastuzumab Biosimilar) 
CT-P6 (Celltrion, Trastuzumab Biosimilar) 
ABP-980 (Amgen, Trastuzumab Biosimilar) 
2.1.11 
Women of childbearing potential and men must agree to use 
adequate contraception (hormonal or barrier method of birth control; 
abstinence) prior to study entry, for the duration of study participation, 
and for 7 months after completion of study. 
 
 
 
 
 
 
Physician Signature 
 
Date 
OPTIONAL: 
This signature line is provided for use by institutions wishing to 
use the eligibility checklist as source documentation. 
 
Rev.2/16 
Rev. 2/16 
Rev. 2/16 
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18 
3. 
Ado-trastuzumab emtansine Treatment Plan 
3.1 
Administration Schedule 
Ado-trastuzumab emtansine will be administered 3.6 mg/kg intravenously every 3 
weeks (±3 days) on a 21 day schedule until toxicity or progression in an 
outpatient setting. The dose should be calculated based on the patient's weight 
(kg) as measured every cycle, prior to treatment. 
3.2 
Adverse Event Reporting Requirements 
The Adverse Event Reporting Requirements for all EAY131 subprotocols are 
outlined in the MATCH MASTER protocol.  Please refer to those guidelines when 
determining if an event qualifies as a Serious Adverse Event (SAE) and requires 
expedited reporting via CTEP’s Adverse Event Reporting System (CTEP-AERS). 
In addition, the following section outlines agent specific requirements and must 
be followed to ensure all reporting requirements are met. 
3.2.1 
Additional instructions, requirements and exceptions for EAY131 – 
Subprotocol Q 
Additional Instructions 
For instructions on how to specifically report events that result in 
persistent or significant disability/incapacity, congenital anomaly, or 
birth defect events via CTEP-AERS, please contact the AEMD Help 
Desk at aemd@tech-res.com  or 301-897-7497.  This will need to be 
discussed on a case-by-case basis. 
 
EAY131 – Subprotocol Q specific expedited reporting 
requirements: 
• 
Thrombocytopenia:  All ≥ grade 3 thrombocytopenia must be 
reported via CTEP-AERS according to the timeframes outlined in 
the AE table in section 5.3.6 of the MATCH Master protocol 
• 
Cardiac Changes: All ≥ grade 3 cardiac events must be 
reported via CTEP-AERS according to the timeframes outlined in 
the AE table in section 5.3.6 of the MATCH Master protocol 
• 
Liver Chemistry Changes:  If any of the following 
circumstances occur, the event(s) must be reported via CTEP-
AERS according to the timeframes outlined in the AE table in 
section 5.3.6 of the MATCH Master protocol 
o ≥ Grade 3 ALT or AST 
o ≥ Grade 3 total bilirubin  
o Any grade drug inducted liver injury 
• 
Infusion Associated Reactions, Hypersensitivity:  Any grade 
infusion associated reaction/hypersensitivity must be reported via 
CTEP-AERS according to the timeframes outlined in the AE table 
in section 5.3.6 of the MATCH Master protocol 
 
Rev.2/16 
Rev.3/17 
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• 
Pregnancies:  Pregnancies and suspected pregnancies 
(including a positive or inconclusive pregnancy test, regardless of 
age or disease state) occurring while the female patient is on 
ado-trastuzumab emtansine, or within 7 months of the female 
patient’s last dose of ado-trastuzumab emtansine, are 
considered immediately reportable events. A female partner of a 
male patient who becomes pregnant within 7 months of the 
male’s last dose of ado-trastuzumab emtansine is also 
considered a reportable event. The pregnancy, suspected 
pregnancy, or positive/ inconclusive pregnancy test must be 
reported via CTEP-AERS within 24 hours of the Investigator’s 
knowledge.  Please refer to Appendix VIII in MATCH Master 
protocol for detailed instructions on how to report the occurrence 
of a pregnancy as well as the outcome of all pregnancies. 
NOTE: 
The timeframes and requirements for reporting 
pregnancies on this study is longer than the standard 
28 days as stated in Appendix VIII of the MATCH 
Master Protocol.  Please note on this study, 
pregnancies must be reported if they occur within 7 
months of the subjects last dose of ado-trastuzumab 
emtansine. 
 
EAY131 – Subprotocol Q specific expedited reporting 
exceptions: 
For Subprotocol Q, the adverse events listed below do not require 
expedited reporting via CTEP-AERS: 
• 
If an AE meets the reporting requirements of the protocol, and it 
is listed on the SPEER, it should ONLY be reported via CTEP-
AERS if the grade being reported exceeds the grade listed in the 
parentheses next to the event.  
3.2.2 
Second Primary Cancer Reporting Requirements 
All cases of second primary cancers, including acute myeloid 
leukemia (AML) and myelodysplastic syndrome (MDS), that occur 
following treatment on NCI-sponsored trials must be reported to 
ECOG-ACRIN using Medidata Rave 
• 
A second malignancy is a cancer that is UNRELATED to any 
prior anti-cancer treatment (including the treatment on this 
protocol).  Second malignancies require ONLY routine reporting 
as follows: 
1. Complete a Second Primary Form in Medidata Rave within 14 
days. 
2. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave confirming the diagnosis. 
3. If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
via Medidata Rave. 
Rev. 2/16 
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• 
A secondary malignancy is a cancer CAUSED BY any prior anti-
cancer treatment (including the treatment on this protocol). 
Secondary malignancies require both routine and expedited 
reporting as follows: 
1. Complete a Second Primary Form in Medidata Rave within 14 
days 
2. Report the diagnosis via CTEP-AERS at http://ctep.cancer.gov  
3. Report under a.) leukemia secondary to oncology 
chemotherapy, b.) myelodysplastic syndrome, or c.) treatment 
related secondary malignancy 
4. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave and submit a copy to NCI/CTEP confirming the 
diagnosis. 
5. If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
via Medidata Rave and submit a copy to NCI/CTEP. 
NOTE: 
The Second Primary Form and the CTEP-AERS report 
should not be used to report recurrence or development of 
metastatic disease. 
NOTE: 
If a patient has been enrolled in more than one NCI-
sponsored study, the Second Primary Form must be 
submitted for the most recent trial. ECOG-ACRIN must be 
provided with a copy of the form and the associated 
pathology report and cytogenetics report (if available) even 
if ECOG-ACRIN was not the patient's most recent trial. 
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NCI Update Date: August 12, 2015 
24 
4 Infusion related reaction, which may manifest as flushing, chills, fever, dyspnea, hypotension, wheezing, 
bronchospasm, and tachycardia, have been observed. 
5 Encephalopathy has been only observed in clinical trials ado-trastuzumab as hepatic encephalopathy in 
the context of hepatic failure. 
6 Serious hepatobiliary disorders including nodular regenerative hyperplasia (NRH) of the liver, some 
resulting in fatal liver failure, have been observed. 
7 Allergic reactions (hypersensitivity) including serious anaphylaxis have been observed. 
8 Infection may include any of the 75 infection sites under the INFECTIONS AND INFESTATIONS SOC. 
9 Peripheral neuropathy includes Peripheral motor neuropathy and Peripheral sensory neuropathy under 
the NERVOUS SYSTEM DISORDERS SOC. 
NOTE: 
Ado-trastuzumab emtansine 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. 
 
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3.4 
Dose Modifications  
All toxicity grades below are described using the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0. 
All appropriate treatment areas should have access to a copy of the CTCAE 
version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the 
CTEP website (http://ctep.cancer.gov). 
• 
Patients should be assessed for toxicity prior to each dose of ado-
trastuzumab emtansine; dosing will occur only if the clinical assessment and 
laboratory values are acceptable. 
• 
Dose reduction levels for ado-trastuzumab emtansine are described in Table 
3 below.  No re-escalation of ado-trastuzumab emtansine dose will be 
allowed. Patients requiring a dose reduction will be de-escalated one dose 
level with a maximum of two dose reductions allowed, following which further 
indication for dose reduction will result in the patient being taken off study as 
indicated below.  
Table 3: Dose Reduction levels of ado-trastuzumab emtansine 
DOSE LEVEL 
Ado-trastuzumab emtansine Dose 
0 
3.6mg/kg 
Dose -1 
3 mg/kg 
Dose -2 
2.4mg/kg 
Indication for further dose reduction 
Off ado-trastuzumab emtansine 
• 
In addition to the specific toxicities presented in the tables below, if a patient 
develops any other significant grade 3 or 4 toxicity thought to be related 
specifically to ado-trastuzumab emtansine, ado-trastuzumab emtansine will 
be held until the symptoms resolve to grade ≤ 1 or to the baseline grade.  
When treatment is resumed, the ado-trastuzumab emtansine dose should be 
modified according to the guidelines in Tables 4.1-4.5. If grade ≥ 3 toxicity 
persists for more than 14 days (with the exception of thrombocytopenia, refer 
to table 4.1) or recurs after the maximum dose reduction, the patient will 
discontinue ado-trastuzumab emtansine and come OFF STUDY. 
• 
Ado-trastuzumab emtansine should be permanently discontinued in patients 
with interstitial lung disease (ILD) or pneumonitis. 
• 
Dose modifications will be allowed only based on labs done on days 19-21 
conducted prior to the next treatment cycle and not for any nadir found mid-
cycle. See Study Calendar (Section 4.1) for protocol required lab schedule. 
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Table 4.1: 
Dose Modifications for Thrombocytopenia 
Adverse Event 
Ado-trastuzumab emtansine Dose 
Grade 1 Thrombocytopenia  
(< Lower limit of normal-75,000 mm3) 
No change; continue ado-trastuzumab emtansine dose at same 
dose and schedule.  
Grade 2 Thrombocytopenia  
(50,0000-< 75,000 mm3) 
Grade 3 Thrombocytopenia  
(25,000-< 50,000 mm3) 
Hold ado-trastuzumab emtansine up to 21 days until platelet 
count recovers to Grade ≤ 1 (75,000 mm3) and then treat at 
same dose level.  
Grade 4 Thrombocytopenia  
(< 25,000 mm3) 
Hold ado-trastuzumab emtansine up to 21 days until platelet 
count recovers to Grade ≤ 1 (75,000 mm3) before the next 
scheduled dose and then reduce to next lower dose level 
Table 4.2: 
Dose Modifications for Hepatic Function 
Adverse Event 
Ado-trastuzumab emtansine Dose 
Increased serum transaminases (AST/ALT) 
Grade 1 AST/ALT Elevation (> ULN-3x ULN) 
No change; continue ado-trastuzumab emtansine at 
same dose and schedule 
Grade 2 AST/ALT Elevation (> 3-5x ULN) 
without bilirubin elevation to > 2 x ULN 
Grade 3 AST/ALT Elevation (>5-20x ULN) 
without bilirubin elevation to > 2 x ULN 
Hold ado-trastuzumab emtansine until AST/ALT 
recovers to ≤ Grade 2. If resolves in ≤ 14 days, then 
resume ado-trastuzumab emtansine at next lower 
dose level. 
Grade 4 AST/ALT Elevation  (>20x ULN) 
without bilirubin elevation to > 2 x ULN 
Permanently discontinue ado-trastuzumab emtansine 
Hyperbilirubinemia 
Grade 1 Hyperbilirubinemia  
(> ULN – 1.5x ULN) 
No change; continue ado-trastuzumab emtansine at 
same dose and schedule 
Grade 2 Hyperbilirubinemia  
(> 1.5 – 3x ULN) 
Hold ado-trastuzumab emtansine until total bilirubin 
recovers to ≤ Grade 1, then resume treatment at the 
same dose. 
Grade 3 Hyperbilirubinemia  
(> 3 – 10x ULN) 
Hold ado-trastuzumab emtansine until total bilirubin 
recovers to ≤ Grade 1. If resolves in ≤14 days, then 
resume ado-trastuzumab emtansine at next lower 
dose level.  
Grade 4 Hyperbilirubinemia (> 10x ULN) 
Permanently discontinue ado-trastuzumab emtansine 
Concomitant AST/ALT and hyperbilirubinemia 
AST/ALT > 3 x ULN and total bilirubin > 2 x ULN. Permanently discontinue ado-trastuzumab emtansine 
NOTE: 
Permanently discontinue ado-trastuzumab emtansine in patients diagnosed with 
nodular regenerative hyperplasia (NRH). 
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Table 4.3: Dose Modifications for Peripheral Neuropathy 
Adverse Event 
Ado-trastuzumab emtansine Dose 
Grade 1 peripheral neuropathy 
No change; continue ado-trastuzumab emtansine at same dose and 
schedule 
Grade 2 peripheral neuropathy 
Grade 3 peripheral neuropathy  
1st occurrence:  
Hold ado-trastuzumab emtansine until resolved to grade ≤ 2. If 
resolves in ≤14 days, resume  ado-trastuzumab emtansine at next 
lower dose level.  
2nd occurrence: Permanently discontinue ado-trastuzumab emtansine 
Grade 4 peripheral neuropathy  
Permanently discontinue ado-trastuzumab emtansine 
Table 4.4 Dose Modifications for Left Ventricular Dysfunction 
Symptomatic 
CHF 
LVEF < 40% 
LVEF 40% to ≤ 45% and 
decrease is ≥ 10% points 
from baseline 
LVEF 40% to ≤ 45% 
and decrease is < 
10% points from 
baseline 
LVEF > 
45% 
Discontinue 
ado-
trastuzumab 
emtansine 
Do not administer 
ado-trastuzumab 
emtansine.  
Repeat LVEF 
assessment within 
3 weeks. If LVEF 
<40% is confirmed, 
permanently 
discontinue ado-
trastuzumab 
emtansine  
Do not administer ado-
trastuzumab emtansine.  
Repeat LVEF assessment 
within 3 weeks. If the LVEF 
has not recovered to within 
10% points from baseline, 
discontinue ado-
trastuzumab emtansine. 
Continue treatment 
with ado-
trastuzumab 
emtansine.  
Repeat LVEF 
assessment within 3 
weeks.  
Continue 
treatment 
with ado-
trastuzumab 
emtansine. 
Table 4.5 Dose Modifications for other AEs 
Other significant, related toxicities  
(aside from those described above) that have 
not recovered to grade 1 or baseline. 
Dose may be delayed up to 14 days from the last 
dose. If dosing resumes, it may be at the same dose 
level or one dose level lower, per treating 
investigator’s discretion. 
3.5 
Supportive Care  
3.5.1 
All supportive measures consistent with optimal patient care will be 
given throughout the study.  
3.5.2 
The use of erythropoietin or other specific red blood cell growth 
factors and red blood cell transfusions will be permitted as clinically 
indicated during the study after documentation of anemia secondary 
to the study treatment.  These agents cannot be used prior to this 
occurrence.  
3.5.3 
The use of bone marrow colony stimulating factors (such as 
granulocyte colony-stimulating factor or granulocyte-macrophage 
colony-stimulating factor) is permitted as clinically indicated after 
documentation of neutropenia secondary to the study treatment.  
These agents cannot be used prior to this occurrence. 
3.5.4 
Other concomitant medications may be given as clinically indicated 
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3.6 
Duration of Agent-specific treatment  
In the absence of treatment delays due to adverse event(s), treatment may 
continue until one of the following criteria applies: 
• 
Extraordinary Medical Circumstances: If at any time the constraints of this 
protocol are detrimental to the patient's health, protocol treatment should be 
discontinued. In this event submit forms according to the instructions in the 
MATCH Forms Packet. 
• 
Patient withdraws consent. 
• 
Patient experiences unacceptable toxicity. 
• 
Non-protocol therapies are administered.  
• 
Disease Progression 
3.7 
Duration of Follow-Up 
Refer to the MATCH Master Protocol for specifics on the duration of follow-up. 
  
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4. 
Study Parameters 
4.1 
Therapeutic Parameters for Ado-trastuzumab emtansine Treatment  
NOTE: 
In addition to the study parameters listed in the MATCH Master Protocol, the below parameters must also be 
performed for patients receiving ado-trastuzumab emtansine treatment. 
NOTE: 
All assessments required prior to registration to treatment should be done ≤ 4 weeks prior to registration to 
Steps 1, 3, 5, 7, excluding the radiologic evaluation. 
 
Test/Assessment 
Prior to 
Registration to 
Treatment 
Treatment 
End of 
Treatment 
Follow UpF 
Every Cycle, prior to 
treatment 
Every 3 
Cycles 
H&P, Weight, Vital signsA 
X 
 XH 
 
 
X 
Performance status 
X 
 XH 
 
 
X 
CBC w/diff, pltsB 
X 
 XH 
 
 
X 
Serum chemistryB 
X 
 XH 
 
 
X 
Radiologic evaluationD 
X 
 
 XD 
 
 XF 
β-HCGC 
X 
 
 
 
 
Toxicity Assessment 
 
 XH 
 
X 
 XF 
ECGG 
X 
  
 
 
 
Echocardiogram or Nuclear StudyI 
X 
 
X 
 
 
Tumor biopsy and blood sample for MATCH Master ProtocolE 
 
 
X 
X 
 
A. History and physical, including neuropathy assessment and grade assignment, vital signs and weight at the start of each cycle (up to 3 days 
before start of new cycle). 
B. Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, creatinine, glucose, phosphorus, potassium,  SGOT[AST], SGPT[ALT], 
sodium, magnesium and serum tumor markers (including LDH, PSA if appropriate).  CBC w/diff, platelets and serum chemistries should be 
performed on cycle 1, day 1 (or up to 7 days prior), and at the start of each subsequent cycle (up to 3 days before start of new cycle). CBC with 
differential will be performed more frequently in patients with grade 4 neutropenia or thrombocytopenia until resolution to ≤ grade 3. CBC and 
serum chemistries are only required in follow-up until values return to pre-treatment levels or until progressive disease. 
C. Blood pregnancy test (women of childbearing potential) required prior to beginning treatment. 
D. Disease measurements are repeated every 3 cycles for the first 33 cycles, and every 4 cycles thereafter until PD or start of another MATCH 
treatment step. The baseline evaluation should be performed as closely as possible to the beginning of treatment and never more than 6 weeks 
before registration to treatment step. For multiple myeloma patients, please refer to Section 6.4 of the MATCH Master Protocol for additional 
Rev.2/16 
Rev.2/16 
Rev.2/16 
Rev.2/16, 
12/16 
Rev. 2/16 
Rev. 5/16 
Rev.12/16 
Rev.3/17 
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information on myeloma response criteria and the required disease assessments. Documentation (radiologic) must be provided for patients 
removed from study for progressive disease. 
E.  Additional blood specimens and/or biopsies are to be submitted from consenting patients per Section 9.3.2 of the MATCH Master Protocol. 
Submit at the following time points, as applicable: 
• 
Blood specimens are to be submitted at the end of Cycle 2 (prior to start of Cycle 3 treatment). If patient progresses or treatment is 
discontinued prior to Cycle 3, collect the blood at that time instead. On-treatment kits for blood sample collections will be automatically shipped 
to sites upon registration to the treatment step. 
• 
Screening biopsies for additional aMOI assessments after registration to appropriate screening step, if applicable (Step 2 or Step 4). 
• 
At end of all MATCH study treatments, blood specimens and/or research biopsy after consent and registration to Step 8 
Please refer to Section 4 of the MATCH Master Protocol to determine whether the patient proceeds to the next screening step or to follow-up (with 
a potential end of treatment biopsy for research purposes on Step 8). Samples are to be submitted as outlined in Section 9 of the MATCH Master 
Protocol. To order Step 2/4 Screening or Step 8 kits, complete the EAY131 Collection and Shipping Kit Order Form (See Appendix XII of the 
MATCH Master Protocol) and fax to 713-563-6506. 
F. Every 3 months if patient is < 2 years from study entry, and every 6 months for year 3. Toxicity assessments and radiologic evaluations are not 
required to be done during Follow Up if progression has been previously reported; however if an adverse event occurs post treatment that meets 
the SAE reporting requirements, it still must be reported via CTEP-AERS, even if progression has occurred. 
G. ECG must be done at baseline (within 4 weeks of treatment assignment). Additional ECGs can be done as clinically indicated. 
H. For Cycle 1, if the following tests/assessments occurred within 7 days of Day 1, they do not need to be repeated at this timepoint: H&P, Weight, 
Vital Signs; Performance Status; CBC w/diff, plts; Serum chemistry; Concomitant Medications. The Toxicity Assessment is not required prior to 
Cycle 1, but required every subsequent cycle. 
I. Echocardiogram/nuclear study must be done at baseline (within 4 weeks of treatment assignment), then every three cycles. Additional 
ECHOs/nuclear studies can be done as clinically indicated. 
 
Rev.2/16 
Rev.2/16 
Rev.2/16 
Rev.3/17 
Rev. Add16 
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5. 
Drug Formulation and Procurement 
This information has been prepared by the ECOG-ACRIN Pharmacy and Nursing 
Committees. 
Availability 
NO STARTER SUPPLIES MAY BE ORDERED. Subjects must be enrolled and assigned 
to the treatment subprotocol prior to submitting the clinical drug request to PMB. 
Drug Ordering: NCI supplied agents may be requested by eligible participating 
Investigators (or their authorized designee) at each participating institution.  
Pharmaceutical Management Branch (PMB) policy requires that drug 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 – see general 
information). The CTEP-assigned protocol number must be used for ordering all CTEP-
supplied investigational agents. The eligible participating investigators at each 
participating institution must be registered with CTEP, DCTD through an annual 
submission of FDA Form 1572 (Statement of Investigator), NCI Biosketch, Agent 
Shipment Form, 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. 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) 
application (https://ctepcore.nci.nih.gov/OAOP).  Access to OAOP requires the 
establishment of a CTEP Identity and Access Management (IAM) account 
(https://ctepcore.nci.nih.gov/iam/) and the maintenance of an “active” account status, a 
“current” password, and an active person registration status.  
NCI Supplied Agent(s) – General Information 
Questions about drug orders, transfers, returns, or accountability should be 
addressed to the PMB by calling 240-276-6575 Monday through Friday between 
8:30 AM and 4:30 PM Eastern Time or email PMBAfterHours@mail.nih.gov 
anytime. 
Drug Returns: All undispensed drug supplies should be returned to the PMB. When it is 
necessary to return study drug (e.g., sealed bottles remaining when PMB sends a stock 
recovery letter), investigators should return the study drug to the PMB using the NCI 
Return Agent Form available on the NCI home page (http://ctep.cancer.gov). 
Drug Accountability: The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, disposition, and return of 
agent received from the PMB using the NCI Investigational Agent Accountability Record 
Form available on the NCI home page (http://ctep.cancer.gov).  Maintain separate NCI 
Investigational Agent Accountability Records for each agent, strength, formulation and 
ordering investigator. 
Investigator Brochure Availability: The current versions of the IBs for PMB-supplied 
agents will be accessible to site investigators and research staff through the PMB Online 
Agent Order Processing (OAOP) application.  Access to OAOP requires the 
establishment of a CTEP Identity and Access Management (IAM) account and the 
maintenance of an “active” account status, a “current” password, and active person 
registration status.  Questions about IB access may be directed to the PMB IB 
coordinator at IBCoordinator@mail.nih.gov. 
Rev. 12/16 
Rev.3/17 
Rev. Add16 
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5.1 
Ado-trastuzumab Emtansine (NSC 780263)  
5.1.1 
Other Names  
KADCYLA®, T-DM1, TRASTUZUMAB-MCC-DM1, PRO132365, 
RO5304020 
5.1.2 
Classification  
Humanized monoclonal antibody (IgG1 isotype) directed against the 
extracellular region of HER2 
5.1.3 
Mode of Action  
Ado-trastuzumab emtansine binds to HER2 with affinity similar to that 
of trastuzumab. After binding to HER2, trastuzumab emtansine 
undergoes receptor-mediated internalization, resulting in intracellular 
release of DM1 and subsequent cell death. DM1 is an inhibitor of 
tubulin polymerization. 
5.1.4 
Storage and Stability  
Storage:   
Intact vials should be refrigerated at 2ºC-8ºC (36ºF-46ºF). Do not 
freeze or shake.    
 
Stability: 
Reconstituted single-use vials should be used within 1 hour of 
reconstitution. If not used within this time frame, the reconstituted vials 
can be stored for up to 24 hours in a refrigerator at 2°C–8°C. Vials 
stored beyond this time period should be discarded. 
The diluted solution should be used immediately.  If not used 
immediately, the diluted solution may be stored at 2ºC-8ºC (36ºF-
46ºF) for up to 24 hours.  Diluted solutions stored past 24 hours 
should be discarded. 
5.1.5 
Dose Specifics  
Ado-trastuzumab emtansine is provided as a lyophilized product in 
20-mL single-use vials which contain enough product to deliver 160 
mg of ado-trastuzumab emtansine. When reconstituted, each single-
use vial contains ado-trastuzumab emtansine (20 mg/mL), 
polysorbate 20 [0.02% (w/v)], sodium succinate (10 mM), and sucrose 
[6% (w/v)] with a pH of 5.0 and density of 1.026 g/mL. Ado-
trastuzumab emtansine vials will have either a white or purple flip cap. 
Ado-trastuzumab emtansine will be administered on Day 1 of each 
cycle at 3.6 mg/kg IV.  
RECONSTITUTION: Slowly inject 8 mL of Sterile Water for Injection 
into the 160 mg ado-trastuzumab emtansine vial to yield a solution 
containing 20 mg/mL. Swirl the vial gently until completely dissolved. 
Do not shake. Inspect the reconstituted solution for particulates and 
discoloration. The reconstituted solution should be clear to slightly 
opalescent and free of visible particulates. The color of the 
reconstituted solution should be colorless to pale brown. Do not use if 
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the reconstituted solution contains visible particulates or is cloudy or 
discolored. 
DILUTION:  To prepare the infusion solution from the reconstituted 
lyophilized product, remove the indicated volume of product from the 
vials, based on patient weight, and add to the IV bag. Gently invert the 
bag to mix the solution. Do not shake vigorously. Reconstituted ado-
trastuzumab emtansine should be diluted into polyvinyl chloride 
(PVC), latex-free PVC-free polyolefin bags (PO), polypropylene (PP) 
or polyethylene (PE) bags containing 250 mL 0.9% NS. 
5.1.6 
Route of Administration  
Administer ado-trastuzumab emtansine as an intravenous infusion 
only with a 0.2 or 0.22 micron in-line polyethersulfone (PES) filter. Do 
not administer as an intravenous push or bolus. 
Method of Administration:  
First infusion: Administer infusion over 90 minutes. Patients should be 
observed during the infusion and for at least 90 minutes following the 
initial dose for fever, chills, or other infusion related reactions.  
Subsequent infusions: Administer over 30 minutes if prior infusions 
were well tolerated. Patients should be observed during the infusion 
and for at least 30 minutes after infusion. 
5.1.7 
Incompatibilities  
Dextrose infusion solutions 
Potential Drug Interactions: No formal drug-drug interaction studies 
with ado-trastuzumab emtansine have been conducted. In vitro 
studies indicate that DM1, the cytotoxic component of ado-
trastuzumab emtansine, is metabolized mainly by CYP3A4 and to a 
lesser extent by CYP3A5. Concomitant use of strong CYP3A4 
inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, 
indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, 
and voriconazole) with ado-trastuzumab emtansine should be avoided 
due to the potential for an increase in DM1 exposure and toxicity. 
Consider an alternate medication with no or minimal potential to inhibit 
CYP3A4. If concomitant use of strong CYP3A4 inhibitors is 
unavoidable, consider delaying ado-trastuzumab emtansine treatment 
until the strong CYP3A4 inhibitors have cleared from the circulation 
(approximately 3 elimination half-lives of the inhibitors) when possible. 
If a strong CYP3A4 inhibitor is coadministered and ado-trastuzumab 
emtansine treatment cannot be delayed, patients should be closely 
monitored for adverse reactions.   
5.1.8 
Side Effects  
See Section 3.3 for side effects. 
5.1.9 
Nursing/Patient Implications  
Follow procedures for proper handling and disposal of anticancer 
drugs 
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6. 
Translational Studies 
Please refer to the MATCH Master Protocol for information on the Translational Studies.  
7. 
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official journal of the American Society of Clinical Oncology. Mar 1 
2010;28(7):1124-1130. 
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16. Baselga J, Cortes J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel 
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18. Trail PA, Bianchi AB. Monoclonal antibody drug conjugates in the treatment of 
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20. Yan M, Parker BA, Schwab R, Kurzrock R. HER2 aberrations in cancer: 
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22. Krop IE, Beeram M, Modi S, et al. Phase I study of trastuzumab-DM1, an HER2 
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23. Jelovac D, Emens LA. HER2-directed therapy for metastatic breast cancer. 
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24. Junttila TT, Li G, Parsons K, Phillips GL, Sliwkowski MX. Trastuzumab-DM1 (T-
DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits 
growth of lapatinib insensitive breast cancer. Breast cancer research and 
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25. Lewis Phillips GD, Li G, Dugger DL, et al. Targeting HER2-positive breast cancer 
with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res. Nov 15 
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27. Girish S, Gupta M, Wang B, et al. Clinical pharmacology of trastuzumab emtansine 
(T-DM1): an antibody-drug conjugate in development for the treatment of HER2-
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Version Date: February 28, 2020 
 
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positive cancer. Cancer chemotherapy and pharmacology. May 2012;69(5):1229-
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28. Kadcyla (ado trastuzumab-emtansine) [package insert]. San Francisco, CA2013. 
29. Burris HA, 3rd, Rugo HS, Vukelja SJ, et al. Phase II study of the antibody drug 
conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor 
receptor 2 (HER2)-positive breast cancer after prior HER2-directed therapy. 
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Oncology. Feb 1 2011;29(4):398-405. 
30. Krop IE, LoRusso P, Miller KD, et al. A phase II study of trastuzumab emtansine in 
patients with human epidermal growth factor receptor 2-positive metastatic breast 
cancer who were previously treated with trastuzumab, lapatinib, an anthracycline, a 
taxane, and capecitabine. Journal of clinical oncology : official journal of the 
American Society of Clinical Oncology. Sep 10 2012;30(26):3234-3241. 
31. Hurvitz SA, Dirix L, Kocsis J, et al. Phase II randomized study of trastuzumab 
emtansine versus trastuzumab plus docetaxel in patients with human epidermal 
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32. Miller KD, Dieras V, Harbeck N, et al. Phase IIa trial of trastuzumab emtansine with 
pertuzumab for patients with human epidermal growth factor receptor 2-positive, 
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33. Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive 
advanced breast cancer. The New England journal of medicine. Nov 8 
2012;367(19):1783-1791. 
34. Krop IE, Kim SB, Gonzalez-Martin A, et al. Trastuzumab emtansine versus 
treatment of physician's choice for pretreated HER2-positive advanced breast 
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35. A Study of Trastuzumab Emtansine (T-DM1) Plus Pertuzumab/Pertuzumab 
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36. A Study of Trastuzumab Emtansine Versus Trastuzumab as Adjuvant Therapy in 
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37. LoRusso PM, Weiss D, Guardino E, Girish S, Sliwkowski MX. Trastuzumab 
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Version Date: February 28, 2020 
 
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38. Dieras V HN, Budd GT, et al. Trastuzumab emtansine in HER2-positive metastatic 
breast cancer: pooled safety analysis from seven studies. Cancer Res. 
2012;72((suppl 3)):Abstract P5-18-06. 
39. Dieras V, Harbeck N, Budd GT, et al. Trastuzumab Emtansine in Human 
Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer: An 
Integrated Safety Analysis. Journal of clinical oncology : official journal of the 
American Society of Clinical Oncology. Jul 14 2014. 
40. Barroso-Sousa R, Santana IA, Testa L, de Melo Gagliato D, Mano MS. Biological 
therapies in breast cancer: common toxicities and management strategies. Breast. 
Dec 2013;22(6):1009-1018. 
41. Kadcyla Important Safety Information. 2014; http://www.kadcyla.com/ 
hcp/important-safety-information - See more at: 
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2014/antibody-drug-conjugates-and-t-dm1/5#sthash.yjjLpXf6.dpuf. Accessed July 
11, 2014. 
42. Hartleb M, Gutkowski K, Milkiewicz P. Nodular regenerative hyperplasia: evolving 
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Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol Q: Ado-trastuzumab Emtansine/HER2 Amplification 
Appendix I 
 
Actionable Mutations for Sub-Protocol EAY131-Q 
 
Gene Name 
Variant ID 
Variant Type 
Level of Evidence Code 
aMOI 
ERBB2 
ERBB2 
CNV 
1 
ERBB2 Amplification 
 
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Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol Q: Ado-trastuzumab Emtansine/HER2 Amplification 
Appendix II 
 
Patient Drug Information Handout and Wallet Card 
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements 
The patient ____________________________ is enrolled on a clinical trial using the 
experimental study drug, Ado-trastuzumab emtansine.  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.  
These are the things that you as a healthcare provider need to know: 
Ado-trastuzumab emtansine is broken down by the CYP3A4 enzyme in your liver. 
Some drugs interfere or inhibit the CYP3A4 enzyme and if taken in combination with Ado-
trastuzumab emtansine may result in very high blood levels of Ado-trastuzumab emtansine 
which may make you sick. 
There are also some drugs that make the CYP3A4 enzyme work harder (inducers) and if taken 
in combination with Ado-trastuzumab emtansine may result in low blood levels of Ado-
trastuzumab emtansine which may make your treatment less effective.  
Finally, other drugs, that are also broken down by the CYP3A4 enzyme, may interfere with 
removing Ado-trastuzumab emtansine from your body and when taken in combination with 
Ado-trastuzumab emtansine may cause Ado-trastuzumab emtansine to stay in your body 
longer and cause more side effects. 
Strong inhibitors and inducers of CYP3A4 should not be used in combination with Ado-
trastuzumab emtansine  
Moderate inhibitors and inducers of CYP3A4 should be used with caution in combination with 
Ado-trastuzumab emtansine 
To the patient: Take this paper with you to your medical appointments and keep the 
attached information card in your wallet.   
Ado-trastuzumab emtansine may interact with other drugs which can cause side effects. For 
this reason, it is very important to tell your study doctors of any medicines you are taking before 
you enroll onto this clinical trial.  It is also very important to tell your doctors if you stop taking 
any regular medicines, or if you start taking a new medicine while you take part in this study.  
When you talk about your current medications with your doctors, include medicine you buy 
without a prescription (over-the-counter remedy), or any herbal supplements such as St. John’s 
Wort. It is helpful to bring your medication bottles or an updated medication list with you. 
Many health care providers can write prescriptions.  You must tell all of your health care 
providers (doctors, physician assistants, nurse practitioners, pharmacists) you are taking part in 
a clinical trial.  
These are the things that you and they need to know:  
Ado-trastuzumab emtansine must be used very carefully with other medicines that use certain 
liver enzymes to be cleared from your system. Before you enroll onto the clinical trial, your study 
Rev.2/16 
Rev. 12/16 
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40 
STUDY DRUG INFORMATION WALLET CARD  
You are enrolled on a clinical trial using the 
experimental study drug Ado-trastuzumab 
emtansine.  This clinical trial is sponsored by 
the NCI.  Ado-trastuzumab emtansine may 
interact with other drugs.  Because of this, it is 
very important to: 
 Tell your doctors if you stop taking any 
medicines or if you start taking any new 
medicines. 
 Tell all of your health care providers (doctors, 
physician assistants, nurse practitioners, or 
pharmacists) 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. 
Ado-trastuzumab emtansine is broken down by the CYP3A4 
enzyme in your liver and must be used very carefully with 
other medicines that interact with CYP3A4. 
Strong inhibitors and inducers of CYP3A4 should not be used 
in combination with Ado-trastuzumab emtansine  
Moderate inhibitors and inducers of CYP3A4 should be used 
with caution in combination with Ado-trastuzumab 
emtansine 
Before you enroll onto the clinical trial, your study doctor will 
work with your regular health care providers to review any 
medicines and herbal supplements that may interact with 
Ado-trastuzumab emtansine 
 Before prescribing new medicines, your regular health care 
providers should go to a frequently-updated medical 
reference for a list of drugs to avoid, or contact your study 
doctor. 
 Your study doctor’s name is 
___________________________ and can be  
 
contacted at __________________________.  
doctor will work with your regular health care providers  to review any medicines and herbal 
supplements  that are considered moderate or strong inducers/inhibitors or major substrates of 
CYP3A4.   
• 
Please be very careful!  Over-the-counter drugs (including herbal supplements) may contain 
ingredients that could interact with your study drug.  Speak to your doctors or pharmacist to 
determine if there could be any side effects.  
• 
Your regular health care provider should check a frequently updated medical reference or 
call your study doctor before prescribing any new medicine or discontinuing any medicine.  
Your study doctor’s name is  
_____________________________________ and he or she can be contacted at  
 
_________________________________ 
 
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ECOG-ACRIN 
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Version Date: February 28, 2020 
 
NCI Update Date: August 12, 2015 
41 
Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol Q: Ado-trastuzumab Emtansine/HER2 Amplification 
Appendix III 
 
CS-MATCH-0012 
An Explorative Analysis of the Roles of Tumor Intrinsic and Micro-Environmental Factors 
in the Clinical Response to TDM1 in the NCI-MATCH Q Arm 
Principal Investigators: 
PRINCIPAL INVESTIGATORS: 
, MD PhD 
CO-INVESTIGATORS: 
, MD 
, MD 
, MD 
BIOSTATISTICS: 
, PhD 
SUB-PROTOCOL PRINCIPAL INVESTIGATORS: 
, MD  
, MD 
, MD PhD 
Rev. Add24 
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ECOG-ACRIN 
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Version Date: February 28, 2020 
 
NCI Update Date: August 12, 2015 
42 
I. 
Introduction 
TDM1 may soon join a growing list of cancer therapy that can function in a tissue 
agnostic manner, in particular for patients with HER-2 positive salivary gland cancer. 
Despite this exciting finding, only a minority of patients from the Q arm responded. 
Identification of biomarkers that can predict the response of therapy will allow us to 
better select patients that will more likely benefit from the treatment as well as elucidate 
the mechanism of resistance. Both microenvironmental and tumor intrinsic properties 
may modulate the response of breast cancer to the parental molecule: trastuzumab. In 
this proposal, we will focus on tumor HER-2 status. 
The potential mechanism of resistance to TDM1 therapy was discussed in a recent 
review article (Barok et al., 2014). Breast and GE junction cancers with HER-2 protein 
over-expression, as defined by IHC 3+, or gene amplification, as defined by a HER-2 
copy number greater than 6 or a HER-2/CEP17 ratio of greater than 2.0. Among these 
HER-2 positive tumors, whether higher levels of HER-2 gene amplification or protein 
over-expression predict better clinical outcome to anti-HER-2 therapy remains an open 
question. In this proposal, we will examine if a higher level of HER-2 gene amplification, 
as evaluated by FISH or NCI-MATCH assay, or over-expression, as evaluated by IHC or 
RNAseq, will correlate with improved clinical outcome with TDM1 treatment. 
Both IHC and FISH have been routinely used for HER-2 status evaluation in breast 
cancer. According to the HER-2 scoring system put forth by the ASCO/CAP, uniform 
intense membrane staining in more than 10% of invasive tumor cells is considered 
positive for HER-2 protein over-expression (Wolff et al., 2014). However there are 
differences in HER-2 staining patterns between breast and gastric cancer cells 
(incomplete membrane staining in a basolateral pattern and greater tumor heterogeneity 
are more prominent in gastric cancer cells), a modified HER-2 scoring system specific 
for gastric cancer has been proposed and has been shown to be reproducible and 
adopted in the ToGA trial (Bang et al., 2010). NCCN guidelines recommend that 
assessment for HER-2 status by IHC should follow the modified scoring system used in 
the ToGA trial (NCCN Guidelines Version 2. 2017). These observations importantly 
indicate that though the same biomarker is being interrogated in both tissues, the 
technology involved may need to be individually optimized depending on the tissue 
origin). In order to assess the HER-2 status and the HER-2 protein expression status in 
the matched samples of the Q arm, we will apply both scoring systems independently. 
Since clinically validated scoring criteria for HER-2 IHC testing in non-gastric/GE or non-
breast cancer have not been established, we will use both breast and gastric/GE HER-2 
IHC scoring criteria to all samples independently and analyze according to either criteria 
separately. 
HER-2 testing by FISH and IHC is a well-recognized and widely disseminated HER-2 
testing strategy (Wolff et al., 2014). Its performance in selecting out patients whose 
tumors are more likely to respond to HER-2 targeted therapeutics, based on the HER-2 
protein expression and/or gene amplification, is well established for breast and gastric 
cancers. HER-2 testing is done routinely in the community setting for both breast and 
GE junction cancers. FDA approved testing methodologies include IHC, FISH and CISH. 
HER-2 testing done by NGS, such as the Oncomine assay, is not routinely done in the 
community. Translating the finding from the Q arm study to a clinical scenario most 
familiar to the oncology community in general serves as additional rationale to perform 
HER-2 FISH and Her-2 IHC from Q arm patients that are tested positive for HER-2 
amplification by the NCI-MATCH assay. Though this is not a formal concordance study, 
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this will at least answer the question if HER-2 testing by FISH or IHC can correctly 
identify most, if not all, of the patients that score positive by the MATCHBOX assay- i.e. 
sensitivity close to 100%.  
Another important contribution of HER-2 FISH and IHC assays is direct histological 
assessment of the cancer cells and determine if there is tumor heterogeneity in terms of 
their HER-2 protein over-expression and/or gene amplification and if heterogeneity will 
correlate with response. Tumor heterogeneity in HER-2 status has been previously 
reported in breast cancer though at low incidence, relevant information for other tissue 
types is not available. 
II. 
Objectives 
A. 
Primary objective:  
Determine if HER-2 gene copy number and HER-2 protein over-expression will 
correlate with response to TDM1. 
III. 
Methodology 
Both FISH and IHC tests will be performed with FDA approved testing kits in accordance 
with the ASCO/CAP 2013 guidelines. HER-2 IHC has generally speaking sensitivity of 
70% and specificity close to 100%. HER-2 FISH has specificity and sensitivity in the high 
90%. The concordance rate between HER-2 FISH and IHC is between 80-90+%. HER-2 
FISH and HER-2 IHC will be performed at Dr. 
 Laboratory at MD Anderson. 
IHC and FISH will be performed utilizing autostainers (Leica Bond Max, Leica 
Biosystems, Vista, CA). All antibodies have been optimized for IHC by examination of 
positive and negative controls and testing of the antibodies by Western blotting. 
Expression of the markers in cells will be detected using a Novocastra Bond Polymer 
Refine Detection kit (Leica Microsystems, Buffalo Grove, IL) with a diaminobenzidine 
reaction to detect antibody labeling and hematoxylin counterstaining. To perform 
quantitative image analysis of the expression of each marker, all IHC slides will be 
scanned into a digital image scanner (Aperio™ AT Turbo, Leica Biosystems, Buffalo 
Grove, IL), and analyzed using the Aperio Image Genie Toolbox™ software (Leica 
Biosystems, Buffalo Grove, IL). Five random 1-mm square areas within the tumor region 
will be selected for analysis. The expression of markers in malignant cells will be 
evaluated using the Aperio™ digital H-score system which includes the percentage of 
positive cells (0 to 100) and intensity (0 to 3+), with a total score ranging from 0 to 300. 
Quantification of markers expressed in immune cells will be expressed by cell density 
(number of cells per mm square). 
Scoring will be as follows: 
• 
C-erB-2 (Her2) IHC:  DAKO #A0485, Polyclonal Rabbit anti-Human Oncoprotein.  
Dilute 1:800. 
• 
IHC 0+ and 1+ are negative (not over-expressed) 
• 
IHC 3+ are positive (over-expressed) 
• 
IHC 2+ are equivocal and reflex to HER-2 FISH is needed. 
• 
Dual-probe HER2/cep17 FISH assay: 
• 
Ratio greater or equal to 2, positive (amplified) 
• 
Ratio less than 2 with an average HER-2 copy number greater than or equal to 6, 
positive (amplified). 
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• 
Ratio less than 2 with an average HER-2 copy number less than 4, negative (not 
amplified). 
• 
Ratio less than 2 with an average HER-2 copy number greater than or equal to 4 
but less than 6, intermediate and reflex to IHC is needed. 
IV. 
Statistical Considerstions 
A. 
Endpoints   
Primary: HER-2 gene copy number and HER-2 protein over-expression 
B. 
Case selection and Sample Size 
All consenting cases with adequate biospecimens available from the MATCH-Q 
subprotocoal arm.   
Sample size estimate: 35 patients for tissue analyses 
C. 
Analysis plan:  
We would like to examine if HER-2 gene amplification and/or protein over-
expression status are associated with clinical outcome after treatment with 
TDM1. Specifically we will assess their association with overall response and 
progression-free survival (PFS). 
HER-2 gene amplication will be assessed by FISH as binary (amplication or not) 
and continuous variable (normalized to chromosome 17 centromere). Protein 
expression will be evaluated by IHC. For breast and gastric cancer, it has been 
established that IHC 0+ and 1+ are negative, IHC 3+ are over-expressed and 
IHC 2+ are equivocal. 
For association between PFS and HER2 amplification, log-rank test will be used 
to test for differences in PFS between amplification status. IHC categories may 
be combined into over-expressed vs. not over-expressed (0+ plus 1+ versus 3+). 
For PFS and continuous amplification level (FISH normalized against 
chromosome 17 centromere), spline-based method (Gray 1992) will be used to 
examine the relationship between hazard ratio and the continuous variable.  
For overall response and amplification status or over-expression status, Fisher’s 
exact test will be used to test for differences in proportion amplified or over-
expressed between responders and non-responders. For overall response and 
amplification level, Wilcoxon test will be used to test for differences in 
amplification level between PRs and SDs, and between SDs and PDs. 
Because of the small sample size, exploratory data analysis will be performed. 
Data will be visualized by boxplots or dotplots. Correlation between HER2 
amplification and protein over expression will be examined by scatter plot. 
Response can be overlayed by color. 
V. 
References 
1. Gray RJ. Flexible methods for analyzing survival data using splines, with 
applications to breast cancer prognosis. Journal of the American Statistical 
Association. 1992 Dec 1;87(420):942-51.Herbst, R.S., et al., Predictive 
correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer 
patients. Nature, 2014. 515(7528): p. 563-7 
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2. Barok M, Joensuu H, Isola J. Trastuzumab emtansine: mechanisms of action 
and drug resistance. Breast Cancer Res. 2014 Mar 5;16(2):209. doi: 
10.1186/bcr3621. 
3. Wolff AC, et al. Recommendations for human epidermal growth factor 
receptor 2 testing in breast cancer: American Society of Clinical 
Oncology/College of American Pathologists clinical practice guideline update. 
Arch Pathol Lab Med. 2014 Feb;138(2):241-56. doi: 10.5858/arpa.2013-
0953-SA. Epub 2013 Oct 7.  
4. Bang YJ, et al. Trastuzumab in combination with chemotherapy versus 
chemotherapy alone for treatment of HER2-positive advanced gastric or 
gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, 
randomised controlled trial. Lancet. 2010 Aug 28;376(9742):687-97. doi: 
10.1016/S0140-6736(10)61121-X. Epub 2010 Aug 19.. 
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