A Phase 1b Study of Neratinib, Pertuzumab, and Trastuzumab With Taxol (3HT) in Metastatic and Locally Advanced Breast Cancer, and Phase II Study of 3HT Followed by AC in HER2 + Primary IBC, and Neratinib With Taxol (NT) Followed by AC in HR+ /HER2- Primary IBC
Phase: PHASE1
Conditions: Breast Inflammatory Carcinoma, Locally Advanced Breast Carcinoma, Metastatic Breast Carcinoma, Stage III Breast Cancer AJCC v7, Stage IIIA Breast Cancer AJCC v7, Stage IIIB Breast Cancer AJCC v7, Stage IIIC Breast Cancer AJCC v7, Stage IV Breast Cancer AJCC v6 and v7
Sponsor: M.D. Anderson Cancer Center

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Protocol/Amendment No.: 2016-0537 
PI:  Rachel Layman, MD;  
Date:  1/12/2021 
MD Anderson IND Sponsor Cover Sheet 
Protocol ID 
2016-0537 
Protocol Title 
A phase 1b study of neratinib, pertuzumab and trastuzumab with taxol 
(3HT) in  metastatic and locally advanced breast cancer, and phase II 
study of 3HT followed by AC in HER2 + primary IBC, and neratinib 
with taxol (NT) followed by AC in HR+ /HER2-  primary IBC 
Protocol Version 
21 
Version Date 
1/12/2021 
Protocol PI 
 Rachel Layman 
Department 
Breast Medical Oncology 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
134125 
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Protocol/Amendment No.: 2016-0537 
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Date:  1/12/2021 
 
 
TABLE OF CONTENTS 
 
1.0 Trial Summary .................................................................................................................. 4 
2.0 Objectives & Hypotheses .................................................................................................. 4 
2.1 
Primary Objectives & Hypotheses ........................................................................ 4 
2.2 Secondary Objectives ................................................................................................... 5 
2.3 Exploratory Objective .................................................................................................. 5 
3.0 Background & Rationale .................................................................................................. 5 
3.1 Inflammatory Breast Cancer (IBC) ............................................................................ 5 
3.2 Preclinical Data and Clinical data of Neratinib ......................................................... 6 
3.3 Rationale for Selected Subject Population ................................................................. 7 
3.4 Rationale for the Dose Selection/Regimen/Modification ........................................... 9 
3.5 The Rationale for Adaptive Response Change Assessment utilizing Tissue/Blood 
based Biomarkers – Window period and screening HER2 mutation .............. 10 
3.6 Study Endpoint ............................................................................................................ 11 
3.6.1 Primary endpoint:.................................................................................................. 11 
3.6.2 Secondary endpoints: ............................................................................................ 12 
3.6.3 Correlative endpoints: ........................................................................................... 12 
4.0 Methodology .................................................................................................................... 12 
4.1 Entry Criteria .............................................................................................................. 12 
4.1.1 Common Inclusion Criteria .................................................................................... 12 
4.1.2 Cohorts I and II specific Inclusion Criteria ............................................................ 13 
4.1.3 Exclusion Criteria: ................................................................................................. 14 
4.2 Treatment Plan ........................................................................................................... 15 
4.2.1 Treatment procedures ............................................................................................. 15 
4.2.2 Dosage of combination agents (Table 2 & 3) ........................................................ 15 
4.2.3 Phase Ib dose escalation management ................................................................... 17 
4.3 Study Schema and Flow Chart .................................................................................. 18 
4.4 Outside Physician Participation During Treatment ................................................ 26 
5.0 Common Toxicity and Dose Modification .................................................................... 26 
5.1 Dose modification of each drug ................................................................................. 27 
5.1.1 Pertuzumab: ........................................................................................................... 27 
5.1.2 Trastuzumab: .......................................................................................................... 27 
5.1.3 Paclitaxel: ............................................................................................................... 27 
5.1.4 Neratinib: ............................................................................................................... 27 
5.2 Common toxicity and management ........................................................................... 27 
5.2.1 Management of Diarrhea, and Dose Modification of Neratinib ............................ 27 
5.2.2 Cardiac Left Ventricular Dysfunction and Dose Modification of Neratinib, 
Pertuzumab, and Trastuzumab ............................................................................ 29 
5.2.3 Musculoskeletal Pain, Neuropathy and Paclitaxel Dose Modification. ................. 30 
5.3 Other Toxicity Management ...................................................................................... 31 
5.5 Concomitant Medications/Vaccinations (allowed & prohibited) ........................... 34 
5.5.1 Acceptable Concomitant Medications ................................................................... 34 
5.5.2 Prohibited Concomitant Medications..................................................................... 34 
6.0  Subject withdrawal/discontinuation criteria ............................................................... 35 
7.0 Follow up.......................................................................................................................... 36 
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Protocol/Amendment No.: 2016-0537 
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8.0 Disease Assessment ......................................................................................................... 37 
9.0  Correlative Research ..................................................................................................... 37 
9.1 Tumor Sample Collection / Research Blood Collection .......................................... 37 
9.2 HER2 Expression and HER2 Mutation .................................................................... 38 
9.3 EGFR Expression and downstream pathways ......................................................... 38 
10.0 Safety Monitoring and Reporting................................................................................ 39 
10.1 Adverse Event ........................................................................................................... 39 
10.2 Serious Adverse Event Reporting (SAE) ................................................................ 39 
10.2.1 Internal SAE reporting to Investigational New Drug (IND) Office .................... 39 
10.2.2 Reporting to FDA: ............................................................................................... 40 
10.2.3 Investigator Communication with Supporting Company: ................................... 40 
11.0 Statistical Considerations ............................................................................................. 41 
11.1 Overview .................................................................................................................... 41 
11.2 Phase Ib Design ......................................................................................................... 42 
11.3 Phase II Design .......................................................................................................... 45 
11.4 Toxicity Monitoring in Phase II .............................................................................. 45 
11.5 Secondary Objectives and Analyses ........................................................................ 47 
11.6 Toxicity/Efficacy Report to IND Office .................................................................. 48 
12.0 Labeling, Packaging, Storage and Return of Clinical Supplies ................................ 48 
12.1  Investigational Product ........................................................................................... 48 
12.2 Packaging and Labeling Information ..................................................................... 48 
12.3 Clinical Supplies Disclosure ..................................................................................... 49 
12.4 Storage and Handling Requirements ...................................................................... 49 
12.5 Returns and Reconciliation ...................................................................................... 49 
13.0 Data management ......................................................................................................... 49 
13.1 Data collection for this study including: ................................................................. 49 
13.2 Data confidentiality plan .......................................................................................... 50 
14.0 Reference ....................................................................................................................... 50 
 
 
 
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1.0 TRIAL SUMMARY 
Abbreviated Title 
Combination of neratinib in metastatic and locally advanced 
(stage III) HER2+ breast cancer in phase Ib 
Combination of neratinib in locally advanced (stage III)  
HER2+ IBC and HER2-/HR+ IBC in phase II 
Trial Phase 
Ib/II 
Clinical Indication 
3HT (neratinib, pertuzumab, trastuzumab: triple HER2 
targeting therapy in combination with paclitaxel) in 
metastatic or locally advanced breast cancer in phase Ib 
3 HT follwed by AC in HER2 positive primary IBC, and NT 
(neratinib with paclitaxel) followed by AC in HER2 
negative/ HR positive primary IBC in phase II 
Trial Type 
Open label, non- randomized, single center  
Type of control 
None 
Route of administration 
neratinib: PO 
pertuzumab, trastuzumab, paclitaxel, doxorubicin, 
cyclophosphamide : IV 
Trial Blinding 
Open label 
Treatment Groups  
Three cohorts 
Number of trial subjects 
Maximum 99 
Estimated duration of trial 5 years. Expected to start: March 2017, and end February 
2022 
Duration of Participation 
6 months 
 
2.0 OBJECTIVES & HYPOTHESES 
2.1 Primary Objectives & Hypotheses 
2.1.1 Cohort I: 
 Phase Ib: To determine the maximum tolerated dose (MTD) of neratinib in combination 
with paclitaxel, pertuzumab, and trastuzumab in HER2-positive (HER2+) metastatic or 
locally advanced (stage III) breast cancer within 2 cycles. 
 Phase II: To determine the pathologic complete response (pCR) rate of neratinib in 
combination with paclitaxel, pertuzumab, and trastuzumab followed by doxorubicin and 
cyclophosphamide (AC) in HER2+ metastatic or locally advanced (stage III) 
inflammatory breast cancer (IBC) patients. 
2.1.2 Cohort II:  
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Protocol/Amendment No.: 2016-0537 
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To determine the pCR rate of neratinib in combination with paclitaxel followed by AC in 
HER2-negative/HR-positive (HER2-/HR+) metastatic or locally advanced (stage III) IBC 
patients. 
Hypothesis: The addition of neratinib will improve the pCR rate in both HER2+ and ER+/HER2- 
primary IBC by pan-HER activity that enhances the effective suppression of HER2, EGFR and 
possibly via suppression of HER2 mutation. 
2.2 Secondary Objectives 
• To estimate 2 years progression free survival (PFS) rate of HER2+ metastatic or locally 
advanced (stage III) IBC patients, and HER2-/ HR+ IBC patients treated with neratinib plus 
anthracycline and taxane based chemotherapy (Cohort I Phase II and Cohort II). 
• 
To determine toxicity and safety of the combination therapy. 
2.3 Exploratory Objective 
• 
To determine the adaptive target and downstream changes in pan-HER family members 
induced by one-week window period of neratinib based on tissue and blood based biomarkers. 
• 
To determine the correlation between positive/negative changes in EGFR, HER2 and HER4 
and the occurrence of pCR. 
• 
To determine the rate of HER2 mutation in HER2+ IBC and HER2-/ HR+ IBC.  
• 
To determine the association between HER2 mutation and pCR achieved by study 
combination therapy. 
• 
To determine the correlation between tumor tissue based pharmacodynamic marker changes 
in association with CTC and ctDNA. 
3.0 BACKGROUND & RATIONALE 
3.1 Inflammatory Breast Cancer (IBC) 
Inflammatory breast cancer (IBC) is rare, but the most aggressive form of primary breast 
carcinoma and has distinctive biological features, and confers poor prognosis by local and distant 
metastasis and frequent recurrence[1]. IBC is defined by a rapid onset of diffuse skin erythema, 
edema, involving more than 2/3 of the breast resulting in a pitted appearance (peau d’orange), as 
well as tenderness, induration and warmth of the involved breast[2].  
The outcome for patients with IBC is bleak despite multimodality treatment approaches; 3-OS 
rates after combined chemotherapy, surgery, and radiation are only 40% compared to 80% for non-
inflammatory breast cancer [3, 4]. At the time of initial diagnosis, most IBC patients have lymph 
node involvement and approximately 30% have distant metastases [5].  
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Protocol/Amendment No.: 2016-0537 
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At 
this 
time, 
combined-modality 
treatment 
(neoadjuvant 
anthracycline-taxane-based 
chemotherapy, mastectomy, adjuvant chemotherapy, and radiotherapy) is considered to be a 
standard of care for IBC[3].  
3.2 Preclinical Data and Clinical data of Neratinib  
• Preclinical Data of Neratinib 
Neratinib (HKI-272), an orally administered small molecule, is an irreversible inhibitor of pan 
ErbB receptor tyrosine kinases, by binding to the cysteine residue in the ATP-binding pocket of 
the receptor. Neratinib inhibits tyrosine kinase activity of dimers such as HER1:1, HER1:2, 
HER1:3 and HER2:3. Both inhibitors bind to the ATP sites of these enzymes and prevent 
phosphorylation and activation of downstream signaling pathways. Neratinib has shown to be 
highly active in vitro against cell lines overexpressing ErbB2 or ErbB1[6]. And neratinib 
effectively inhibits the proliferation of EGFR and HER2 expressing cells that are resistant to 
treatment with first-generation ErbB receptor tyrosine kinase inhibitors such as gefitinib[7].  
In BT474 cell lines, HKI-272 effectively repressed phosphorylation of MAPK and Akt signal 
transduction pathways, whereas trastuzumab failed to completely inhibit HER2 receptor 
phosphorylation or downstream signaling events. The Ras-Raf-MAPK pathway and the 
phosphotidylinositol-3-kinase (PI3K)/Akt pathway are the two major downstream pathways 
initiated as a consequence of HER2 receptor activation. Consistent with erbB-2 inactivation, 
neratinib results in inhibition of downstream signal transduction events and cell cycle regulatory 
pathways. As a consequence, neratinib treatment of BT474 cells results in the inhibition of MAPK 
and Akt phosphorylation, down-regulation of cyclin D1 levels, and induction of p27. Actually, 
neratinib was shown to be more effective compared to trastuzumab as a single agent. Moreover 
the combination treatment of neratinib and trastuzumab significantly reduced tumor size compared 
to trastuzumab alone (P<0.001) or neratinib alone (P<0.05)[8].When compared to trastuzumab, 
inhibition of these pathways was more complete with neratinib[6].  
Given the highly specific and potent tyrosine kinase inhibition of neratinib, it is postulated that 
breast cancer cells resistant to trastuzumab on the basis of enhanced signaling through alternative 
pathways (i.e. HER2/HER3 heterodimerization) or mechanisms preventing antibody binding to 
HER2 would retain sensitivity to neratinib. Neratinib shows activity in some cell lines which are 
innate and acquired trastuzumab resistance, and innate lapatinib resistance in HER2 positive breast 
cancer as an irreversible inhibitor of EGFR, HER2 and HER4 tyrosine kinase activity [9]. In 
preclinical studies, neratinib has shown to inhibit HER2/HER2, EGFR/HER2, and HER2/HER3 
homo- and hetero-dimers and downstream signaling effectors (RAF, ERK, AKT) regardless of 
trastuzumab resistance or ligand association[6, 10-12]. The specificity, potency and irreversibility 
of neratinib may be even more effective at promoting complete inhibition of HER pathway 
signaling and bypassing resistant mechanisms. Neratinib also showed to increase ADCC responses 
of trastuzumab by stabilizing and accumulating inactive HER2 receptor dimers (HER2/HER2, 
HER2/EGFR, HER2/HER3) at the cell surface, thereby, increasing trastuzumab binding and 
immune-mediated action[13, 14]. In tumor xenografts with HER2 overexpressed cell lines, 
neratinib shown to suppress tumor growth in a dose-dependent manner, that further support 
efficacy induced by neratinib itself [6].    
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The other interesting data regarding neratinib includes the anti-HER2 mutation activity. Seven 
activating HER2 mutations were detected in HER2 gene amplification negative breast cancer, and 
all of these mutations were sensitive to neratinib. Other HER2 targeted drugs were less potent and 
not effective in reducing the growth of cells bearing HER2 mutations.  
• Clinical Data of Neratinib 
Neratinib has demonstrated its antitumor activity in phase I and II clinical studies in patients with 
HER2 positive breast cancer, including ones with or without prior exposure to trastuzumab, as 
well as in patients with other solid tumors.[15, 16]  
In a Phase I clinical trial of neratinib, the dose-limiting toxicities (DLT) were diarrhea, nausea and 
vomiting, anorexia, and rash. DLT was reached at 320 mg orally per day. The MTD was 240 
mg/day. The overall response rate observed in breast cancer patients in the Phase I study was 32% 
(8/25), and within 18 patients with HER2+ by IHC (3+) was 39% (7/18). 
A Phase II study evaluated neratinib as monotherapy at a dose of 240 mg per day in patients with 
HER2+MBC. Response rate was 24% in 63 patients who had previous treatment with trastuzumab 
and 56% in 64 patients who were trastuzumab-naïve. The most common adverse events, all grades, 
in both cohorts included diarrhea 89% to 97% (grade 3-4 43%), nausea 30% to 42%, and 
rash/dermatitis 13% to 27%. Hand-foot syndrome was not observed [16].  
In adjuvant setting, sequential therapy with 1 year of trastuzumab followed by 1 year of neratinib—
ExteNET study showed improved disease-free survival. In this study, stage 2–3 HER2-positive 
breast cancer who had completed trastuzumab therapy up to 1 year previously. Patients were 
randomly assigned (1:1) to receive oral neratinib 240 mg per day or matching placebo, and the 
PFS was 93.9% in neratinib group vs 91.6%. While further longer follow up is warranted to 
confirm this early signal, this study proved the benefit of additional use of neratinib in HER2 
positive breast cancers [17].  
3.3 Rationale for Selected Subject Population 
• Cohort I phase Ib: HER2+ metastatic and locally advanced breast cancer 
This phase Ib is performed to determine MTD and recommended phase 2 dose (RP2D) of neratinib, 
pertuzumab, trastuzumab and paclitaxel combination. 
• Cohort I phase II: HER2+ in IBC  
HER2+ subtype is higher in IBC (40%) than non-IBC [18], Table 1 shows, HER2+ IBC patients 
have worse prognosis compared with HER2+ non-IBC. Therefore, it is of significant importance 
to develop new effective HER2 therapies for this subgroup of patients with IBC.  In the US, 
pertuzumab in combination with trastuzumab and chemotherapy has rapidly gained acceptance as 
the new standard of care for stage II and III HER-2+ non-IBC and IBC based in NeoSphere[19] 
and TRYPHAENA[20] studies.  The pCR rates were 45.8% and 66.2%, respecetively.  In the 
NeoSphere study (n=417), trastuzumab and pertuzumab, either alone or combined or added to 
docetaxel, were evaluated preoperatively in women with locally advanced and inflammatory breast 
cancer. The pCR were as follows: trastuzumab plus docetaxel (TH), 29%; trastuzumab, 
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pertuzumab plus docetaxel (THP), 46%; trastuzumab and pertuzumab (HP), 17%; and pertuzumab 
plus docetaxel (TP), 24%. pCR with THP was significantly higher (p=0.014) than with TH which 
was significantly higher than with HP (p=0.020)[19]. However, the resistance to first and second 
generation HER2 targeted therapy still occurs. Given the higher proportion among molecular 
subtypes, and the lower pCR rate compared to non-IBC patients, our question is whether simple 
double HER2 targeting therapy in HER-2+ IBC is sufficient (e.g., pertuzumab and trastuzumab). 
Therefore additional HER family blockade by a irreversible inhibitor of pan ErbB receptor tyrosine 
kinase, neratinib, may induce additional or synergistic benefit. In breast cancer, HER2/HER3 
dimerization promotes the strongest mitogenic signaling, primarily through the PI3K/AKT 
pathway, which is critical in maintaining cell proliferation and survival[21]. Resistance to targeted 
therapies is a result of constitutive activation of the PI3K/AKT pathway through upregulation of 
the HER3 receptor that directly binds and activates PI3K via ligand-dependent and ligand-
independent mechanisms [22, 23]. Pertuzumab enhances the efficacy of anti-HER2 inhibition 
especially with antibody-dependent cell mediated cytotoxicity (ADCC)[8, 24, 25].  Pertuzumab 
prevents the heterodimerization of HER2: HER3. In HER2 overexpressing cells and tumors that 
are ligand-independent, enhanced downstream signaling is inhibited by trastuzumab whereas 
ligand-dependent signaling can be blocked by the addition of pertuzumab to disrupt HER2 homo- 
and heterodimers [26, 27]. However, small molecule inhibitor also has its own benefit. Neratinib 
showed a higher response rate than lapatinib in phase non-randomized II trials in HER-2+ MBC. 
Lapatinib and neratinib response rates in trastuzumab-refractory patients was 5.1% vs. 24%, 
respectively and in trastuzumab-naïve patients 24% vs. 56%, respectively[16, 28, 38] This data 
support the rationale that a small molecule TKI may add to the efficacy of trastuzumab and 
pertuzumab in the neoadjuvant setting. Pertuzumab, another antibody to HER2, binds to domain 
II and prevents the heterodimerization of HER2:HER3.  
 
Cohort II: HER2-/HR+ in IBC     
From our previous study, the pCR rate in IBC patients was worse than non-IBC patients. IBC 
patients’ pCR rate of ER+/HER2-is worse compared with other subtypes. (ER+/HER2+:13.6%; 
N=96, ER+/HER2-:8.2%; N=231, ER-/HER2+: 31.7%; N=180, ER-/HER2-: 15.2%; N=224; 
Table 1). Therefore, we need new drug combinations to improve pCR[29] across all molecular 
subtypes, especially, in ER +/HER2- IBC.  
The rate of HER2 mutation in overall breast cancer has previously shown to be approximately 
1.6%[9], however from our unpublished data (Matsuda et al), HER2 mutation was found in 4/28 
patients in hormone receptor positive IBC patients (14%), which is significantly higher than 
previously reported rate of mutation. This finding suggests that ER+ IBC patients have more 
frequent HER2 mutation compared to ER- IBC patients. As shown in above section, neratinib also 
has activity against HER2 mutated breast cancer cells, offering the second rationale of utilizing 
neratinib in HER2 negative but hormone receptor positive IBC patients.  
More interestingly, our preclinical analysis of IBC cell lines shows that ER+ IBC cell lines over-
expressing p-EGFR. EGFR was overexpressed in 30% of IBC, and has been clearly correlated 
with worse prognosis in patients with IBC [30]. In our ongoing single-arm phase II study in 
patients with primary HER2- IBC treated with panitumumab, nab-paclitaxel, and carboplatin and 
FEC preoperative systemic chemotherapy, panitumumab, EGFR tyrosine kinase inhibitor, has 
antitumor activity against IBC, and supports the role of EGFR aberration in IBC. In this study, 3 
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out of 15 ER+/HER2- patients (20%) achieved pCR. So an EGFR targeted therapy using neratinib 
may have a promising role in this sub-type of IBC. 
Table1: Summary for pCR rate in IBC (N=731, MDACC data; from 1989 to 2011) and non-
IBC (historic data)  
  
TNBC 
ER+/HER2- 
ER+/HER2+ 
ER-HER2+ 
pCR in IBC 
15% 
8.2% 
14%  
32% 
pCR in non-IBC 
30-40% 
7-16%  
35% 
40-60% 
* Most recent small data set HER2 + IBC pCR rate: 39% 
We hypothesize that in HR +/HER2- IBC patients, neratinib improve the pCR possibly via: 1) 
EGFR targeting, 2) HER2 mutation targeting despite lack of clinical amplification of HER2. To 
test both hypotheses in HR+/HER2- IBC population, we propose a phase II study using neratinib 
in HR+ HER2- IBC patients, and design a cohort that has expansion criteria for HER2 mutation 
patients. While the data is accumulating after introduction of trastuzumab and pertuzumab, 
MDACC’s most recent collection of HER2 positive IBC patients showed 9/23 patients achieving 
pCR (39%), still not optimal and less compared to non-IBC patients. 
Taken together, these provide the rationale for adding neratinib, irreversible tyrosine kinase 
inhibitor of the ErbB family of receptors (epidermal growth factor receptor (EGFR)/HER1, HER2, 
and HER4), which covalently binds to the cytoplasmic domain of ErbB receptors and prevents 
downstream signaling [6, 31], for HER2+ and HER2-/HR+ IBC patients. Using neratinib 
combination therapy is a promising approach for these patients for whom more effective agents 
have been needed to achieve pCR.  
3.4 Rationale for the Dose Selection/Regimen/Modification 
Anthracycline-containing regimens (e.g., AC, FAC, EC or FEC) and taxanes (paclitaxel or 
docetaxel) are the most effective cytotoxic agents in the management of early and advanced breast 
cancer including IBC[2]. However, with best available chemotherapy combination, the pCR rate 
among IBC patients is still limited as shown in table 1. This is why targeted agents should be 
introduced to standard anthracycline (AC) and taxane regimen. However, novel combination 
should also be safe, and able to be tolerated in breast cancer patients. 
The feasibility of safe combination of neratinib and paclitaxel/ neratinib with trastuzumab has been 
tested in a previous clinical trial, allowing to safely launch of our phase II study. Neratinib dosing 
of 200 mg/day was chosen as the maximal tolerated dose of NSABP FB-8, a Phase I dose 
escalation study evaluating the combination of weekly paclitaxel with neratinib and trastuzumab 
in women with metastatic HER2+ MBC, based on the results of this phase I study, this dose was 
later evaluated in phase II trial in HER-2+ stage II/III BC, NSABP B-7. The analysis of this phase 
Ib study showed grade 2 or greater diarrhea occurred in 7 of 17 patients with most patients 
experiencing diarrhea within 1 to 3 days of starting therapy. Typically, after the first two weeks of 
therapy, diarrhea diminished and was easily managed. During the course of this study, the diarrhea 
management was intensified from the recommendation to start anti-diarrheal at the first loose stool 
to initiation of anti-diarrheal with the first dose of neratinib. Taken together, we selected neratinib 
200mg/day in cohort II when only paclitaxel is combined with neratinib.  
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There are no data of safety and tolerability of four-drug combination, neratinib, pertuzumab, 
trastuzumab and paclitaxel. Therefore we will perform a phase Ib dose escalation study evaluating 
the combination of neratinib with pertuzumab, trastuzumab and paclitaxel in women with 
metastatic and locally advanced HER2+ breast cancer in cohort I. The Bayesian modified Toxicity 
Probability Interal (mTPI) dose-escalation algorithm will be used to estimate the MTD from the 
five doses. 
3.5 The Rationale for Adaptive Response Change Assessment utilizing Tissue/Blood based 
Biomarkers – Window period and screening HER2 mutation  
The primary setting provides a unique opportunity to discover candidate predictive markers of 
response to study drugs since pretreatment tissue can be obtained as core biopsy samples. The 
molecular profile obtained from the core biopsy samples can be correlated with pathologic and 
clinical response without the need for long-term follow-up. One of our main exploratory questions 
in this study is whether we can identify tumors that have higher efficacy of neratinib via molecular 
profiling. Molecular profiling can be done from both tissue and blood based analysis. The answer 
could be as simple as the level of gene amplification or expression of HER2 itself or as complex 
as co-expression levels of other members of the EGFR family of receptors, presence of HER2 
mutation, or the activation profile of a downstream signaling pathway. We will use various 
molecular profiling techniques to test and discover markers that can identify tumors that are 
selectively responsive to neratinib. To achieve this goal, it is critical to find what exact panel of 
biomarkers change after neratinib, a pan-HER inhibitor will be introduced as an adaptive response. 
Here are supportive reasons why this is critical. 
First, to date, no biomarkers have been established to identify patients who might benefit from 
dual inhibition of HER2 and EGFR. In phase I and II clinical studies in patients with HER2-
positive breast cancer, neratinib has demonstrated antitumor activity, but we do not know the 
selective biomarker of patients who had additional benefit [15, 16]. Secondly, while neratinib has 
shown to be more potent irreversible HER2 inhibitor, subsequent downstream changes that are 
different from other HER2 inhibitors related changes have not been investigated further. Thirdly 
and more importantly, the core biology of cancer that can potentially associated with eventual 
achievement of pCR and longer PFS that are induced by HER pathway suppression have not been 
well established in clinical setting, and need to be further elucidated. Well-designed patient tissue 
and blood sample analysis comparing before and after neratinib treatment will enlighten such 
important biological questions, and thus mandated in at least 20 patients per cohort, in our protocol. 
Specifically in cohort II, HER2 somatic mutations in HER2 gene-amplification negative breast 
cancer patients through cancer genome sequencing have been identified, and Rose R., et al 
(2013)[9] found seven activating HER2 mutation and neratinib was a very potent inhibitor for all 
of these HER2 mutations. Therefore, we like to enroll a minimum of 18 patients with HER2 
mutation confirmed with in house platform PCR based mutation testing to discover the rate, and 
different efficacy to induce pCR of neratinib containing regimen. 
In terms of EFGR expression, in the results of a phase II trial in patients with advanced non-small-
cell lung cancer, neratinib showed significant and durable response among the small cohort of 
patients with G719X mutation in EGFR [32], and therefore justifying the rationale to study the 
association between EGFR mutation or over expression with clinical outcome.  
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Plasma RNA seq 
As we aim to identify other new biomarkers by employing a novel approach, that allows serial 
monitoring over the course of the combination treatment. Thermostable group II intron reverse 
transcriptases (TGIRT)-seq is a new strand-specific RNA-seq method based on technology 
developed by our collaborator Dr. Alan Lambowitz at UT Austin exploits the beneficial properties 
of TGIRTs to obtain more comprehensive RNA-seq libraries 1,2. TGIRT enzymes have higher 
processibility and fidelity compare to retroviral reverse transcriptases, and a novel template-
switching activity that enables addition of RNA-seq adapters without RNA ligation, an inefficient 
and bias-inducing step in other RNA-seq methods 3. TGIRT-seq offer additional advantage of the 
ability to comprehensively profile mRNAs and long non-coding (nc) RNAs in the same RNA-seq 
as small ncRNAs 1. The latter include not only miRNAs but also structured small ncRNAs, 
including tRNAs and tRNA fragments, which are potential cancer biomarkers and have been 
suggested to play a key role in breast cancer etiology and metastasis 1,2,4. TGIRT-seq is the only 
method that can readily distinguish tRNA fragments from strong stops to reverse transcription 
during RNA-seq library preparation 5. TGIRT-seq will allow us to completely annotate and 
quantify a larger number of gene transcripts than other methods, provide information on alternative 
and novel splicing events relevant to chemotherapy resistant IBC, and detect known as well as 
novel mRNA. Furthermore, this novel assay can be conducted on multiple blood based samples, 
allowing serial monitoring on the whole RNA information. 
Circulating Tumor DNA 
The ability to detect cancer mutations in blood provides a possible solution to these and many 
other challenges that arise from multiple tumor biopsies. Advanced-stage tumors often shed cell-
free DNA (cfDNA)6, or circulating tumor DNA (ctDNA) into the bloodstream, which can be 
isolated from a non-invasive blood draw and detected by polymerase chain reaction (PCR)-based 
assays or next-generation sequencing (NGS)-based testing. ctDNA sequencing have benefit of 
easy access to the sample, less invasiveness, and cost effectiveness, and has shown its value in 
breast cancer as well7. More recently, with advancement of field, now ctDNA detection can be 
employed in the early detection, or monitoring of the therapeutic response. ctDNA approach is the 
ability to monitor the quantities and identities of tumor-derived genetic lesions over time via 
routine and minimally invasive blood draws. Taking advantage of benefit from ctDNA as available 
technique, we will collect serial blood sample that can monitor the different genomic population 
for the patients with IBC, at baseline and throughout the course of treatment. We expect to see the 
change in the downstream molecules, e.g., Akt and mTOR with different existence of sub-
population and emergence of new subpopulation over the course of treatment using neratinib and 
others we use in this protocol. 
3.6 Study Endpoint 
3.6.1 Primary endpoint: 
• pCR rate after study combination that is determined by pathological complete response in 
breast and axillary lymph nodes (pCR breast & nodes) in HER2+ and HER2-/ HR+ IBC treated 
with neratinib-based treatment. The determination of pCR will be performed by one of our 
breast pathologist.  
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Protocol/Amendment No.: 2016-0537 
PI:  Rachel Layman, MD;  
Date:  1/12/2021 
 
 
• To determine MTD in neratinib, pertuzumab, trastuzumab and paclitaxel treatment.. 
3.6.2 Secondary endpoints: 
• Two years progression-free survival (PFS) rate of HER2+, and HER2-/ HR+ IBC subgroups. 
• Toxicity profile of combination therapy 
3.6.3 Correlative endpoints: 
• To determine the rate of HER2 mutation in HER2+ IBC and HER2-/ HR + IBC 
• To determine the association between HER2 mutation and pCR achieved by combination 
therapy 
• To determine one week window period of neratinib induced changes of pEGFR, EGFR by 
mRNA and protein assay and correlation with pCR 
• To determine neratinib induced EGFR and HER2 downstream pathway molecules, e.g., Akt, 
STAT, Foxm1 and correlation with pCR 
• To determine the correlation between tumor tissue based pharmacodynamic marker changes 
in association with CTC and ctDNA 
 
4.0 METHODOLOGY  
4.1 Entry Criteria  
In order to be eligible for study participation, subject must meet the following criteria. 
4.1.1 Common Inclusion Criteria 
1. Histological confirmation of breast cancer 
2. 18 years of age or older 
3.  Able to provide written informed consent for the trial. 
4. Performance status of ≤1 on the ECOG performance scale. 
5. Able to swallow oral medication. 
6. LVEF assessment by 2-D echocardiogram or MUGA scan performed within 90 days prior to 
registration must be ≥ 50%. 
7. Adequate organ function as determined by the following laboratory values: 
• Absolute neutrophil count ≥ 1,500 /μL 
• Platelets ≥ 100,000 / μL 
• Hemoglobin ≥ 9 g/dL 
• Creatinine clearance > 50 ml/min 
• Total bilirubin ≤ 1.5 X ULN. For patients with congenital unconjugated hyperbilirubinemia 
(Crigler-Najjar syndrome type 1 and 2, Gilbert syndrome) that transient hyperbilirubinemia 
can occur due to physiological condition, as long as there is clear documentation of 
diagnosis, allowed to be enrolled if direct (conjugated) bilirubin is ≤ 1.5 X ULN 
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Protocol/Amendment No.: 2016-0537 
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Date:  1/12/2021 
 
 
• Alanine aminotransferase and aspartate aminotransferase < 2.5 X ULN except in patients 
with AST/ALT elevation that is declared to be caused due to liver metastasis, they are 
allowed to be enrolled as long as <5 x ULN. 
8.  Subject of childbearing potential should be willing to use effective methods of birth control  
     or be surgically sterile, or abstain from heterosexual activity for the course of the study     
     through at least 4 months after the last dose of study drug. Subject of childbearing potential    
is defined as has not been surgically sterilized or  free from menses for > 1  year.  
Effective methods of birth control include: 
1) Use of hormonal birth control methods: pills, shots/injections, implants (placed under the 
skin by a health care provider), or patches (placed on the skin);  
2) Intrauterine devices (IUDs);  
3) Using 2 barrier methods (each partner must use 1 barrier method) with a spermicide.   Males 
must use the male condom (latex or other synthetic material) with spermicide.  Females must 
choose either a Diaphragm with spermicide, or Cervical cap with spermicide, or a sponge 
(spermicide is already in the contraceptive sponge). Female patients of childbearing potential 
must have a negative urine pregnancy test no more than 7 days prior to starting study drug. 
4) For male participant, they must agree and commit to use a barrier method of contraception 
while on treatment and for 3 months after the last dose of investigational product. 
 
4.1.2 Cohorts I and II specific Inclusion Criteria 
Cohort I:  
Phase Ib: Patient must have HER2 + (regardless of hormonal receptor status) metastatic or locally 
advanced breast cancer (IBC or Non-IBC). 
Phase II:  Patient must have HER2+ (regardless of hormonal receptor status) stage III IBC or Stage 
IV IBC if the metastatic sites are amenable for local therapy (i.e. radiation and/ or surgery) and 
will have breast surgery. 
Cohort II  
Patient must have HER2-/ HR+ stage III IBC or Stage IV IBC if the metastatic sites are 
amenable for local therapy (i.e. radiation and/ or surgery) and will have breast surgery.  
Definition: 
HER2 positive status is defined as strongly positive (3+) staining score by IHC, or gene 
amplification using FISH, if performed. If IHC is equivocal (2+), please refer to Appendix H for 
current ASCO guidelines algorithm for evaluation of HER2.    
HER2 negative status, which is determined by assays using IHC require negative (0 or 1+) staining 
score. If IHC is equivocal (2+) staining score, please refer to Appendix H for current ASCO 
guidelines algorithm for evaluation of HER2.    
Hormone receptor (HR) positivity is determined by ER ≥10% and /or PR ≥10% by IHC staining. 
If patients have paraffin blocks or unstained slides from outsides the institution, the material can 
be used for baseline biomarker tissue as validation. 
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Protocol/Amendment No.: 2016-0537 
PI:  Rachel Layman, MD;  
Date:  1/12/2021 
 
 
IBC is determined by using international consensus criteria:  
• Onset: Rapid onset of breast erythema, edema and/or peau d’orange, and/or warm breast, 
with/without an underlying breast mass 
• Duration: History of such findings no more than 6 months 
• Extent erythema occupying at least 1/3 of whole breast 
• Pathology: Pathologic confirmation of invasive carcinoma 
 
4.1.3 Exclusion Criteria:  
1. Excisional breast biopsy or lumpectomy for the current breast cancer.   
2. Any other previous malignancies (except for cervical in situ cancers treated only by local 
excision, and basal and squamous cell carcinomas of the skin) within 5 years. 
3. Any other previous antitumor therapies for the current cancer diagnosis event. This exclusion 
does not apply to phase Ib part of cohort I.  
4. Breast-feeding at screening or planning to become pregnant during the course of therapy. 
5. History of active or known autoimmune disease that can cause diarrhea like (but not limited 
to) Addison's Disease, Celiac Disease/Gluten Intolerance/Irritable Bowel Syndrome, 
Scleroderma. 
6. Active infection or chronic infection requiring chronic suppressive antibiotics. 
7.  Known hepatitis B or hepatitis C with abnormal liver function tests. 
8. Malabsorption syndrome, ulcerative colitis, inflammatory bowel disease, resection of the 
stomach or small bowel, or other disease or condition significantly affecting gastrointestinal  
function. 
9. Persistent ≥ grade 2 diarrhea regardless of etiology. 
10. Sensory or motor neuropathy ≥ grade 2  
11. Conditions that would prohibit intermittent administration of corticosteroids for paclitaxel 
premedication. However, corticosteroid can be dropped after confirming of no asthma like 
reaction to paclitaxel after 3 doses. 
12. Uncontrolled hypertension defined as a systolic BP > 150 mmHg or diastolic BP > 90 mmHg, 
with or without anti-hypertensive medications. 
13. Cardiac disease (history of and/or active disease) that would preclude the use of any of the 
drugs included in the treatment regimen. This includes but is not confined to: 
---Active cardiac diseases including: 
• symptomatic angina pectoris within the past 180 days that required the initiation of or 
increase in anti-anginal medication or other intervention; 
• ventricular arrhythmias except for benign premature ventricular contractions; 
• supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with 
medication; 
• conduction abnormality requiring a pacemaker; 
• valvular disease with documented compromise in cardiac function; and 
• symptomatic pericarditis. 
---History of cardiac disease: 
• myocardial infarction documented by elevated cardiac enzymes or persistent regional wall 
abnormalities on assessment of LV function; 
• history of documented CHF; and 
• documented cardiomyopathy.       
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Protocol/Amendment No.: 2016-0537 
PI:  Rachel Layman, MD;  
Date:  1/12/2021 
 
 
14. If you are pregnant, you will not be enrolled on this study 
 
4.2 Treatment Plan 
4.2.1 Treatment procedures 
After obtaining informed consents, all eligible patients will be registered in the Clinical Oncology 
Research system. Based on biomarker status (HER2 and hormonal receptor), patients will be 
assigned to Cohort I and Cohort II.  
In Cohort I, patients will receive Neratinib, Paclitaxel, Pertuzumab and Trastuzumab (for both 
Cohort I phase Ib and Cohort I phase II), then followed by doxorubicin/cyclophosphamide 
(Cohort I Phase II only)    
 
• Cohort I Phase Ib: We will enroll patients in phase Ib first until maximum tolerated dose 
is reached, and recommended phase II dose (RP2D) is determined. A maximum of 20 
patients will be treated in this group.  
• Cohort I Phase II: Upon determination of RP2D, maximum of 31 patients will be treated 
in this cohort.  
 In Cohort II, 31 patients will receive neratinib and paclitaxel. We will enroll additional up to  17 
ER+ HER2- patients with a HER2 mutation for the expansion cohort until we have total 18 such 
patients (See 11.1cohort II).  
Post–neoadjuvant chemotherapy patient treatment who are enrolled in this trial will follow 
standard of care for IBC patients, as summarized in our review paper Yamauchi et al. Oncologist 
201237. 
4.2.2 Dosage of combination agents (Table 2 & 3) 
Table 2: Cohort I Phase II Patients will receive 4 cycles of neratinib, pertuzumab, 
trastuzumab and paclitaxel followed by 4 cycles of doxorubicin and cyclophosphamide  
 
Premedications 
Dose 
Route 
Schedule 
Each cycle 
is 
 3 weeks 
Neratinib 
Loperamide and 
budesonide (see 
section 5.2.1.2 ) 
Phase Ib: starting dose at 80 
mg, see Figure 5 for Dose-
Escalation Rules and Table 8 
for dose modification, no 
dose escalation in the same 
patient 
 
phase II: 
recommended phase II dose  
 
oral 
single agent 
daily during 
window 
period 
 
C1-4 daily 
 
 
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Protocol/Amendment No.: 2016-0537 
PI:  Rachel Layman, MD;  
Date:  1/12/2021 
 
 
Pertuzumab 
Use institutional 
guideline 
840 mg loading dose, 
followed by 420 mg 
IV over approx.. 60 
min 
If no reaction to the 
first dose of 
pertuzumab, 
approx..30 min for 
subsequent dose 
C1-4  
every 3 
weeks 
Trastuzumab 
Use institutional 
guideline 
8 mg/kg loading dose, 
followed by 6 mg/kg 
IV over approx 90 
min 
If no reaction to the 
first dose of 
trastuzumab, 
approx..30 min for 
subsequent dose 
C1-4 
every 3 
weeks 
Paclitaxel 
Use institutional 
guideline 
80 mg/m2 
 
IV over approx.. 60 
min 
C1-4   
(weekly x 
12) 
 
Doxorubicin 
Use institutional 
guideline 
60 mg/m2 
IV, follow 
institutional 
guideline 
C5-8 
every 2-3 
weeks 
Cyclophosphamide 
 
Use institutional 
guideline 
600 mg/m2 
IV, follow 
institutional 
guideline 
C5-8 
every 2-3 
weeks 
Note: Doxorubicin and cyclophosphamide are per standard of care, administration of dose 
dense will be permitted per physician’s discretion. 
 
Table 3. Cohort II Patients will receive 4 cycles of neratinib and paclitaxel followed by 4 
cycles of doxorubicin and cyclophosphamide 
 
 
Premedications  
Dose 
Route 
Schedule 
Neratinib 
Loperamide and budesonide (see 
section 5.2.1.2 ) 
200mg 
oral 
C1-4 daily  
 
Paclitaxel 
Use institutional guideline 
80 mg/m2 
IV over approx.. 
60 min 
C1-4   
(weekly x 12) 
 
Doxorubicin 
Use institutional guideline 
60 mg/m2 
IV, follow 
institutional 
guideline 
C5-8 
every 2-3 weeks 
Cyclophosphamide 
 
Use institutional guideline 
600 mg/m2 
IV, follow 
institutional 
guideline 
C5-8 
every 2-3 weeks 
Note: Doxorubicin and cyclophosphamide are per standard of care, administration of dose 
dense will be permitted per physician’s discretion. 
 
Infusion reactions during Pertuzumab and Traztuzumab administration is per institutional policy, 
instructions present in treatment plan.  
 
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Protocol/Amendment No.: 2016-0537 
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Date:  1/12/2021 
 
 
4.2.3 Phase Ib dose escalation management 
The Phase Ib portion of the trial will be restricted to cohort I patients only.  MTD will be 
determined from the five doses listed below, starting at Dose Level 0 (neratinib at 80mg/day). 
 
Dose Level 
Neratinib Dose 
-1 
40 mg 
0 
80 mg 
1 
120 mg 
2 
160 mg 
3 
200 mg 
 
Definition of DLT 
DLT includes any of the following possibly, probably, or definitely due to study therapy, assessed 
during the first 2 cycles [42 days]: 
• Any death not clearly due to the underlying disease or extraneous causes 
• Non- hematologic toxicity  
o    Grade 3 or higher non-hematologic toxicity, except grade 3 diarrhea is a DLT if it 
lasts ≥ 2 days despite prophylactic medication 
o    Grade 2 diarrhea lasting ≥ 5 days despite prophylactic medication 
o    Hy's Law case, defined as a patient meeting all of the following criteria: 
a.  ALT or AST ≥ 3 x Upper Limit of Normal (ULN) 
b.  Total bilirubin >2 x ULN 
c.  Little or no evidence of cholestasis (alkaline phosphatase <2 x ULN) 
d.  No other identified explanation for the injury (such as hepatitis A, B, C, 
or other viral hepatic injury, alcohol ingestion, congestive heart failure).  
o    Neutropenic fever  
• Hematologic toxicity  
o    Grade 4 neutropenia or thrombocytopenia >7 days 
o    Grade 3 thrombocytopenia with bleeding  
 
The targeted maximum DLT rate is 20%, and we will enroll patients in cohorts of size 2.  A 
maximum of 20 patients will be treated at the five dose levels.  The Figure 5 in section 11.2 
provides the rules for escalation and de-escalation once each cohort of patients has been assessed. 
The MTD is defined as the highest dose for which the posterior probability of toxicity is closest to 
20%. Once MTD is determined, Phase Ib is completed and eligible patients will start to be enrolled 
to Cohort I phase II part.  
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Protocol/Amendment No.: 2016-0537 
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Date:  1/12/2021 
 
 
4.3 Study Schema and Flow Chart 
Figure 1. Schema of  Cohort I phase Ib Upon completion of 4 cycles of paclitaxel, neratinib, 
pertuzumab and trastuzumab (continuing the same regimen is allowed if clinically indicated),  
further treatment of choice will be determined by the treating physician. 
 
Figure 2. Schema of  Cohort I Phase II  
 
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Protocol/Amendment No.: 2016-0537 
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Figure3. Schema of Cohort II Phase II   
 
 
 
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Protocol/Amendment No.: 2016-0537 
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Date:  1/12/2021 
 
 
Table 4. Cohort I Phase Ib  
 
Pre- 
Study 
 
 (within 
4 
weeks) 
Wk 
1 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Before next treatment 
(continue on the same 
regimen h or treatment 
of physician’s choice) 
±7D 
Wk 
2±1D 
Wk 
3±1D 
Wk 
4±1D 
Wk 
5±1D 
Wk 
6±1D 
Wk 
7±1D 
Wk 
8±1D 
Wk 
9±1D 
Wk 
10±1D 
Wk 
11±1D 
Wk 
12±1D 
Wk 
13±1D 
Neratinib(daily) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Paclitaxel 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pertuzumab 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Trastuzumab 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEs 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Physical exam, PS 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Photography of bilateral 
breastsk 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
CBC w/diff, Platelet a,j 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SMA (serum chemistry) b,j 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
ECGECHO or MUGA 
(within 90 days) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xg 
Urine/Blood pregnancy test 
for childbearing potential 
(within7 days prior to 
starting treatment) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PET/CT or chest and 
abdominal CT scan plus 
bone scan, chest X-ray 
(SOC as clinical indicated) 
X 
Every 3 cycles as clinical indicated 
Bilateral mammography, 
breast MRI, involved 
breast ultrasound with 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xd 

 
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Protocol/Amendment No.: 2016-0537 
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axillary(SOC as clinical 
indicated) 
Tissue collection e 
Xf 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Liquid Biopsy i  
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
a. Before each cycle, may repeat until recovery (absolute neutrophil count≥1.5, Platelets ≥100,000 per mm3). Only WBC, platelets, ANC and hemoglobin will 
be captured in RedCap database 
b. Na, K, Cl, CO2,  BUN, creatinine, magnesium, calcium, SGOT [AST], SGPT [ALT], glucose, LDH,  total bilirubin, 
c. Bilateral mammography, breast MRI involved breast, involved breast and ipsilateral nodal basin ultrasound as SOC as clinical indicated. 
d. Mammography of involved breast, ultrasound of involved breast with regional lymphatic chains, or breast MRI as clinically needed as SOC as clinical 
indicated. 
e. For patients with untreated newly diagnosed locally advanced disease or de novo metastatic disease only, up to 20 patients’ breast core needle biopsy (3-6 
cores) for frozen section will be obtained. 
f. 1) If patient is consented for both 2006-1072 (IBC registry) and this protocol, core biopsy (7cores) will be performed in one setting. 4) If patient is only 
consented for this protocol, core biopsy (3-4 cores) will be performed. Core biopsy tissue can be collected any time before therapy. 
g: Echocardiogram or MUGA scan will be performed every 3 monthly as following standard of care for anti-HER2 regimen during study time  
h. If patients do not show progression or excessive toxicity under treating physician’s discretion, Patients with metastatic disease may continue same regimen for 
up to an additional 4 cycles per physician discretion, and patients with locally advanced disease only may continue same regimen for up to an additional 2 
cycles, per physician discretion  All Labs (except research blood collections) / imaging/ physical exams will continue as in C1-C4,  
i. Research blood collection- One 10 ml EDTA and one 10 ml Streak tube at baseline, after the pharmacodynamics window and after Cycle 4 (Wk 13). 
j. For patients with metastatic disease, in the event that the patient’s condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to 
initiation of the next cycle of therapy. 
k. If applicable. 
 
 

 
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Table 5. Cohort I Phase II 
 
Pre- 
Study 
(within 
4 
weeks) 
Wk 
1 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
AC 
 
Wk 
2±1D 
Wk 
3±1D 
Wk 
4±1D 
Wk 
5±1D 
Wk 
6±1D 
Wk 
7±1D 
Wk 
8±1D 
Wk 
9±1D 
Wk 
10±1D 
Wk 
11±1D 
Wk 
12±1D 
Wk 
13±1D 
Every 2-
3 wks 
±3D x 4 
cycles 
Before 
surgery 
Neratinib(daily) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Paclitaxel 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Pertuzumab 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
Trastuzumab 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEs 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Physical exam, PS 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Photography of bilateral 
breasts 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Xh 
X 
CBC w/diff, Platelet a, 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SMA (serum chemistry) b, 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
ECG, ECHO or MUGA 
(within 90 days) 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
Xj 
 
Urine pregnancy test for 
childbearing potential 
(within7 days prior to 
starting treatment) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PET/CT or chest and 
abdominal CT scan plus 
bone scan, chest X-ray 
(SOC) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mammography, breast 
MRI, breast ultrasound 
with axillary 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xd 
Xd 
Tissue collection e 
Xf 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Xg 

 
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Protocol/Amendment No.: 2016-0537 
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Liquid Biopsy i 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
a: Before each cycle, may repeat until recovery (absolute neutrophil count≥1.0, Platelets ≥100,000 per mm3 per physician discretion, growth factor support 
can be given per physician’s discretion). Only WBC, platelets, ANC and hemoglobin will be captured in RedCap database 
b: Na, K, Cl, HCO3,  BUN, creatinine, Mg, calcium, SGOT [AST], SGPT [ALT], glucose, LDH,  total bilirubin 
c: Bilateral mammography, breast MRI involved breast, involved breast and ipsilateral nodal basin ultrasound.. 
d: Mammography of involved breast, ultrasound of involved breast with regional lymphatic chains, or breast MRI as clinically needed. 
e. Breast core needle biopsy (3-4 cores) for frozen section and paraffin block collection are mandatory for the primary site that obtained for all patients. 10 slides 
are needed for each patient.   
f. 1) If patient is consented for both 2006-1072 (IBC registry) and this protocol, core biopsy (7 cores) will be performed in one setting. . 4) If patient is only 
consented to this protocol, core biopsy (3-4 cores) will be performed. Core biopsy tissue can be collected any time before therapy. 
g. Surgical sample collections. 
h. Only one time before Cycle 1 of AC treatment. 
i. Research blood collection- One 10 ml EDTA and one 10 ml Streak tube at baseline, after the pharmacodynamics window and prior to Cycle # 1 of AC. 
j. Echocardiogram or MUGA scan will be performed every 3 monthly as following standard of care for anti-HER2 regimen during study time 
 
 
 
 

 
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Table 6. Cohort II 
 
 
Pre- 
Study 
(within 4 
weeks) 
Wk 
1 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
AC 
 
Wk 
2±1D 
Wk 
3±1D 
Wk 
4±1D 
Wk 
5±1D 
Wk 
6±1D 
Wk 
7±1D 
Wk 
8±1D 
Wk 
9±1D 
Wk 
10±1D 
Wk 
11±1D 
Wk 
12±1D 
Wk 
13±1D 
Every 
2-3 
wks±3D 
x 4 
cycles 
Before 
surgery 
Neratinib(daily) 
 
X 
X  
X 
X  
X 
X 
X 
X  
X 
X  
X 
X 
X 
 
 
Paclitaxel 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEs 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Physical exam, PS  
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Photography of bilateral 
breasts 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Xh 
X 
CBC w/diff, Platelet a, 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SMA (serum chemistry) b, 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
ECG, ECHO or MUGA 
(within 90 days)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xj 
 
Urine/Blood pregnancy test 
for childbearing potential 
(within 7 days prior to 
starting treatment) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PET/CT or chest and 
abdominal CT scan and 
bone scan, chest X-ray 
(SOC) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
Mammography, breast 
MRI, involved breast and 
nodal basin ultrasound 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xd 
Xd 
Tissue collection e 
Xf 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Xg  

 
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Liquid Biopsy i 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
a: Before each cycle, may repeat until recovery (absolute neutrophil count≥1.0, Platelets ≥100,000 per mm3 per physician discretion, growth factor support 
can be given per physician’s discretion). Only WBC, platelets, ANC and hemoglobin will be captured in RedCap database 
b: Na, K, Cl, HCO3,  BUN, creatinine, Mg, calcium, SGOT [AST], SGPT [ALT], glucose, LDH,  total bilirubin,  
c: Bilateral mammography, breast MRI involved breast, involved breast and ipsilateral ultrasound. 
d: Mammography of involved breast, ultrasound of involved breast with regional lymphatic chains, or breast MRI as clinically needed as SOC. 
e. Breast core needle biopsy (3-4 cores) for frozen section and paraffin block collection are mandatory for the primary site that obtained for all patients. 10 slides 
are needed for each patient.   
f. At baseline, if a patient is consented for both 2006-1072 (IBC registry) and this protocol, core needle biopsy (up to 7 cores) will be performed in one 
setting and tissues will be collected separately for both studies. If core biopsy is already performed for protocol 2006-1072, and patient is subsequently 
consented for this study, core biopsy (3-4 cores) will be performed. 1 core biopsy will be collected for Whole Exome Sequencing for IPCT.  Core biopsy 
tissue can be collected any time before therapy. 
g. Surgical sample collections. 
h. Only one time before Cycle 1of AC treatment 
i. Research blood collection-. One 10 ml EDTA and one 10 ml Streak tube at baseline, after the pharmacodynamics window and prior to Cycle # 1 of AC. An 
additional one 10 ml Streak tube for IPCT at baseline only. 
j. Echocardiogram or MUGA scan will be performed every 3 monthly as following standard of care for anti-HER2 regimen during study time 
 

 
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4.4 Outside Physician Participation During Treatment 
1.  MDACC physician communication with the outside physician is required prior to the patient 
returning to the local physician. This will be documented in the patient record. 
2.  A letter to the local physician outlining the patient's participation in a clinical trial will request 
local physician agreement to participate in the patient's care (Appendix D in PDOL). 
3.  Protocol required evaluations outside MDACC will be documented by telephone, fax or e-
mail.  Fax and/or e-mail will be dated and signed by the MDACC physician, indicating that they 
have reviewed it. 
4.  Changes in drug dose and/or schedule must be discussed with and approved by the MDACC 
physician investigator, or their representative prior to initiation, and will be documented in the 
patient record. 
5.  All decisions regarding dose adjustments and treatment interruptions or re-initiation of 
treatment, grading and attribution of adverse events and assessment of efficacy will be done by 
MDACC investigators. The home physician will not make any decisions regarding dose 
adjustments and/or treatment interruptions or resumption of treatment, grading and/or attribution 
of adverse events, or assessment of efficacy. These will all be done by the MDACC investigators.  
6.  Only routine, standard-of-care laboratory assessments will be done by the home physician. All 
protocol-specific tests will be done at MDACC.  
7.  A copy of the informed consent, protocol abstract, treatment schema and evaluation during 
treatment will be provided to the local physician. 
8.  Documentation to be provided by the local physician will include drug administration records, 
progress notes, reports of protocol required laboratory and diagnostic studies, and documentation 
of any hospitalizations. 
9.  The home physician will be requested to report to the MDACC physician investigator all life 
threatening events within 24 hours of documented occurrence. 
10. Patients will return to MDACC every 3 weeks during the first 4 cycles, before the first dose 
of AC (phase II) or other regimens (phase Ib) and before surgery for evaluation.  
 
5.0 COMMON TOXICITY AND DOSE MODIFICATION 
In this study, neratinib and paclitaxel must be fundamentally reduced for drug-related toxicities 
and severe or life-threatening adverse events (AEs). However, if AEs still remain in spite of 
neratinib and paclitaxel reduction or discontinuation, pertuzumab and trastuzumab should be 
discontinued.  Patient will be taken off from the study. 
If there is overlapping toxicity from two drugs, e.g., diarrhea – which can be caused by both 
neratinib and pertuzumab, neratinib dose will first be reduced. Pertuzumab, without flexibility of 
dose modification will be continued. However even after proper supportive management, and dose 
reduction of neratinib still does not control significant level of toxicity (grade 3 or above for non-
hematologic and hematologic), treatment combination will be stopped and patient will be taken 
off from the study.  
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Protocol/Amendment No.: 2016-0537 
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Date:  1/12/2021 
 
 
5.1 Dose modification of each drug 
5.1.1 Pertuzumab:  
Loading dose 840 mg, followed by 420 mg every 3 weeks. No dose reduction allowed. 
5.1.2 Trastuzumab:  
Loading dose 8 mg/kg, followed by 6 mg/kg every 3 weeks. No dose reduction allowed. 
5.1.3 Paclitaxel:  
There are total 3 levels of dose down for paclitaxel as in table 7. Standard of care for paclitaxel 
administration will be used.  
 
Table 7. Dose modification levels of paclitaxel 
 
Dose Level 0 
Dose Level -1  
Dose Level -2 
Dose Level -3 
Paclitaxel 
80 mg/m2 
70 mg/m2 
60 mg/m2 
Discontinue 
 
5.1.4 Neratinib:  
There are total 4 levels of dose modification for neratinib in phase Ib in cohort1as in table 8 and 
RP2D is decided.  
RP2D is taken in phase II cohort I. 
There are total 3 levels of dose modification for neratinib in phase II as in table 9. With the use of 
mandated primary diarrheal prophylaxis, the RP2D was determined to be 200 mg/day in neratinib, 
trastuzumab and paclitaxel combination therapy.[33] 
 
Table 8. Dose escalation levels of neratinib for phase Ib in cohort I 
 
Dose Level -1 
Dose Level 0 
Dose Level 1 
Dose Level 2 
Dose Level 3 
Neratinib 
40 mg  
80 mg  
120 mg  
160 mg  
200mg 
 
Table 9. Dose modification levels of neratinib for cohort II 
 
Dose Level 0 
Dose Level -1  
Dose Level -2  
Dose Level -3 
Neratinib 
200 mg  
160 mg  
120 mg  
Discontinue 
 
5.2 Common toxicity and management 
5.2.1 Management of Diarrhea, and Dose Modification of Neratinib  
5.2.1.1  Patients Education 
Diarrhea is a commonly occurring toxicity. Monotherapy with neratinib has a median time of 3 
days to onset of diarrhea. With combination therapy, it is anticipated that diarrhea may occur 
earlier. For the majority of patients, diarrhea subsides after about 2 weeks.  
 
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Protocol/Amendment No.: 2016-0537 
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Date:  1/12/2021 
 
 
Therefore it is critical that intensive prophylactic measures begin at the start of therapy.  
•  Inform patients that they will experience diarrhea while taking neratinib.  
•  Patients must be instructed to:  
− start prophylactic antidiarrheal therapy (see below) on day 1, with the first dose of neratinib  
− continue prophylactic therapy as directed  
− promptly report diarrhea symptoms  
− record the number of stools per day  
− record each dose of antidiarrheal medicine taken each day  
− report constipation before taking any laxatives or stopping antidiarrheal medication. 
 
5.2.1.2 Intensive primary prophylaxis  
Antidiarrheal medication (loperamide, budesonide) must begin with the first dose of neratinib.  
Patients must take an initial dose of loperamide (Imodium®) 4 mg p.o. with the first dose of 
neratinib, then followed by 4 mg TID for the first 14 days.  After two weeks on study, patients will 
take 4 mg twice a day (BID) for the remainder of the first two cycle of neratinib. Thereafter, 
loperamide will be administered as needed throughout neratinib treatment (Table 10).  
 
Budesonide will be taken with neratinib and intensive loperamide prophylaxis at a dose of 9 mg 
once daily during week 1 and cycle 1 for 28 days. 
 
Table 10: Loperamide Dosing for Neratinib Treatment 
 
Loperamide  Dose                                                         Day 
 
4 mg TID with a total daily dose of 12 mg                    Days 1-14 (Cycle 1) 
 
4 mg BID with a total daily dose of 8 mg                     Days 15-49 (Cycle 1-2) 
 
Daily dose as needed (not to exceed 16 mg per day)    Days 50+ (Cycle 3 and beyond) 
 
For Grade 2 diarrhea lasting ≥ 5 days despite prophylactic medication, and higher grade (Grade 3 
and 4), we recommend to follow the guideline as noted in below figure 4 (focusing on the yellow 
box). This figure also contains other adjunctive measures that can help patients to manage the 
diarrhea related issues, e.g., hydration, diet changes: 
 
Figure 4. Management Guideline for Neratinib-related Diarrhea 
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Protocol/Amendment No.: 2016-0537 
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Date:  1/12/2021 
 
 
 
 
5.2.2 Cardiac Left Ventricular Dysfunction and Dose Modification of Neratinib, 
Pertuzumab, and Trastuzumab 
Neratinib, doxorubicin, pertuzumab and trastuzumab must be discontinued for patients who have 
a symptomatic decrease in LVEF.  
• Congestive heart failure (grade 3): 
Patients should be monitored for signs and symptoms of CHF (e.g., dyspnea, tachycardia, cough, 
neck vein distention, cardiomegaly, hepatomegaly, paroxysmal nocturnal dyspnea, orthopnea, 
peripheral edema). If the patient develops any of these signs and symptoms, neratinib, and/or 
pertuzumab, doxorubicin, and trastuzumab must be held. The investigator must confirm the 
diagnosis of CHF with either an echocardiogram or a MUGA scan. Once the diagnosis of CHF is 
confirmed, trastuzumab and neratinib must be permanently discontinued.  
• Severe refractory/poorly controlled CHF (grade 4):  
Neratinib, pertuzumab, doxorubicin, and trastuzumab should be discontinued if patient develops 
severe refractory/poorly controlled CHF. 
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Protocol/Amendment No.: 2016-0537 
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For asymptomatic patients, the decision to continue or stop doxorubicin, neratinib, pertuzumab 
and trastuzumab is based on two factors, the value of the measured ejection fraction and the change 
in ejection fraction from baseline, which was performed at the time of registration. Investigators 
should reference the pertuzumab and trastuzumab labels (see Appendix E and F in PDOL). 
5.2.3 Musculoskeletal Pain, Neuropathy and Paclitaxel Dose Modification. 
The treatment management instructions for neuropathy is in Table 11. If symptoms are in greater 
degree, dose modification is warranted as below. 
 
Table 11. Dose modification of paclitaxel for neuropathy  
 
The treatment management instructions in Table 12 apply to patients with musculoskeletal pain 
not controlled by analgesics. Use of narcotics and NSAIDs is encouraged to maintain the paclitaxel 
dose if possible. 
 
Table 12. Dose modification of paclitaxel for muscular pain 
Paresthesias/Dysesthesias 
1 – 7 Days Duration 
Persistent for > 7 Days or  
Caused a Dose Delay 
Grade 1 Paresthesias/dysesthesias that 
do not interfere with function 
 Maintain paclitaxel dose 
Grade 2 Paresthesias/dysesthesias 
interfering with function, but not 
activities of daily living 
Maintain paclitaxel dosea 
Decrease paclitaxel  
one dose levelb 
Grade 3 Paresthesias/dysesthesias with 
pain or with function impairment that 
also interfere with activities of daily 
living 
First episode:  
Decrease paclitaxel one dose 
levela  
Second episode:  
Discontinue paclitaxel  
Discontinue paclitaxel 
Grade 4 Persistent 
paresthesias/dysesthesias that are 
disabling or life-threatening 
Discontinue paclitaxel 
 
a. Must be resolved to ≤ grade 1 on Day 1 of the next treatment cycle.  
b. Hold paclitaxel for persistent grade 2 neuropathy. When ≤ grade 1, resume treatment with dose  
modification. If grade 2 toxicity persists after 2 weeks of delay, discontinue paclitaxel. 
Musculoskeletal 
Pain 
1 – 7 Days Duration 
Persistent for > 7 Days or  
Caused a Dose Delay 
Grade 1 
(despite 
analgesics) 
 Maintain paclitaxel dose 
Grade 2  
(despite 
analgesics) 
Maintain paclitaxel dose 
Maintain paclitaxel dose  
or  
Decrease paclitaxel one dose level* 
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Protocol/Amendment No.: 2016-0537 
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5.3 Other Toxicity Management  
Table 13. Other toxicity management 
Dose level management  
• Refer to dose level table for paclitaxel and neratinib (Table 3).  
• If paclitaxel is discontinued, neratinib must be discontinued; if neratinib is discontinued, paclitaxel must be 
discontinued.  
Adverse Event 
CTCAE 
Ver 4.0 
Grade 
Paclitaxel 
Neratinib 
Allergy/immunology 
Allergic 
reaction/hypersensitivity 
(including drug fever) 
Investigator must 
determine attribution of 
AE and only follow 
instructions for the 
causal agent. 
1 
Treat as per institutional policy and 
re-challenge (maintain dose) 
 
Maintain dose with no delay 
 
2 
Hold until ≤ grade 1; 
may re-challenge (maintain dose) 
or D/C 
 
3 
Treat as per institutional policy; 
may re-challenge (maintain dose) 
or D/C 
 
Treat as per institutional policy; 
may re-challenge (maintain dose) 
or D/C 
 
4 
D/C 
D/C 
Platelets 
 
2, 3, 4 
Only if present on the scheduled 
treatment day: 
Hold until ≥ 75,000/mm3. If 
recovery takes: 
1-2 weeks – ↓ one dose level 
> 2 weeks – D/C 
Continue with no delay (Platelets 
do NOT need to be ≥ 75,000/mm3 
to continue neratinib.) 
Cardiac arrhythmia 
•Conduction 
abnormality 
• Supraventricular and 
nodal arrhythmia 
• Ventricular arrhythmia 
• Other 
      2 
 
Hold until rhythm is controlled; then resume and maintain dose 
3 
Hold until rhythm is controlled, 
then resume (maintain dose) or D/C 
Hold until rhythm is controlled, 
then resume (maintain dose) or D/C 
4 
D/C 
D/C 
Cardiac general 
Cardiac 
ischemia/infarction 
2 
Hold study therapy and conduct a cardiac evaluation. Based on this 
evaluation, continuation of paclitaxel and/or neratinib is at the 
investigator's discretion. 
3,4 
D/C 
D/C 
Left ventricular 
dysfunction 
2, 3, 4 
Refer to Section 4.2.2 
Grade 3  
(despite 
analgesics) 
First episode:  
Decrease paclitaxel one dose level 
Second episode:  
Discontinue paclitaxel  
First episode:  
Decrease paclitaxel one dose level*  
or  
Discontinue paclitaxel  
Second episode: Discontinue paclitaxel 
Grade 4 
(despite 
analgesics) 
 Discontinue paclitaxel 
* Hold paclitaxel for persistent grade 2 or 3 musculoskeletal pain. (Targeted therapy should be continued  
while paclitaxel is held.) When ≤ grade 1, resume treatment with paclitaxel dose modification. If grade 2 
 or grade 3 toxicity persists after 2 weeks of delay, discontinue paclitaxel. 
 
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Protocol/Amendment No.: 2016-0537 
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Dose level management  
• Refer to dose level table for paclitaxel and neratinib (Table 3).  
• If paclitaxel is discontinued, neratinib must be discontinued; if neratinib is discontinued, paclitaxel must be 
discontinued.  
Adverse Event 
CTCAE 
Ver 4.0 
Grade 
Paclitaxel 
Neratinib 
Dermatology/Skin  
• Rash/desquamation  
• Rash: acne/acneiform  
Note: Clinical 
management of 
acne/acneiform rash is 
at the investigator's 
discretion.  
 
2 
 
Management, dose holding, and 
dose reduction per treating 
physician’s discretion per SOC.  
 
1st appearance: Continue without 
delay or hold until improvement; 
maintain dose  
2nd appearance: If recurrent or 
intolerable, hold until improving 
and ↓ one dose level  
3rd appearance: ↓ one dose level or 
D/C if intolerable  
3 
Hold until ≤ grade 2  
1st appearance: ↓ one dose level  
2nd appearance: D/C  
4 
D/C 
Nail changes 
(Paronychia)  
Note: See Section 9.8.2 
for neratinib-related nail 
change instructions.  
2 
Maintain dose with no delay unless 
medically contraindicated  
 
1st appearance: Continue without 
interruption or hold until 
improvement and maintain dose  
2nd appearance: If recurrent or 
intolerable, hold until improving 
and ↓ one dose level  
3rd appearance: ↓ one dose level or 
D/C if intolerable  
 
 
3 
Hold until ≤ grade 2  
1st appearance: Maintain dose or ↓ 
one dose level  
2nd appearance: ↓ one dose level or 
D/C  
 
Gastrointestinal  
Diarrhea attributed to 
therapy (see Sections 
5.2.1.2 Table 10 and 
Figure 4 for important 
instructions regarding 
diarrhea management).  
1 
Management, dose holding, and 
dose reduction per treating 
physician’s discretion per SOC.  
 
Maintain dose without delay; 
continue antidiarrheal medication 
management 
2 
Hold until ≤ grade 1 
1st appearance: Maintain dose 
2nd appearance: ↓ one dose level 
3rd appearance: ↓ one dose level or 
D/C 
Note: If anti-diarrheal medication 
use was not maximized, maintain 
dose when ≤ grade 1 
3 
Hold until ≤ grade 1 
1st appearance: ↓ one dose level 
2nd appearance: D/C 
Note: If anti-diarrheal medication 
use was not maximized, maintain 
dose when ≤ grade 1 
4 
D/C 
D/C 
 
 
•Mucositis/stomatitis  
•Vomiting (despite 
antiemetics)  
2 
Management, dose holding, and 
dose reduction per treating 
physician’s discretion per SOC.  
 
Hold until ≤ grade 1  
1st appearance: Maintain dose  
2nd appearance: ↓ one dose level  
3rd appearance: ↓ one dose level or 
D/C  
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Protocol/Amendment No.: 2016-0537 
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Dose level management  
• Refer to dose level table for paclitaxel and neratinib (Table 3).  
• If paclitaxel is discontinued, neratinib must be discontinued; if neratinib is discontinued, paclitaxel must be 
discontinued.  
Adverse Event 
CTCAE 
Ver 4.0 
Grade 
Paclitaxel 
Neratinib 
 
3 
Hold until ≤ grade 1  
1st appearance: ↓ one dose level  
2nd appearance: D/C  
4 
D/C 
 
Hepatic Function  
• Total bilirubin  
• ALT  
• Alkaline phosphatase  
• AST  
 
2 
Management, dose holding, and 
dose reduction per treating 
physician’s discretion per SOC.  
 
Hold until ≤ grade 1  
1st appearance: ↓ one dose level  
2nd appearance: D/C  
3 
Hold until ≤ grade 1  
1st appearance: ↓ one dose level  
2nd appearance: D/C  
4 
D/C 
Infection  
• Febrile neutropenia  
• Infection with grade 3 
or 4 neutropenia  
• Infection with normal 
ANC or grade 1 or 2 
neutrophils  
Note: If adding G-CSF, 
only filgrastim on Days 
2-6, 9-13, and 16-20 
may be used; 
pegfilgrastim is 
prohibited.  
3 
Hold until clinically stable  
1st appearance: Maintain dose and 
add G-CSF  
2nd appearance: ↓ one dose level  
3rd appearance: ↓ one dose level or 
D/C  
1st appearance: Maintain dose with 
no delay (unless it is in the patient's 
best interest to hold neratinib)  
2nd appearance: Maintain dose 
with no delay (unless it is in the 
patient's best interest to hold 
neratinib)  
3rd appearance: ↓ one dose level or 
D/C  
4 
Hold until clinically stable  
1st appearance: ↓ one dose level 
and add G-CSF  
2nd appearance: D/C  
Hold until clinically stable  
1st appearance: Resume neratinib 
and ↓ one dose level  
2nd appearance: D/C  
Pulmonary/Upper 
Respiratory  
Dyspnea  
2,3,4 
Hold study therapy until ≤ grade 1 and CHF and interstitial pneumonitis 
have been ruled out.  
• If caused by CHF or interstitial pulmonary toxicity, D/C therapy.  
• If caused by infection or asthmatic process, resume paclitaxel and 
neratinib therapy when symptoms have resolved to ≤ grade 1.  
Pneumonitis/pulmonary 
infiltrates/other 
pulmonary events  
• Hypoxia  
• Pulmonary fibrosis  
 
2,3 
If a patient develops symptoms suggestive of interstitial pneumonitis, 
ARDS, or non-cardiogenic pulmonary edema, hold paclitaxel and 
neratinib and conduct a pulmonary evaluation.  
• If pulmonary infection is documented, paclitaxel and neratinib may be 
resumed when pulmonary AE has resolved to ≤ grade 1.  
• If non-infectious interstitial lung disease is confirmed, D/C therapy.  
4 
D/C 
D/C 
Other AEs requiring 
dose modification per 
investigator  
Note: Investigator must 
determine attribution of 
AE and only follow 
dose modifications for 
the causal agent  
3 
Hold until ≤ grade 1  
Modify only if the AE is attributed 
to paclitaxel.  
1st appearance: ↓ one dose level  
2nd appearance: ↓ one dose level  
3rd appearance: D/C  
Hold until ≤ grade 1  
Modify only if the AE is attributed 
to neratinib: 1st appearance: ↓ one 
dose level  
2nd appearance: ↓ one dose level  
3rd appearance: D/C  
4 
D/C 
D/C 
 
5.4 Unanticipated Dose Interruptions  
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Dosing interruptions are permitted in the case of logistical reasons not related to study therapy. 
Subjects should be placed back on study therapy within 3-5 days of the scheduled interruption, 
unless otherwise discussed with the Sponsor. The reason for interruption should be documented in 
the patient's medical record. 
5.5 Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during 
the ongoing trial.  If there is a clinical indication for one of these or other medications or 
vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The final decision on any supportive therapy or vaccination rests 
with the investigator and/or the subject's primary physician.  .  
5.5.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be administered 
at the discretion of the investigator in keeping with the community standards of medical care. 
Concomitant medication will be recorded as standard of care inthe patient’s EMR. .  
Monitoring will be needed if the medications listed are taken with neratinib: 
1. Patients taking anticoagulant therapy (e.g., warfarin or its derivatives, low molecular   
             weight heparin, unfractionated heparin) should be monitored regularly for changes in    
             relevant coagulation parameters as clinically indicated, as well as for any clinical         
             bleeding episodes. The dose of anticoagulant should be adjusted as needed.  
 
2. Patients taking concomitant digoxin should have digoxin levels monitored closely and 
their digoxin dose adjusted as needed.  
 
 
5.5.2 Prohibited Concomitant Medications  
Subjects are prohibited from receiving the following therapies during the study.  
1. Any other anti-cancer agents.  
2. Radiation therapy for curative purpose. 
3. Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid 
(oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however intranasal influenza vaccines (e.g. Flu-Mist®) are 
live attenuated vaccines, and are not allowed. 
Medications listed are prohibited from concomitant use with neratinib.  
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         4.    Agents known to be strong cytochrome P450 (CYP) 3A4 inducers or inhibitors. 
                Refer to Table 14 for a list of selected inhibitors and inducers of the cytochrome P450    
                CYP3A4, 5, 7 isoenzymes. Patients should also avoid grapefruit and herbal remedies,  
               including St John's Wort as well. 
 
5. Chronic immunosuppressive therapies including systemic corticosteroids. Steroids given 
for physiological replacement, as premedication for paclitaxel, as anti-emetics or inhaled 
as well as short course of oral/topical steroids given for allergic reactions or asthma flares 
are allowed.  
Subjects who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the trial. Subjects may receive other 
medications that the investigator deems to be medically necessary. 
Table 14. List of selected inhibitors and inducers of the Cytochrome P450 CYP3A,5,7 
isoenzymes 
INHIBITORS* 
INDUCERS* 
3A4 
OTHER 
3A4 
OTHER 
Clarithromycin 
Amiodarone 
Carbamazepine 
Barbiturates 
Erythromycin 
Cannabinoids 
Dexamethasone** 
Cotrimoxazole 
Fluvoxamine 
Fluoxetine 
Phenobarbital 
Efavirenz 
Grapefruit juice 
Lopinavir 
Phenytoin 
Ethosuximide 
Grapefruit-containing 
products 
Metronidazole 
Primidone  
Methadone 
Indinavir 
Quinine 
Rifabutin 
Metyrapone 
Ketoconazole 
Sertraline 
Rifampin 
Mexiletine 
Mibefradil 
Zafirlukast 
St John's Wort 
Nevirapine 
Miconazole 
 
 
Oral contraceptives 
Nefazodone 
 
 
Troglitazone 
Nelfinavir 
 
 
 
Norfloxacin 
 
 
 
Ritonavir 
 
 
 
Saquinavir 
 
 
 
Troleandomycin 
 
 
 
Voriconazole 
 
 
 
 
* In boldface are identified strong CYP3A4, 5, 7 inducers/inhibitors. This list is not meant to be 
considered all inclusive. Extracted from: Tatro BO. Drug Interaction Facts 2003: The Authority 
on Drug Interactions, 2003.  
** Dexamethasone is permitted when given as premedication for paclitaxel 
6.0 SUBJECT WITHDRAWAL/DISCONTINUATION CRITERIA 
Disease progression 
Disease progression is defined as rapid growth of multiple measurable, non-measurable, or new 
lesions, or at least a 20% increase in the sum of diameters of target (measurable) lesions, taking as 
reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). 
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Protocol/Amendment No.: 2016-0537 
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In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of 
at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). 
 Noncompliance 
If the patient is not able to be compliant with the treatment schedule in the absence of toxicity, the 
study treatment should be discontinued for the patient. 
Sustained toxic effects  
Study treatment will be discontinued for patients who have sustained toxic effects that are 
attributed to the study drug and require a dose interruption lasting more than 12 weeks. 
Initiation of new anticancer treatment 
In patients for whom the investigator, in his or her judgment, determines new treatment for breast 
cancer is warranted, the study treatment may be discontinued. 
Prohibited Concomitant Medications 
Medications or vaccinations specifically prohibited in the exclusion criteria, section 5.2.4 and 
Table 14 are not allowed during the ongoing trial.  If there is a clinical indication for one of these 
medications or vaccinations specifically prohibited during the trial, discontinuation from trial is 
required.   
Patient withdraws consent 
In the event that a patient withdraws consent, the reason(s) for withdrawal must be documented. 
Patients must be informed that their participation in the study is voluntary and that they may choose 
not to take part in the study or to stop taking part at any time. If a patient chooses not to take part 
in the study or to stop at any time, his/her future medical care or medical benefits will not be 
affected. 
7.0 FOLLOW UP    
Duration of follow-up 
Cohort I, Phase Ib  
Patients will be followed for safety for 30 days (+/-10 days) following the last dose of study drug, 
or until initiation of another anticancer therapy, whichever comes first via telephone calls, patient 
medical records, and/or clinic visits. 
Patients who have an ongoing major study treatment−related AE upon study completion or at 
discontinuation from the study will be followed up to 4 weeks until the event has resolved to 
baseline grade, the event is assessed by the investigator as stable, new anticancer treatment is 
initiated, the patient is lost to follow-up, the patient withdraws consent, or until it has been 
determined that study treatment or participation is not the cause of the AE. 
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 Cohort I Phase II and Cohort II  
Patients will be monitored until 1 month after surgical resection of the tumor. The date of the last 
follow-up visit should be within 30 days (+/-10 days) of surgical resection via telephone calls, 
patient medical records, and/or clinic visits.   
For patients who discontinue protocol therapy early, they will be followed for safety for 30 days 
(+/-10 days) following the last dose of study drug, or until initiation of another anticancer therapy, 
whichever comes first.   
Patients who have an ongoing major study treatment−related AE upon study completion or at 
discontinuation from the study will be followed up to 4 weeks until the event has resolved to 
baseline grade, the event is assessed by the investigator as stable, new anticancer treatment is 
initiated, the patient is lost to follow-up, the patient withdraws consent, or until it has been 
determined that study treatment or participation is not the cause of the AE. 
After treatment discontinuation, information on survival follow-up and new anti-cancer therapy 
will be collected via telephone calls, patient medical records, and/or clinic visits approximately 
every 6 months for 2 years (unless the patient withdraws consent or the study is terminated ). 
8.0 DISEASE ASSESSMENT 
Cohort I Phase II and Cohort II  
For patients in Cohort I Phase II and Cohort II, treatment response is determined by the surgical 
pathology report.  
Pathologic response will be assessed by RCB criteria according to the American Joint Committee 
on Cancer (AJCC) guidelines per MDACC Department of Pathology policy.   
9.0 CORRELATIVE RESEARCH      
To further understand the biological effect of neratinib as a single agent and to discover novel 
biomarkers, we will collect tumor samples at baseline, post neratinib window study and during 
breast surgery. 
9.1 Tumor Sample Collection / Research Blood Collection  
Correlative research will be performed on biologic specimens from each 20 patients in Cohort 1 
phase Ib, Cohort I phase II and Cohort II.  Pharmacodynamic markers to be measured in this 
proposed study. The pEGFR, HER2 expression changes induced by neratinib will be analyzed and 
compared between dose levels. 
• mRNA sequencing at baseline, after pharmacodynamics window, at the time of surgery if 
viable tissue available. This will assess the adaptive changes, downstream changes, and if 
remnant disease – can investigate the predictor of resistance markers. 
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• Plasma RNA, PBMC and Circulating tumor DNA collection at baseline, after the 
pharmacodynamics window and after cycle 4 (week 13).  
 
Table 15.  Correlative studies  
 Correlative Studies 
Baseline 
Cycle 1 Week 2  
(Post neratinib 
window) 
After Cycle 4 
(Week 13) 
Biopsy - Up to 20 patients, (Each cohort* ) 
• Using RNA seq to assess EGFR and additional 
HER 2 pathway related genomic landscape 
change. RNA seq will be performed at IPCT or 
core facility at MD Anderson. 
*(For cohort I phase Ib locally advanced patients only, 
baseline and Cycle I, Week 2 only) 
 
x 
X 
 
Blood-   (Each cohort) 
• 
Plasma RNA sequencing, PMBC (UT Austin 
Collaboration)  
• 
Circulating tumor DNA to be stored in Core 
Facility  
x 
x 
x 
Biopsy- Up to 48 patients, (Cohort II) 
Using Whole Exome Seq to check HER2 mutation and 
other associated mutations in IPCT 
x 
 
 
 
Blood-  Up to 48 patients, (Cohort II) 
• 
Normal control by Whole Exome Seq (WES) in 
IPCT 
x 
 
 
 
9.2 HER2 Expression and HER2 Mutation  
HER2 expression level is detected by immunohistochemical (IHC) staining or fluorescence in situ 
hybridization (FISH) per most recent ASCO CAP guideline. HER2 mutation level is detected by 
the RNA sequencing data (RNA-seq). All techniques for measuring HER2 expression and HER2 
mutation level have been standardized at M. D. Anderson. 
9.3 EGFR Expression and downstream pathways 
EGFR expression level, as well as its putative downstream including nodal-Axl pathway is 
detected by IHC staining and FISH. Both techniques (IHC, FISH) for measuring EGFR expression 
level have been standardized at M. D. Anderson.  All tissues and blood based samples will be bio-
banked for further analysis upon our ongoing EGFR targeting based preclinical and clinical 
studies. 
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10.0 SAFETY MONITORING AND REPORTING 
10.1 Adverse Event 
Adverse events will be assessed according to the CTCAE version 4.0. All study patients who have 
received neratinib as a single agent and as combination therapy will be evaluable for safety. The 
ongoing review of safety data will include review of clinical AEs and SAEs. The Study PI or 
designee will be responsible for assigning attribution of adverse events to the study agent and 
signing the case report form.  
AEs (>/=2 non-hematological and >/=3 hematological AEs) occurring  after first protocol 
intervention signing observed by the investigator or reported by the subject (whether or not 
attributed to investigational product), will be documented in the medical record and recorded in 
RedCap. Abnormal laboratory values will not be reported as AEs; however, any clinical 
consequences of the abnormality should be reported as AEs. Baseline toxicities will be captured 
in the medical record/ RedCap.   
10.2 Serious Adverse Event Reporting (SAE)  
10.2.1 Internal SAE reporting to Investigational New Drug (IND) Office 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either the 
investigator or the sponsor, it results in any of the following outcomes: 
• 
Death. 
• 
A life-threatening adverse drug experience – any adverse experience that places the patient, 
in the view of the initial reporter, at immediate risk of death from the adverse experience as it 
occurred. It does not include an adverse experience that, had it occurred in a more severe form, 
might have caused death. 
• 
Inpatient hospitalization or prolongation of existing hospitalization. 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions. 
• 
A congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered a serious adverse drug experience when, based upon appropriate 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. Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
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• 
Important medical events as defined above, may also be considered serious adverse events. 
Any important medical event can and should be reported as an SAE if deemed appropriate by 
the Principal Investigator or the IND Sponsor. 
• 
All events occurring during the conduct of a protocol and meeting the definition of a SAE 
must be reported to the IRB in accordance with the timeframes and procedures outlined in 
“The University of Texas M. D. Anderson Cancer Center Institutional Review Board Policy 
for Investigators on Reporting Unanticipated Adverse Events for Drugs and Devices”.  Unless 
stated otherwise in the protocol, all SAEs, expected or unexpected, must be reported to the 
IND Office, regardless of attribution (within 5 working days of knowledge of the 
event).                 
• 
All life-threatening or fatal events, that are unexpected, and related to the study drug, must 
have a  written report submitted within 24 hours (next working day) of knowledge of the event 
to the  Safety Project Manager in the IND Office. 
• 
Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for safety 
reporting to the IND Office and MDACC IRB.  
• 
Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 30 days after the last dose of drug, unless the participant withdraws consent. 
Serious adverse events must be followed until clinical recovery is complete and laboratory 
tests have returned to baseline, progression of the event has stabilized, or there has been 
acceptable resolution of the event. 
• 
Additionally, any serious adverse events that occur after the 30 day time period that are related 
to the study treatment must be reported to the IND Office. This may include the development 
of a secondary malignancy. 
10.2.2 Reporting to FDA: 
• 
Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project Manager 
IND Office) according to 21 CFR 312.32. 
It is the responsibility of the PI and the research team to ensure serious adverse events are reported 
according to the Code of Federal Regulations, Good Clinical Practices, the protocol guidelines, 
the sponsor’s guidelines, and Institutional Review Board policy. 
10.2.3 Investigator Communication with Supporting Company: 
The MDACC Internal SAE Report Form will be used for reporting to Puma Biotechnology Inc., 
and reporting timeline is as below: 
• 
Death that is unanticipated and definitely, probably or possibly related to study intervention 
that occur during and within 30 days after the last day of active study intervention will be 
reported to Puma Biotechnology Inc. within 24 working hours. 
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Protocol/Amendment No.: 2016-0537 
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Date:  1/12/2021 
 
 
• 
All other SAEs that are serious, unanticipated, and definitely, probably or possibly related to 
study drugs will be reported to Puma Biotechnology Inc. within 24 hours.  
• 
Investigator will report Serious Adverse Events (as such term is defined in the Protocol) 
requiring expedited reporting to Puma using MDACC Internal SAE Report Form. For 
expedited reports, Investigator will send the MDACC Internal SAE Report Form to Puma no 
later than seven (7) days for initial life-threatening reports, and fifteen (15) days for all other 
initial or follow-up serious and unexpected suspected adverse reaction (SUSAR), from the 
time of receipt of the SAE by Investigator. For non-expedited reports (i.e., unrelated to study 
drugs or listed/expected event), Investigator will send the MDACC Internal SAE Report Form 
to Puma no later than thirty (30) days from the time of receipt of the SAE by Investigator. 
Investigator shall send all MDACC Internal SAE reports to Puma via email to 
PumaSAE@parexel.com 
11.0 STATISTICAL CONSIDERATIONS 
11.1 Overview 
There will be two cohorts in this trial, as defined in Section 3.3. 
 
Cohort I: 
For Cohort I, the primary objectives of this phase Ib/II trial are to determine the MTD of neratinib 
in combination with paclitaxel, pertuzumab, trastuzumab, and doxorubicin/cyclophosphamide or 
other regimens in HER2-positive metastatic or locally advanced breast cancer patients (phase Ib) 
and to assess the efficacy of neratinib in combination with paclitaxel, pertuzumab, trastuzumab, 
and doxorubicin/cyclophosphamide in metastatic or locally advanced HER2-positive IBC patients 
(phase II). Secondary objectives include assessing progression-free survival, the association 
between pCR and HER2 and EGFR expression, and toxicity and safety.   
 
The phase Ib portion of the trial uses the Bayesian modified Toxicity Probability Interal 
(mTPI)[34] dose-escalation algorithm to determine the MTD of neratinib from among five dose 
levels.  Up to 20 HER2-positive metastatic breast cancer and locally advanced IBC and non-IBC 
patients will be included.  In the phase II portion, enrollment will be for the same population,  
metastatic or locally advanced HER2-positive IBC patients.  Patients will be treated at the MTD 
of neratinib chosen during the phase Ib portion in combination with the other drugs.  The primary 
endpoint is the pCR rate at the end of neoadjuvant chemotherapy. For the phase II portion, a 
maximum of 31 patients will be treated, although we expect the actual number to be less (see 
below). Toxicity will be monitored in the Phase II portion by the monitoring rule described below. 
 
 
Cohort II: 
 
For cohort II, the primary objective is to assess the efficacy of neratinib in combination with 
paclitaxel followed by AC in stage III or IV HER2-/ HR+ IBC patients.  Secondary objectives 
include assessing progression-free survival, the association between pCR and HER2 and EGFR 
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Protocol/Amendment No.: 2016-0537 
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expression, and toxicity and safety.  A maximum of 31 patients will be included in this cohort.  
Response is monitored by using Simon’s two-stage design [35] (details below). 
 
For the expansion cohort, we will enroll additional HER2- patients with a HER2 mutation until we 
have total 18 such patients.  Eighteen patients will provide reasonable power for secondary 
biomarker endpoints.   We expect that 5-20% of the 31 Cohort II patients will have the HER2 
mutation; thus, we will need to enroll between 12 and 17 additional patients for expansion cohort 
to meet our target of 18. Toxicity will be monitored in the Phase II portion by the monitoring rule 
described below. 
 
11.2 Phase Ib Design 
The Phase Ib portion of the trial will be restricted to cohort I patients only.  The mTPI approach 
of Ji et al will be used to estimate the MTD from the five doses listed in Table 16, starting at Dose 
Level 0 (neratinib at 80mg/day).  Dose -1 is included in case Dose 0 is too toxic.  DLT will be 
evaluated within the first 2 cycles. 
Table 16.  Dose levels 
Dose 
Level 
Neratinib 
Dose 
Pertuzumab Dose# 
Trastuzumab Dose# 
Paclitaxel* 
-1 
40 mg 
loading dose 840 mg, followed 
by 420 mg 
loading dose 8 mg/kg, followed 
by 6 mg/kg 
80mg/kg 
0 
80 mg 
loading dose 840 mg, followed 
by 420 mg 
loading dose 8 mg/kg, followed 
by 6 mg/kg 
80mg/kg 
1 
120 mg 
loading dose 840 mg, followed 
by 420 mg 
loading dose 8 mg/kg, followed 
by 6 mg/kg 
80mg/kg 
2 
160 mg 
loading dose 840 mg, followed 
by 420 mg 
loading dose 8 mg/kg, followed 
by 6 mg/kg 
80mg/kg 
3 
200 mg 
loading dose 840 mg, followed 
by 420 mg  
loading dose 8 mg/kg, followed 
by 6 mg/kg 
80mg/kg 
# This is current standard treatment dose, dose modification is not recommended.  
* Dose reduction allowed as needed per standard treatment guideline at all levels 
DLT includes any of the following possibly, probably, or definitely due to study therapy, assessed 
during the first 2 cycles [42 days]: 
• Any death not clearly due to the underlying disease or extraneous causes 
• Non- hematologic toxicity  
o    Grade 3 or higher non-hematologic toxicity, except grade 3 diarrhea is a DLT if it 
lasts ≥ 2 days despite prophylactic medication 
o    Grade 2 diarrhea lasting ≥ 5 days despite prophylactic medication 
o    Hy's Law case, defined as a patient meeting all of the following criteria: 
a.  ALT or AST ≥ 3 x Upper Limit of Normal (ULN) 
b.  Total bilirubin >2 x ULN 
c.  Little or no evidence of cholestasis (alkaline phosphatase <2 x ULN) 
d.  No other identified explanation for the injury (such as hepatitis A, B, C,   
or other viral hepatic injury, alcohol ingestion, congestive heart failure).  
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o    Neutropenic fever  
• Hematologic toxicity  
o    Grade 4 neutropenia or thrombocytopenia >7 days 
o    Grade 3 thrombocytopenia with bleeding  
 
The targeted maximum DLT rate is 20%, and we will enroll patients in cohorts of size 2.  We 
assume a prior distribution of Beta (1,1) for the toxicity rate at each dose level, and we also assume 
an equivalence interval around the toxicity rate of 5% in either direction; i.e., (15%, 25%).  A 
maximum of 20 patients will be treated at the dose levels shown in Table 16.  Figure 5 provides 
the rules for escalation and de-escalation once each cohort of patients has been assessed. 
Figure 5. Dose-Escalation Rules 
Number of Patients in Cohort 
 
 
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
Number of dose limiting toxicities (DLT's) 
0 E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
1 D 
S 
S 
S 
E 
E 
E 
E 
E 
E 
2 DU D 
S 
S 
S 
S 
S 
S 
E 
E 
3 
DU DU S 
S 
S 
S 
S 
S 
S 
4 
DU DU DU D 
S 
S 
S 
S 
S 
5 
DU DU DU DU S 
S 
S 
S 
6 
DU DU DU DU DU DU S 
S 
7 
DU DU DU DU DU DU DU 
8 
DU DU DU DU DU DU DU 
9 
DU DU DU DU DU DU 
10 
DU DU DU DU DU DU 
11 
DU DU DU DU DU 
12 
DU DU DU DU DU 
13 
DU DU DU DU 
14 
DU DU DU DU 
15 
DU DU DU 
16 
DU DU DU 
17 
DU DU 
18 
DU DU 
19 
 
DU 
20 
 
DU 
 
 
 
 
 
 
E = Escalate to the next higher dose 
S = Stay at the current dose 
D = De-escalate to the next lower dose 
U = The current dose is unacceptably toxic 
DLT = Maximum 20% 
Sample Size = 20 
Epsilon1 = 0.05 
Epsilon2 = 0.05 
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Protocol/Amendment No.: 2016-0537 
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The MTD is defined as the highest dose for which the posterior probability of toxicity is closest to 
20%. The table below summarizes the operating characteristics of the proposed design for this trial 
for 6 scenarios defined by different toxicity rates for the 5 doses. These operating characteristics 
are based on 2000 simulations of the trial. 
Table 17. Operating Characteristics of Phase Ib Study Design 
Dose Level 
-1 
0 
1 
2 
3 
No Dose 
Chosen 
Scenario 1 
  
  
  
  
  
True Toxicity Rate 
0.010 
0.025 
0.05 
0.10 
0.15 
 
Selection Probability 
0.001 
0.016 
0.065 
0.199 
0.719 
0 
Avg. # of Patients Treated 
0.1 
2.8 
3.5 
4.3 
9.3 
 
Total Patients 
 
20.0 
 
 
 
 
Overall Toxicity 
 
0.10 
 
 
 
 
Scenario 2 
 
True Toxicity Rate 
0.025 
0.05 
0.15 
0.25 
0.35 
 
Selection Probability 
0.006 
0.106 
0.362 
0.355 
0.172 
0 
Avg. # of Patients Treated 
0.3 
4.5 
6.7 
5.3 
3.2 
 
Total Patients 
 
20.0 
 
 
 
 
Overall Toxicity 
 
0.18 
 
 
 
 
Scenario 3 
 
True Toxicity Rate 
0.025 
0.05 
0.20 
0.35 
0.45 
 
Selection Probability 
0.011 
0.199 
0.505 
0.229 
0.058 
0 
Avg. # of Patients Treated 
0.4 
5.5 
8.3 
4.3 
1.6 
 
Total Patients 
 
20.0 
 
 
 
 
Overall Toxicity 
 
0.21 
 
 
 
 
Scenario 4 
 
True Toxicity Rate 
0.25 
0.35 
0.45 
0.55 
0.65 
 
Selection Probability 
0.581 
0.158 
0.067 
0.006 
0 
0.190 
Avg. # of Patients Treated 
7.5 
7.8 
2.4 
0.5 
0.1 
 
Total Patients 
 
18.2 
 
 
 
 
Overall Toxicity 
 
0.33 
 
 
 
 
Scenario 5 
 
True Toxicity Rate 
0.30 
0.35 
0.45 
0.55 
0.65 
 
Selection Probability 
0.51 
0.142 
0.057 
0.009 
0.001 
0.282 
Avg. # of Patients Treated 
7.3 
7.3 
2.2 
0.5 
0.1 
 
Total Patients 
 
17.4 
 
 
 
 
Overall Toxicity 
 
0.35 
 
 
 
 
Scenario 6 
 
 
 
 
 
 
True Toxicity Rate 
0.01 
0.03 
0.06 
0.09 
0.12 
 
Selection Probability 
0.001 
0.025 
0.07 
0.160 
0.746 
0 
Avg. # of Patients Treated 
0.1 
2.9 
3.6 
3.9 
9.4 
 
Total Patients 
 
20.0 
 
 
 
 
Overall Toxicity 
 
0.09 
 
 
 
 
 
 
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11.3 Phase II Design 
In both cohorts, the primary endpoint will be the pCR rate at the end of neoadjuvant chemotherapy. 
Patients evaluable for efficacy are those who have completed the course of treatment per protocol 
and have surgery. Non-evaluable patients will be replaced. 
 
In cohort I, HER2-positive patients, we will use Simon’s optimum two-stage design to monitor the 
pCR rate.  We will target a maximum one-sided alpha of 5% and a beta of 20%.  The historical 
pCR rate in these patients is 40%, which we hope to increase to 65% with the introduction of 
neratinib.  We will enroll 11 patients in the first stage, and if at least 6 have a pCR, we will enroll 
an additional 20.  If at least 17 patients of the total of 31 respond, we will be able to conclude that 
the pCR rate in the HER2+ cohort is significantly higher than the historical rate of 40%.  If the 
true pCR rate in this group is 40% or lower, the probability that the study stops after the first look 
is at least 75%.  
In cohort II, HER2-negative/ HR-positive patients, we will also use Simon’s minimax two-stage 
design to monitor the pCR rate.  We will also target a maximum one-sided alpha of 5% and a beta 
of 20%.  The historical pCR rate in these patients is 8.2%, which we hope to increase to 25% with 
neratinib.  We will enroll 16 patients in the first stage, and if at least 2 have a pCR, we will enroll 
an additional 15.  If at least 6 patients of the total of 31 have a pCR, we will be able to conclude 
that the pCR rate in HER2-/HR+ patients is significantly higher than the historical rate of 8.2%.  
If the true pCR rate in this group is 8.2% or lower, the probability that the study stops after the 
first look is at least 61%. 
 
11.4 Toxicity Monitoring in Phase II 
Toxicity in Phase II will be monitored separately by cohort by the method of Thall and Sung 
[36].  We wish to assure that the DLT rate in the Phase II portion is no higher than 30% in either 
cohort.  DLT will be assessed at the same time as in the Phase I portion of the design; i.e., at the 
end of 2 cycles of treatment. 
 
In Cohort I, we will denote the probability of DLT as PDLT1 and assume a Beta (0.6, 1.4) prior 
distribution for this probability, which has a mean of 0.3, corresponding to the target rate of 30%.  
We will monitor DLT in this cohort by using the following rule: stop accrual into the cohort if at 
any time 
Pr (PDLT1 > 0.30 | data from patients in cohort) > 0.95 
 
This rule leads to the stopping boundaries found in Table 18. 
 
Table 18. Stopping Boundaries for DLT Monitoring Rule for Cohort I 
 
If there are this many patients 
with DLT 
Stop accrual if this many patients have 
been evaluated for DLT 
3 
3 
4 
4-5 
5 
5-8 
6 
6-10 
7 
7-12 
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8 
8-15 
9 
9-18 
10 
10-20 
11 
11-23 
12 
12-25 
13 
13-27 
14 
14-30 
15 
Always Stop 
 
This rule was simulated using the program MultcLean Desktop, version 2.1.0.  The operating 
characteristics are found in Table 19 below.  If Cohort I is stopped, Cohort II may continue. 
Table 19. Operating Characteristics of DLT Monitoring Rule for Cohort I 
 
 
 
Sample Size 
True PDLT Early Stopping Probability 25th Median 75th 
10% 
0.001 
31 
31 
31 
20% 
0.017 
31 
31 
31 
30% 
0.151 
31 
31 
31 
40% 
0.473 
12 
31 
31 
50% 
0.822 
7 
12 
23 
 
In Cohort 2, we will denote the probability of DLT as PDLT2 and assume a Beta (0.6, 1.4) prior 
distribution for this probability, which has a mean of 0.3, corresponding to the target rate of 30%.  
Accounting for up to 17 additional patients with a HER2 mutation, we may enroll up to 48 
patients in this cohort.  We will monitor DLT by using the following rule: stop accrual into 
Cohort 2 if at any time 
Pr (PDLT2 > 0.30 | data from patients in cohort) > 0.975 
 
This rule leads to the stopping boundaries found in Table 20. 
 
Table 20. Stopping Boundaries for DLT Monitoring Rule for Cohort II 
 
If there are this many patients 
with DLT 
Stop accrual if this many patients have 
been evaluated for DLT 
3 
3 
4 
4-5 
5 
5-7 
6 
6-9 
7 
7-11 
8 
8-13 
9 
9-16 
10 
10-18 
11 
11-21 
12 
12-23 
13 
13-26 
14 
14-29 
15 
15-31 
16 
16-34 
17 
17-37 
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18 
18-39 
19 
19-42 
20 
20-45 
21 
21-47 
22 
Always Stop 
 
This rule was simulated using the program MultcLean Desktop, version 2.1.0.  The operating 
characteristics are found in Table 21 below.  If Cohort II is stopped, Cohort 1 may continue. 
Table 21. Operating Characteristics of DLT Monitoring Rule for Cohort II 
 
 
 
Sample Size 
True PDLT Early Stopping Probability 25th Median 75th 
10% 
0.001 
48 
48 
48 
20% 
0.017 
48 
48 
48 
30% 
0.118 
48 
48 
48 
40% 
0.488 
18 
48 
48 
50% 
0.888 
7 
16 
31 
 
11.5 Secondary Objectives and Analyses 
Secondary and exploratory analyses include assessing progression-free survival, toxicity, safety, 
determining the adaptive target and downstream changes in pan-HER family members, assessing 
the association between changes in EGFR, HER2, and HER4 and pCR, assessing the rate of 
HER2 mutations and the association with pCR, and assessing the association between 
pharmacodynamic markers and circulating tumor cells (CTC) and ctDNA. 
 
Adaptive target and downstream changes will be measured by the change in PI3K and Akt 
phosphorylation from baseline. 
 
Progression-free survival (PFS) will be estimated by the Kaplan-Meier method, and distributions 
will be compared using the log-rank test.  Cox proportional hazards regression models may be fit 
to assess the relationship between PFS and disease, clinical, and demographic covariates of 
interest. 
 
Adverse events will be summarized using standard methods; i.e., mean, median, quartiles, and 
standard deviation for continuous parameters and frequency summaries for categorical 
parameters. 
 
Logistic regression will be used to assess the association between the probability of pCR and 
disease, clinical, and demographic covariates of interest, including changes in EGFR, HER2, and 
HER4, and HER2 mutations. 
 
The assocation between changes in adaptive targets, changes in pharmacodynamic marker 
changes, and changes in CTC and ctDNA will be assessed using linear regression. 
 
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11.6 Toxicity/Efficacy Report to IND Office 
Phase Ib 
A Toxicity/Efficacy Summary will be submitted to the IND Office Medical Monitor after the first 
2 evaluable patients complete the first 2 cycles of study therapy, and every 2 evaluable patients 
thereafter, prior to dose modification or initiation of Phase 2.  
Phase II 
Cohort I 
 A toxicity summary will be submitted to the IND Office Medical Monitor after 3 evaluable 
patients complete 2 cycles of treatment and every 2 evaluable patients thereafter. An 
Efficacy Summary will be submitted after the first 11 evaluable patients have been treated 
at the RP2D, and after the total treated population of 31 patients have completed the study 
therapy.  
    Cohort II 
  A toxicity summary will be submitted to the IND Office Medical Monitor after 3 evaluable 
patients complete 2 cycles of treatment and every 2 evaluable patients thereafter. An 
Efficacy Summary will be submitted after the first 16 evaluable patients have been treated, 
and after the total treated population of 31 patients have completed the study therapy. 
12.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES 
12.1  Investigational Product  
The investigator shall take responsibility for and shall take all steps to maintain appropriate records 
and ensure appropriate supply, storage, handling, distribution and usage of investigational product 
in accordance with the protocol and any applicable laws and regulations. 
Clinical Supplies will be provided by Puma Biotechnology Inc.  as summarized in the table below. 
Product Descriptions 
Product Name & Potency 
Dosage Form 
Neratinib : 40mg/tablet 
Oral Drug 
 
12.2 Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements. 
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12.3 Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or designee 
are not blinded to treatment. Drug identity (name, strength) is included in the label text; random 
code/disclosure envelopes or lists are not provided. 
12.4 Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage conditions 
specified on the label.   
Receipt and dispensing of trial medication must be recorded by an authorized person at the trial 
site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
12.5 Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received from 
Puma Biotechnology Inc or designee, the amount dispensed to and returned by the subjects and 
the amount remaining at the conclusion of the trial.  
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s responsibility 
to arrange for disposal of all empty containers, provided that procedures for proper disposal 
have been established according to applicable federal, state, local and institutional guidelines and 
procedures, and provided that appropriate records of disposal are kept. 
13.0 DATA MANAGEMENT 
The Principal Investigator is responsible for assuring that the data entered into the database are 
complete and accurate and that data entry is performed in a timely manner. CORe/RedCap will be 
used as the electronic case report form for this protocol and protocol specific data will be entered 
into CORe/RedCap. 
13.1 Data collection for this study including: 
• Demographic information (sex, race, and date of birth) 
• Date of initial breast cancer diagnosis, pathology report of primary breast cancer, biomarker 
status, and date and location of distant metastases at disease progression 
• History of breast cancer surgery, and radiation therapy, if applicable 
• Date and type of chemotherapy and/or hormonal therapy for metastatic disease  
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PI:  Rachel Layman, MD;  
Date:  1/12/2021 
 
 
All AEs will be collected, however only >/=2 non-hematologic AEs and >/=3 hematological AEs 
will be recorded.  Other abnormal laboratory values will not be reported as AEs; however, any 
clinical consequences of abnormality should be reported as AEs.  
Concomitant medication will be recorded per standard of care in clinic database, and will not be 
recorded in the study database.  
13.2 Data confidentiality plan 
All laboratory and clinical data gathered in this protocol will be stored in a password-protected 
database. All patient information will be handled using anonymous identifiers. Linkage to patient 
identity will be possible only after accessing a password-protected database. Access to the database 
will be available only to individuals directly involved in the study. 
Information gathered for this study will not be reused or disclosed to any other person or entity, or 
for other research. Once the research has been completed, identifiers will be retained for as long 
as is required by law and by institutional regulations, and at that point will be destroyed. 
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Date:  1/12/2021 
 
 
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