Clinical trial NCT05243641
Conditions: Metastatic Breast Cancer Breast Cancer
Sponsor: M.D. Anderson Cancer Center
Start date: 2022-08-18; Completion date: 2024-11-19
Enrollment: 10 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This study is to learn if the combination therapy of capmatinib and neritinib can help to control metastatic or locally advanced breast cancer. Researchers also want to find the highest tolerable dose of the combination therapy of capmatinib and neritinib that can be used in this study drug combinations. The safety of this drug combination and the CELsignia MP test methodology will also be studied.

Detailed description:
This is an open-label, phase Ib/II study of neratinib plus Capmatinib in patients with metastatic breast cancer and patients with metastatic IBC.

Phase 1b - Dose Escalation of Neratinib with Capmatinib

This phase of the study will employ the Bayesian optimal interval (BOIN) design with the 3+3 design run-in, to find the MTD. The BOIN design is implemented in a simple way similar to the traditional 3+3 design, but is more flexible and possesses superior operating characteristics that are comparable to those of the more complex model-based designs, such as the continual reassessment method (CRM). The maximum sample size for dose escalation is 18. Patients are treated in cohorts of 3, beginning with Neratinib PO dose level 1 (120 mg, Dose 1-7, 160 mg, through end of treatment, see Table 2) in combination with Capmatinib PO level 1 (400 mg, see Table 3), with a maximum of 12 patients per dose. The target toxicity rate for the maximum tolerable dose (MTD) is 25%.

Phase II

Phase II will be a prospective, open label, interventional study for patients with previously treated HER2-negative metastatic breast cancer or metastatic inflammatory breast cancer. Subjects receive Capmatinib in combination with Neratinib (including an AI for patients with ER+/HER2- breast cancer). The MTD determined during Phase 1b will be used.

This portion of the trial will be conducted to assess the overall response rate (ORR) for patients treated at the MTD. The target ORR will be 25%, with unacceptable ORR as 5%. We assess the ORR using the Bayesian optimal phase 2 (BOP2) design (Zhou, Lee and Yuan, 2017).

Up to an additional 29 evaluable subjects with measurable disease will be enrolled. An interim analysis will be performed when the number of enrolled patients reaches 15.

Arms: arm 1: This portion of the study will enroll a maximum of 27 patients in the dose-finding trial including the possibility of adding up to 6 additional ER+ patients in a safety assessment of aromatic inhibitor treatment arm 2: This portion of the study will enroll a maximum of 29 patients
Interventions: intervention 1: Neratinib intervention 2: Capmatinib
Intervention descriptions: intervention 1: Nertatinib will be supplied as 40 mg tablets, equivalent to 48.31 mg neratinib maleate. intervention 2: Capmatinib will be supplied at 200 mg and 150 mg tablets

Protocol documents:
Prot_SAP_001.pdf: 
Protocol Number: 2020-0198 
 
Protocol Date: 2/1/2024 
PI: Rachel M. Layman 
 
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MD Anderson IND Sponsor Cover Sheet 
 
Protocol ID 
2020-0198 
Protocol Title 
Neratinib and Capmatinib combination (phase Ib/II) in metastatic breast 
cancer and inflammatory breast cancer patients with abnormal HER-
family and c-Met pathway activity as measured by the CELsignia 
Signaling Analysis Test 
 
Protocol Version 
06 
Version Date 
2/1/2024 
 
Protocol PI 
Rachel M. Layman 
 
 
Department 
Breast Medical Oncology 
 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
159611 


Protocol Number: 2020-0198 
 
Protocol Date: 2/1/2024 
PI: Rachel M. Layman 
 
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PROTOCOL TITLE 
Neratinib and Capmatinib combination (phase Ib/II) in 
metastatic breast cancer and inflammatory breast cancer patients 
with abnormal HER-family and c-Met pathway activity as 
measured by the CELsignia Signaling Analysis Test  
 
STUDY NUMBER: 
2020-0198 
VERSION NUMBER: 
06 
TEST PRODUCTS: 
Capmatinib and Neratinib  
PRINCIPAL 
INVESTIGATOR: 
 
Rachel M. Layman, MD 
Tel:  713-745-8401 
Fax:  713-794-4385 
Email: rlayman@mdanderson.org 
 
CO-PRINCIPAL 
INVESTIGATORS: 
Bora Lim, MD 
Azadeh Nasrazadani, MD  
Vicente Valero, MD 
COLLABORATORS: 
 
 
 
 
 
 
 
Ying Yuan, Ph.D 
Bettyann Asche Murray Distinguished Professor, Deputy Chair 
Department of Biostatistics 
University of Texas MD Anderson Cancer Center 
yyuan@mdanderson.org 
 
Clark Andersen, MS 
Department of Biostatistics 
University of Texas MD Anderson Cancer Center 
crandersen@mdanderson.org 
SUPPORT PROVIDED 
BY: 
Celcuity  
Novartis  (study drug, capmatinib) Puma Biotechnology (study 
drug, neratinib) 
 
 
 


Protocol Number: 2020-0198 
 
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PI: Rachel M. Layman 
 
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Table of Contents 
Study Synopsis ................................................................................................................................ 5 
1.0 Background Information ........................................................................................................... 8 
1.1 Metastatic and Inflammatory Breast Cancer and Clinical Unmet Need ................................... 8 
1.2 A need to develop a HER2 and c-Met Signaling Activity Test in the Clinic ........................... 8 
2.0 Scientific/Medical Rationale ................................................................................................... 11 
2.1 Rationale for Open-Label Study ............................................................................................. 12 
2.2 Rationale to Combine the Neratinib and Capmatinib in IBC with HER2 and c-Met Pathway 
Activity ......................................................................................................................................... 12 
3.0 Objectives ............................................................................................................................... 12 
3.1 Primary objective .................................................................................................................... 12 
3.2 Secondary objectives .............................................................................................................. 12 
3.3 Exploratory Objectives ........................................................................................................... 12 
4.0 Study design ............................................................................................................................ 13 
4.1 Phase 1b – Dose Escalation of Neratinib with Capmatinib .................................................... 13 
4.2 Phase II.................................................................................................................................... 14 
4.3. Subject Population to be included: ........................................................................................ 14 
4.4 Number of Subjects per Study Group: .................................................................................... 14 
5.0 Study Endpoints ...................................................................................................................... 15 
5.1 Primary Endpoints .................................................................................................................. 15 
5.2 Secondary Endpoint(s): ........................................................................................................... 15 
5.3 Exploratory Endpoints: ........................................................................................................... 16 
6.0 Eligibility Criteria ................................................................................................................... 16 
6.1 Inclusion Criteria .................................................................................................................... 16 
6.2 Exclusion Criteria ................................................................................................................... 18 
7.0 Study Procedures .................................................................................................................... 21 
7.2 Dosing level and Drug Administration ................................................................................... 21 
7.3 General Treatment Guidelines ................................................................................................ 23 
7.4 Dose Limiting Toxicity (DLT) ............................................................................................... 23 
7.5 Duration of therapy ................................................................................................................. 26 
7.6 Study Discontinuation ............................................................................................................. 26 
7.7 Follow up ................................................................................................................................ 27 
7.8 End of Study ........................................................................................................................... 27 
7.9 Correlative Research ............................................................................................................... 27 
7.10. Study Calendar ..................................................................................................................... 28 
7.11. Remote Procedures .............................................................................................................. 29 
7.12. Drug Accountibility and Reconcilation ............................................................................... 29 
8.0 Clinical Safety Information for Study Drugs .......................................................................... 30 
8.1 Neratinib: ................................................................................................................................ 30 
8.1.1 Incidence of Treatment-emergent Adverse Events of Single-agent Studies ....................... 30 
8.1.2 Adverse Drug Reactions with Neratinib Monotherapy ....................................................... 31 
8.1.3 Reference Safety Information for Assessment of Expectedness of Serious Adverse .......... 32 
8.1.4 Interaction With Other Medicinal Products and Other Forms of Interaction ...................... 33 
8.1.5. Adverse Events of Special Interest ..................................................................................... 34 
8.1.6. Special Precautions ............................................................................................................. 35 
8.2 Capmatinib .............................................................................................................................. 35 


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8.2.1  Reference Safety Information for Capmatinib .................................................................... 35 
8.2.2 Summary of clinical safety for capmatinib administered as single agent ............................ 37 
9.0 Concomitant and Prohibited Therapy ..................................................................................... 40 
9.1 Prohibited Concomitant Therapy and Cautions for Capmatinib Use: .................................... 40 
9.2 Prohibited Concomitant Therapy for Neratinib use: ............................................................... 41 
10.0 Common Toxicity and Dose Modification ........................................................................... 41 
10.1 Neratinib Dose Modifications and Management – General Toxicities ................................ 41 
10.2 Management of Diarrhea ...................................................................................................... 41 
10.3 Management of Cardiac Left Ventricular Dysfunction ........................................................ 44 
10.4 Neratinib Dose Modifications for Hepatic Impairment ........................................................ 44 
10.5 Capmatinib Dose Reduction and Toxicity Management ...................................................... 45 
10.5.1 Capmatinib Dose Reduction Levels ................................................................................... 45 
10.5.2 Capmatinib Treatment Interrruption and Dose Reduction Guidance ................................ 45 
10.5.3 Toxicity Follow-up ............................................................................................................ 51 
11.0 Tumor Response Evaluation Criteria .................................................................................... 58 
11.1 Evaluation of Target Lesions ................................................................................................ 58 
11.2 Evaluation of Non-Target Lesions ........................................................................................ 58 
12.0 Safety Monitoring and Reporting ......................................................................................... 58 
12.1 Adverse Event ....................................................................................................................... 58 
12.2 Serious Adverse Event Reporting (SAE) .............................................................................. 60 
12.2.1 Internal SAE reporting to Investigational New Drug (IND) Office .................................. 60 
12.2.3 Investigator Communication with Supporting Company .................................................. 61 
13.0 Statistical Consideration ....................................................................................................... 62 
13.1 Phase 1b Dose-Finding Design ............................................................................................. 62 
13.2 Phase II Single-Arm Toxicity Monitoring and Efficacy Trial .............................................. 66 
14.0 Data Management ............................................................................................................... 709 
14.1 Data collection .................................................................................................................... ..69 
14.2 Data confidentiality plan ....................................................................................................... 69 
14.3 Data and Safety Monitoring .................................................................................................. 70 
14.4 Clinical Trial Monitoring ...................................................................................................... 71 
15.0 Consent Process and Documentation  ................................................................................... 71 
16.0 References ............................................................................................................................. 71 
Appendix 1: Phase Ib Trial and Design Specifications ............................................................ 7575 
Appendix 2: CELsignia Collection Kit User Instruction Card ................................................... 756 
Appendix 3: CELsignia Specimen Collection 
Requisition………………………………………758


Protocol Number: 2020-0198 
 
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Study Synopsis 
Title 
Neratinib and Capmatinib combination (phase Ib/II) in metastatic breast cancer 
and inflammatory breast cancer patients with abnormal HER-family and  
c-Met pathway activity as measured by the CELsignia Signaling Analysis Test 
Protocol No. 
2020-0198 
Phase 
Ib/II 
IND Number: 
159611 
IND Sponsor 
MD Anderson Cancer Center 
Primary 
Objectives 
• Phase Ib: To determine maximum tolerated dose for use in the Phase II 
portion of the trial 
• 
Phase II: To determine overall response rate (ORR: CR+PR) 
Secondary 
Objectives 
• To further characterize the safety and tolerability of neratinib + 
capmatinib and of neratinib + capmatinib in combination with an 
aromatase inhibitor in ER+ MBC 
• To determine clinical benefit rate: (CBR: CR + PR + SD ≥ 24 weeks)  
• To determine the duration of response  
• To determine progression free survival (PFS)  
• 
To determine 2 years overall survival (OS) 
Exploratory 
Objectives 
• To determine the functional status of the HER2, c-Met, and EGFR 
pathways using the CELsignia test 
• To determine the ORR, CBR, DOR, PFS, and OS for the sub-group of 
patients with metastatic inflammatory breast cancer and for the sub-
group of patients with metastatic non-inflammatory breast cancer   
• Assess response per molecular subtype, Hormone Receptor positive (ER 
and/or PR, HER2 negative) and Triple Negative Breast Cancer 
• Assess genomic profile of cancers treated on study to explore potential 
mechanisms of response and resistance. 
Treatment 
Regimen 
Neratinib PO once daily  and Capmatinib PO twice daily (all patients). 
Aromatase inhibitor PO daily +/- ovarian suppression for patients with ER+ breast 
cancer. 


Protocol Number: 2020-0198 
 
Protocol Date: 2/1/2024 
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Study Design 
This is an open-label, phase Ib/II study of neratinib plus Capmatinib in 
patients with metastatic breast cancer and patients with metastatic IBC. 
 
Phase 1b – Dose Escalation of Neratinib with Capmatinib 
This phase of the study will employ the Bayesian optimal interval (BOIN) 
design with the 3+3 design run-in, to find the MTD.  The BOIN design is 
implemented in a simple way similar to the traditional 3+3 design, but is 
more flexible and possesses superior operating characteristics that are 
comparable to those of the more complex model-based designs, such as the 
continual reassessment method (CRM). The maximum sample size for dose 
escalation is 18.  Patients are treated in cohorts of 3, beginning with 
Neratinib PO dose level 1 (120 mg, Dose 1-7, 160 mg, through end of 
treatment, see Table 2) in combination with Capmatinib PO level 1 (400 
mg, see Table 3), with a maximum of 12 patients per dose.  The target 
toxicity rate for the maximum tolerable dose (MTD) is 25%.  
 
Phase II  
Phase II will be a prospective, open label, interventional study for patients 
with previously treated HER2-negative metastatic breast cancer or 
metastatic inflammatory breast cancer. Subjects receive Capmatinib in 
combination with Neratinib (including an AI for patients with ER+/HER2- 
breast cancer). The MTD determined during Phase 1b will be used. 
 
This portion of the trial will be conducted to assess the overall response rate 
(ORR) for patients treated at the MTD.  The target ORR will be 25%, with 
unacceptable ORR as 5%.  We assess the ORR using the Bayesian optimal 
phase 2 (BOP2) design (Zhou, Lee and Yuan, 2017).     
 
Up to an additional 29 evaluable subjects with measurable disease will be 
enrolled. An interim analysis will be performed when the number of 
enrolled patients reaches 15. 
Number of 
Patients 
Total: 47 patients  
Number of Sites 
1 site 
Study 
Population 
Phase 1b: previously treated HER2-positive and HER2-negative, ER-
positive and ER-negative metastatic and inflammatory breast cancer 
patients. 
 
Phase II: previously treated HER2-negative, ER-positive and ER-negative 
metastatic and inflammatory breast cancer patients with abnormal HER-
family and c-Met signaling tumors. The CELsignia Multi-Pathway 
(CELsignia MP) Test will characterize the subjects’ HER-family and c-
Met-driven signaling pathways as either hyperactive or normally active.   


Protocol Number: 2020-0198 
 
Protocol Date: 2/1/2024 
PI: Rachel M. Layman 
 
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Study 
Endpoints 
Primary Endpoints: 
•   Safety 
The primary safety endpoint is to determine the safety, tolerability, and 
dose limiting toxicities (DLT) (Phase 1b) of the combination of 
Neratinib + Capmatinib in ER- MBC and of Neratinib + Capmatinib in 
combination with an aromatase inhibitor for ER+ MBC.    
•   Efficacy  
For the Phase 2 portion of the study, the primary efficacy endpoint is 
overall response rate (ORR), defined as the rate of patients who 
achieved partial response or complete response as the best response.  
All tumor response will be evaluated by RECIST 1.1 and measured by 
QIAC system, via research collaboration. 
Secondary Endpoint(s):  
• Clinical benefit rate (CBR) 
Defined as the rate of patients who achieved complete response, partial 
response and stable disease for ≥ 24 weeks as the best response of 
treatment. 
• Duration of response (DOR)  
DOR is defined as the period measured from the date of the first 
occurrence of a CR or PR (whichever status is recorded first) until the 
first date that progressive disease or death is documented. Patients who 
have not progressed and who have not died by the date of data cutoff 
for analysis will be censored at the time of last tumor assessment date. 
If tumor assessments were performed after the date of the first 
occurrence of a CR or PR showed different response, DOR will be 
censored at the date of the first occurrence of a CR or PR plus 
remaining stable response from that time point. 
• Progression free survival (PFS)  
PFS is defined as the time between date of treatment start to the date of 
documented disease progression or death, whichever occurs first. Data 
from patients who have not experienced disease progression or death 
will be censored at the last tumor assessment date and known to be free 
of disease progression. Data from patients with no post-baseline tumor 
assessment will be censored at the treatment start date plus 1 day. 
• 2 year overall survival (OS) 
2 year OS definition: the proportion of patients in the study who are 
alive 2 years after enrollment on to the study 
Exploratory Endpoints:  
• For exploratory purposes, ORR, CBR, DOR, PFS, and OS will also 
be analyzed separately for the sub-group of IBC patients and for the 
sub-group of advanced or metastatic non-IBC breast cancer patients. 
• Assess response per molecular subtype, Hormone Receptor positive 
(ER and/or PR) and Triple Negative Breast Cancer 
• Assess genomic profile of cancers treated on study to explore 
potential mechanisms of response and resistance. 


Protocol Number: 2020-0198 
 
Protocol Date: 2/1/2024 
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1.0 Background Information 
1.1 Metastatic and Inflammatory Breast Cancer and Clinical Unmet Need 
Targeting the HER family receptor tyrosine kinases (RTKs) with small molecule inhibitors or 
monoclonal antibodies has been a common therapeutic strategy against multiple cancers. In 
particular, over expression of HER2 in breast cancer has been targeted successfully by anti-
HER2 agents like neratinib, trastuzumab, and pertuzumab (1-3). The use of these agents led to 
remarkable improvements in outcomes for patients with HER2 overexpressing breast cancer. 
However, HER2 overexpression as detected by IHC or FISH is limited to 15-20% of all breast 
cancers and to 40% of inflammatory breast cancer (IBC). Moreover, some clinical trials have 
also indicated a weak correlation between HER2 expression or amplification levels and HER2 
targeted therapy benefit (4-5).  In addition to HER2 expression and amplification, somatic 
mutations in HER2 have been identified in 1-4% of breast cancers, mostly in HER2 
amplification-negative breast cancer (6). Bose et al. have shown that some of these HER2 
mutations conferred resistance to the reversible HER2/EGFR TKI lapatinib, but were sensitive to 
the irreversible HER2/RGFR TKI neratinib when tested in breast cancer cell lines (7).  They also 
examined the location of these mutations and found that majority of these mutations (68%) 
mapped to the kinase domain. Seven of the 13 HER2 somatic mutations they characterized were 
activating mutations that are likely true driver mutations. These findings by Bose and his 
colleagues indicate that breast tumors considered to be HER2-negative may still be “addicted” to 
HER2 signaling as a consequence of harboring HER2 activating mutations, and hence may be 
susceptible to select anti-HER2 agents. 
Preclinical data have also shown that c-Met and other HER family signaling pathways also 
participate in extensive crosstalk that can drive cancer progression (8,9).  c-Met is the cognate 
receptor for Hepatocyte Growth Factor (HGF). In breast cancer, c-Met and HGF overexpression 
correlates with poor outcomes (10). Lindemann et al reported c-Met overexpression in 25% of 
HER2-positive breast tumors, supporting the hypothesis that both HER2 and c-Met receptors 
could synergize in promoting tumor growth (11). Shattuck et al showed that c-Met contributes to 
trastuzumab resistance, and a subset of HER2-positive breast cancer patients may benefit from 
combined inhibition of both HER2 and MET (12). 
Phase II trials with c-Met targeting therapeutics in combination with the HER1 (EGFR) inhibitor 
erlotinib showed promising results in progression-free survival (13). However, Phase III clinical 
trials in NSCLC using MET overexpression as an indicator for c-Met targeted therapy and trials 
enrolling unselected patients to receive combination c-Met/HER targeting treatment failed to 
demonstrate clinical efficacy (14). These disappointing results suggest that the current 
methodologies to identify patients likely to respond to these therapies are not effective. Hence an 
alternative approach may be to identify patients with dysfunctional c-Met signaling who may 
respond to existing therapies.  
1.2 A need to develop a HER2 and c-Met Signaling Activity Test in the Clinic 
To address this unmet need, Celcuity developed a functional cellular analysis diagnostic 
platform, ‘CELsignia,’ to measure real-time cell signal transduction activity in living tumor cells 


Protocol Number: 2020-0198 
 
Protocol Date: 2/1/2024 
PI: Rachel M. Layman 
 
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of individual cancer patients (15,16).  This approach overcomes the limitations of static genetic 
analyses of fixed cells by determining whether the dynamic signaling activity of certain known 
oncogenic pathways is normal or abnormal and can be inhibited by a matching targeted therapy. 
The CELsignia platform quantifies specific dynamic signal transduction activities in a patient’s 
tumor cells. 
To elucidate the role of HER-family signaling and the involvement of c-Met signaling as a 
cancer driver, the CELsignia Multi-Pathway (MP) test was developed using an impedance 
biosensor and live cells derived from each patient’s tumor. The CELsignia MP test measures ex 
vivo real-time live cell response to specific HER-family and c-Met agonists to diagnose breast 
tumors with hyperactive HER1, HER2, HER3, HER4, and c-Met signaling activity. This 
functional assay is being utilized to select HER2-negative breast cancer patients with abnormal 
HER2-driven signaling activity in their tumor specimens for treatment with neoadjuvant HER2 
therapies in two trials. These early stage breast cancer patients will be treated with HER2 
inhibitors in combination with chemotherapy cycles followed by surgery and then assessed for 
pathological complete response (17,18).   
To determine the prevalence of abnormal HER-family and c-Met signaling in HER2-negative 
breast cancer patients, the CELsignia MP test evaluated fresh tumor samples from 79 HER2-
negative breast cancer patients (19). Of these, 19 of 79 samples had both hyperactive c-Met 
signaling and at least one hyperactive signaling HER-family receptor. Using 6 of these tumor 
samples, the IC50 values of multiple pan-HER inhibitors and c-Met inhibitors was determined 
along with the efficacy of the combinations of each pan-HER inhibitor with each c-Met inhibitor 
(20). The IC50 values for these inhibitors obtained using the CELsignia MP test were 
comparable to those derived using cell-free methods. In drug efficacy studies, every combination 
of pan-HER and c-Met inhibitors provided comparably high (at least 80%) of inhibitory activity 
effect ex vivo (22). These results suggest the sub-group of HER2-negative breast cancer patients 
diagnosed with coincident hyperactive c-Met and ErbB signaling by the CELsignia MP test may 
respond to a pan-HER and c-MET inhibitor combination. Chou and Talalay analyses using the 
CELsignia MP test were performed to characterize the linkage between c-MET and HER-family 
dysfunctional signaling in order to determine whether combined c-Met and pan-HER inhibitors 
would act additively, synergistically, or antagonistically.  The analysis revealed that the 
mechanism of pan-HER inhibitors and c-MET inhibitors are not mutually exclusive and that this 
inhibitor combination is synergistic.  The synergistic activity of these two classes of drugs 
suggests that the threshold drug concentrations for efficacy when the drug combination is used is 
less than what is required when these inhibitors are used as single agents.  Thus, lower doses of 
these inhibitors can likely be used in combination than when used as single agents without 
affecting efficacy. 
Hence, we propose a trial wherein we will identify HER2-negative advanced breast cancer and 
inflammatory breast cancer patients with hyperactive c-Met/HER-family activation in the tumor 
using the CELx MP test and treating them with a combination of neratinib, an irreversible 
tyrosine kinase inhibitor of the ErbB family of receptors (epidermal growth factor receptor 
(EGFR)/HER1, HER2, and HER4) and Capmatinib, a tyrosine kinase inhibitor of c-Met.  


Protocol Number: 2020-0198 
 
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CELsignia Platform 
Patient cancer cells are first isolated from tumor tissue using Celcuity’s proprietary cell 
microenvironment technology.  Dynamic cell signaling activity is then measured using these 
patient tumor cells with an impedance biosensor instrument. An impedance biosensor is an 
analytical platform that converts changes in cellular activity to a measurable electrical signal. 
This instrument measures dynamic changes in cell adhesion and morphology initiated by signal 
pathway activation or inhibition in live patient tumor cells.  
To determine the activity of a specific signaling pathway, an activating agent specific to a 
pathway receptor is used to turn on the pathway and a corresponding inhibitory agent specific to 
the pathway receptor is used to turn signaling off. When signaling pathways are stimulated in 
this manner, adhesion molecules are affected and cause a change in the impedance measured in a 
well.  By relying on the principle of detecting signaling pathway activity, tests can be developed 
for a range of disease types and targeted therapies that affect various cellular pathways.  
CELsignia Multi-Pathway Signaling Activity Test 
The CELsignia Multi-Pathway Test (MP) is a qualitative Laboratory Developed Test (LDT) that 
measures HER1/EGFR, HER2, HER3 and c-Met signaling activity in tumor cells obtained from 
patients previously diagnosed with HER2-negative breast cancer.  Fresh tissue specimens 
obtained from a biopsy procedure are collected in a Celcuity provided specimen collection kit at 
the clinical site and then delivered directly to Celcuity’s CLIA-certified and CAP-accredited 
laboratory where the test is performed, and the test report is issued.  
The CELsignia MP Test incorporates the following steps: 
1) Measures signaling driven by HER2 dimerization with HER1 and HER3 and by HER1, 
HER3, and c-Met homodimerization: 
A. Contacts cells with HER3 ligand (NRG1), HER1 ligand (EGF), and c-Met ligand 
(HGF) to activate corresponding pathways. 
B. Contacts cells with HER2 dimer-blocker  
2) Quantifies amount of HER1, HER2, HER3, and c-Met signaling  
3) Transforms quantitative result into a final qualitative result that characterizes the activity 
level of HER-family and c-Met signaling in the tested patient tumor cells as either normally 
active or hyperactive. 
Celcuity has completed analytical validation studies in accordance with applicable FDA 
guidance and Clinical and Laboratory Standards Institute (CLSI) standards in its CLIA/CAP 
certified laboratory to characterize the performance of the CELsignia MP test.  A summary of the 
results is below: 
 
 


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Table 1. Results of Analytical Validation Studies for CELsignia MP Test 
Performance Characteristics 
Results 
Analytical Precision (Qualitative)  
 
Analytical Sensitivity (95% CI) 
 
Analytical Specificity (95% CI) 
 
95.8% - 100% (88/88)  
95.8% - 100% (88/88) 
Detection Limits  
 
Limit of Blank 
 
Limit of Detection 
 
Limit of Quantification 
 
0.0020 cell attachment units 
0.0099 cell attachment units 
0.1000 cell attachment units 
Cut-Off Characterization 
HER2 
c-Met 
 
250 signaling units 
 
1.3 Co-activation of ER and HER2 pathway and need of co-inhibit.  
Preclinical and clinical data suggest the possibility that tumors can alternate between ER and 
HER2 as the dominant pathway, with targeted therapy against one pathway causing reactivation 
of the other growth factor pathways. For example, more than 20% of ER positive breast cancers 
activate HER2 pathways by many ways including ERBB2 mutation, amplification, or biological 
activation noted in both pre-clinical and clinical settings (20-22). While the data on whether the 
HER2 inhibition will re-activate the ER dependency of cancers may not be well established, 
enough accumulated data supports the additional inhibition of ER to the proposed combination 
of HER2 and c-MET inhibition. Therefore, we will add aromatase inhibitor therapy to the 
proposed study combination for patients with ER positive breast cancer in our study.   
2.0 Scientific/Medical Rationale  
For previously treated metastatic breast cancer or IBC patients, the prognosis is poor, which may 
be due to untreated dysregulated pathways, such as HER2 and c-Met.  For HER2-negative breast 
cancer patients diagnosed with dysregulated HER-family and c-Met signaling by the CELsignia 
MP test, there is a strong scientific basis for treating these patients with neratinib and capmatinib, 
which are designed to inhibit this dysregulated signaling activity.  Of note, metastatic IBC 
harbors the worst clinical prognosis compared to any other breast cancers. Moreover, once it 
becomes resistant to first line therapy – the response rate to second or above lines of therapy is 
poor (5-10% by history).  
 
The primary study endpoints are the safety and efficacy of the combination of capmatinib and 
neratinib. Overall Response Rate (ORR) is the primary efficacy endpoint.  This endpoint is 
typically used to assess the activity of a drug or drug combination when treating a patient 
population believed to have a disease mechanism corresponding to the therapy’s mechanism of 
action. 


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2.1 Rationale for Open-Label Study 
Once there is clear response rate observed here, we will further conduct confirmatory phase II or 
phase III studies. However, given the rarity of advanced breast cancer with HER2 activity while 
not called as HER2 positive, IBC, and their well-established poor outcomes, we believe a single 
arm phase II is sufficient to offer a clinical signal of this novel combination therapy that will 
possibly offer new options to patients who are in desperate need of better treatment. 
2.2 Rationale to Combine the Neratinib and Capmatinib in IBC with HER2 and c-Met 
Pathway Activity 
We believe that utilizing the CELsignia MP test to identify patients with hyperactive HER-
family/c-MET signaling pathways can identify the cancer driver in HER2-negative breast cancer 
patients that traditional IHC methodology may not detect.  The linkage between c-MET and 
HER-family dysfunctional signaling has been established both by Celcuity and other researchers 
and further analysis by Celcuity revealed that the mechanism of pan-HER inhibitors and c-MET 
inhibitors are not mutually exclusive and that this inhibitor combination is synergistic.   
Furthermore, the synergistic activity of these two classes of drugs suggests that the threshold 
drug concentrations for efficacy when the drug combination is used is less than what is required 
when these inhibitors are used as single agents.  Thus, lower doses of these inhibitors can likely 
be used in combination than when used as single agents without affecting efficacy, as is 
proposed here.  Therefore, we propose a phase Ib/II trial to study the combination of Neratinib 
and Capmatinib in HER2-negative advanced recurrent or metastatic breast cancer and 
inflammatory breast cancer patients whose tumors have hyperactive HER-family and c-Met 
signaling activity as determined by the CELx MP Test.  
3.0 Objectives 
3.1 Primary objective  
• Phase Ib: To determine maximum tolerated dose for use in the Phase II portion of the trial 
• Phase II: To determine overall response rate (ORR: CR+PR) 
3.2 Secondary objectives 
• To further characterize the safety and tolerability of neratinib + capmatinib in ER- MBC 
and of neratinib + capmatinib with Aromatase Inhibitor in ER+ MBC 
• To determine clinical benefit rate: (CBR: CR + PR + SD ≥ 24 weeks)  
• To determine the duration of response  
• To determine progression free survival (PFS)  
• To determine 2 year overall survival (OS) 
3.3 Exploratory Objectives 
• To determine the functional status of the HER2, c-Met, and EGFR pathways using the 
CELsignia test 


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• To determine the ORR, CBR, DOR, PFS, and OS for the sub-group of patients with 
metastatic inflammatory breast cancer and for the sub-group of patients with metastatic 
non-inflammatory breast cancer   
• Assess response per molecular subtype, Hormone Receptor (HR) positive (ER and/or 
PR), HER2 negative and Triple Negative Breast Cancer 
• Assess genomic profile of cancers treated on study to explore potential mechanisms of 
response and resistance. 
 
4.0 Study design 
This is an open-label, phase Ib/II study of Neratinib plus Capmatinib in patients with metastatic 
breast cancer and metastatic IBC. In both phase Ib/II, patients with ER positive, breast cancer 
will also receive an aromatase inhibitor  +/- ovarian suppression (for pre/peri menopausal 
patients). 
4.1 Phase 1b – Dose Escalation of Neratinib with Capmatinib 
This phase of the study will employ the Bayesian optimal interval (BOIN) design (Liu and Yuan, 
2015 Yuan et al., 2016) (24, 25), with the 3+3 design run-in, to find the MTD.  The BOIN design 
is implemented in a simple way similar to the traditional 3+3 design, but is more flexible and 
possesses superior operating characteristics that are comparable to those of the more complex 
model-based designs, such as the continual reassessment method (CRM) (Zhou et al., 2018) (26). 
The maximum sample size for dose escalation is 18. Patients are treated in cohorts of 3, 
beginning with Neratinib PO dose level 1 (120 mg, Dose 1-7 , 160 mg, through end of treatment, 
see Table 2) in combination with Capmatinib PO level 1 (400 mg, see Table 3), with a maximum 
of 12 patients per dose.  The target toxicity rate for the maximum tolerable dose (MTD) is 25%.  
This trial was designed and will be conducted using the shiny app “BOIN” (BOIN V2.6.3.0) 
available at http://www.trialdesign.org.. Further information about the design can be found in 
Section 13. 
Table 2. Phase Ib Neratinib PO dose levels, in combination of Capmatinib PO. 
Dose Level 
1 
2 
3 
Neratinib PO 
120 mg,  Dose 1-7 , 
160 mg, through end 
120 mg,  Dose 1-7, 
160 mg,  Dose 8-14, 
200 mg, through end 
120 mg,  Dose 1-7, 
160 mg,  Dose 8-14, 
240 mg, through end 
Capmatinib PO 
400 mg  b.i.d. 
400 mg  b.i.d. 
400 mg  b.i.d. 
 
Table 3 :  Fallback Dose levels. 
 
Dose level -1 
Dose level -2 
Neratinib PO 
120 mg,  Dose 1-7, 
160 mg, through end 
120 mg,  Dose 1-7, 
through end 
Capmatinib PO 
300 mg  b.i.d. 
200 mg  b.i.d. 


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Note: dose reduction should be based on the worst toxicity demonstrated at the last dose. 
Dose reduction below 200 mg is not allowed 
 
This protocol will be monitored by IND Office and safety data will be reviewed by IND Office 
after all subjects in a given cohort have completed the DLT assessement period (Cycle 1 and 2, 
total 56 days) and the dose level for next cohort will be determined based on the results. 
 
Prior to advancing/changing dose levels, a cohort summary will be completed and submitted to 
the IND Medical Monitor for review and approval.   
 
4.2 Phase II  
Phase II will be a prospective, open label, interventional study with previously treated HER2-
negative metastatic breast cancer and metastatic inflammatory breast cancer patients. Subjects 
receive capmatinib in combination with neratinib. The MTD determined during Phase 1b will be 
used. 
 
This portion of the trial will be conducted to assess the overall response rate (ORR) for patients 
treated at the MTD.  The target ORR will be 25%, with unacceptable ORR as 5%.  We will 
assess the ORR using the Bayesian optimal phase 2 (BOP2) design (Zhou, Lee and Yuan, 2017).     
 
Up to an additional 29 evaluable subjects with measurable disease will be enrolled. An interim 
analysis will be performed when the number of enrolled patients reaches 15. 
 
The study Phase II portion safety and efficacy data will be monitored by the IND Office. 
 
Treatment response will be evaluated per RECIST tumor response through QIAC. 
 
4.3. Subject Population to be included: 
In the Phase 1b portion of the study, previously treated HER2-positive and HER2-negative, HR-
positive and HR-negative metastatic and inflammatory breast cancer patients will be enrolled.   
In the Phase II portion of the study, previously treated HER2-negative, HR-positive and HR-
negative metastatic and inflammatory breast cancer patients with abnormal HER-family and c-
Met signaling tumors will be enrolled. The CELsignia Multi-Pathway (CELsignia MP) Test will 
characterize the subjects’ HER-family and c-Met-driven signaling pathways as either hyperactive 
or normally active.   
 
4.4 Number of Subjects per Study Group: 
 
Phase Ib  
This portion of the study will enroll a maximum of 18patients in the dose-finding trial including 
the possibility of adding up to 6 additional ER+ HER2 negative patients in a safety assessment of 
aromatase inhibitor treatment.  The statistical considerations used to derive this sample size are 
presented in Section 13.1. 
                                                                                                                                                                                    
Phase II 


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This portion of the study will enroll a maximum of 29 patients.  The statistical considerations 
used to derive this sample size are presented in Section 13.2. 
 
Total accrual of this study will be up to 47 patients. We plan the enrollment for Phase Ib dose 
escalation to be 1-3 per 2 months since the DLT observation period is 2 months; and for Phase II 
to be 0-2 per month for each open site. 
5.0 Study Endpoints  
5.1 Primary Endpoints 
•   Safety 
The primary safety endpoint is to determine the safety, tolerability, and dose limiting 
toxicities (DLT) (Phase 1b) of the combination of capmatinib and neratinib, and of neratinib 
+ capmatinib in combination with an aromatase inhibitor in ER+ MBC.       
•   Efficacy  
For the Phase 2 portion of the study, the primary efficacy endpoint is overall response rate 
(ORR), defined as the rate of patients who achieve partial response or complete response as 
the best response.  
All tumor response will be evaluated by RECIST 1.1 and measured by QIAC system, via 
research collaboration. 
5.2 Secondary Endpoint(s):  
• Clinical benefit rate (CBR) 
Defined as the rate of patients who achieved complete response, partial response and stable 
disease for ≥ 24 weeks as the best response of treatment. 
• Duration of response (DOR)  
DOR is defined as the period measured from the date of the first occurrence of a CR or PR 
(whichever status is recorded first) until the first date that progressive disease or death is 
documented. Patients who have not progressed and who have not died by the date of data 
cutoff for analysis will be censored at the time of last tumor assessment date. If tumor 
assessments performed after the date of the first occurrence of a CR or PR showed a 
different response, DOR will be censored at the date of the first occurrence of a CR or PR 
plus remaining stable response from that time point. 
• Progression free survival (PFS)  
PFS is defined as the time between date of treatment start to the date of documented disease 
progression or death, whichever occurs first. Data from patients who have not experienced 
disease progression or death will be censored at the last tumor assessment date known to be 
free of disease progression. Data from patients with no post-baseline tumor assessment will 
be censored at the treatment start date plus 1 day. 
• 2  year overall survival (OS) 


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2  year OS definition: the proportion of patients in the study who are alive 2 years after 
enrollment on to the study. 
5.3 Exploratory Endpoints:  
• For exploratory purposes, ORR, CBR, DOR, PFS, and OS will also be analyzed 
separately for the sub-group of IBC patients and for the sub-group of advanced or metastatic 
non-IBC breast cancer patients. 
• Assess response per molecular subtype, Hormone Receptor positive (ER and/or PR), 
HER2 negative and Triple Negative Breast Cancer 
• Assess genomic profile of cancers treated on study to explore potential mechanisms of 
response and resistance. 
6.0 Eligibility Criteria 
6.1 Inclusion Criteria 
1. Signed Informed Consent Form (ICF) and comply with the requirements of the study 
protocol 
2. Age ≥ 18 years.  
3. ECOG performance status 0-1  
4. Confirmed diagnosis of metastatic breast cancer or inflammatory breast cancer according 
to international consensus criteria30:  
-Onset: Rapid onset of breast erythema, edema, and/or peau d’orange, and/or warm 
breast, with or 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 
5.  Patients who have metastatic disease which is not amenable to curative treatment with 
available local and systemic therapy. Patients must have received at least 1 line or up to 6 
lines of therapy in the metastatic setting with at least 2 weeks washout period before the 
initiation of study treatment.  
i. Unless a contraindication to therapy exists, patients with ER+ breast cancer must 
have received prior endocrine therapy combined with a CDK4/6 inhibitor, patients 
with BRCA1 or BRCA2 mutations must have received prior PARP inhibitor, and 
patients with PD-L1+ triple negative breast cancer must have received prior 
immunotherapy.  
ii. Patients with HER2-positive disease must have received at least 2 regimens of 
anti-HER2 therapy in metastatic setting. 


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6. For Phase Ib, any ER, PR, and HER2 status, For Phase 2, HER2-negative per ASCO/CAP 
guidelines and any ER and PR status. 
7.  For Phase II only, Patients with measurable disease according to the Response Evaluation 
Criteria in Solid Tumor (RECIST, v1.1) (local or distant) and at least one metastatic lesion 
amenable for biopsy (core or punch)  
NOTE: 
Measurable disease: Measurable lesions are defined as those that can be 
accurately measured in at least one-dimension (longest diameter to be recorded) 
as ≥ 20mm by chest X-ray, ≥ 10mm by computed tomography (CT) scan, ≥ 
10mm with calipers by clinical exam. 
Measurable malignant lymph nodes: To be considered pathologically 
enlarged and measurable, a lymph node must be ≥ 15mm in short axis when 
assessed by CT scan. 
Non-measurable disease: All other lesions (or sites of disease), including small 
lesions, are considered non-measurable. Bone lesions, leptomeningeal disease, 
ascites, pleural/pericardial effusions, lymphangitis, cutis/pulmonitis, 
inflammatory breast disease, and abdominal masses [not followed by CT or 
magnetic resonance imaging (MRI)] are considered non-measurable. 
 
8.  Left Ventricular Ejection Fraction ≥ 50% measured by MUGA scan or Echocardiogram.  
9.  Abnormal HER-family and c-Met signaling activity based on CELsignia MP Test results 
(for phase II patients only).  
10. Participants must have adequate organ function including the following laboratory values 
at the screening visit. Screening must occur within 28 days prior to the first dose of study drug. 
Screening samples for hematology and serum chemistries must be drawn within 14 days prior 
to the first dose of study drug: 
• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L without growth factor support 
• Platelets (PLT) ≥ 75 x 109/L 
• Hemoglobin (Hgb) ≥ 9 g/dL 
• Calculated creatinine clearance (using Cockcroft-Gault formula) ≥ 45 mL/min 
•  Total bilirubin (TBIL) ≤ ULN (upper limit of normal) with the following exception: 
Patients with known Gilbert disease who have serum bilirubin level ≤ 3 x ULN may 
be enrolled. 
• Aspartate transaminase (AST) ≤ 3 x ULN, except for participants with liver 
metastasis, who may only be included if AST ≤ 5 x ULN 
• Alanine transaminase (ALT) ≤ 3 x ULN, except for participants with liver metastasis, 
who may only be included if ALT ≤ 5 x ULN 
• Alkaline phosphatase (ALP) ≤ 5.0 x ULN 


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• Asymptomatic serum amylase ≤ grade 2. Participants with grade 1 or grade 2 serum 
amylase at the beginning of the study must be confirmed to have no signs and/or 
symptoms suggesting pancreatitis or pancreatic injury (e.g., elevated P-amylase, 
abnormal imaging findings of pancreas, etc.) 
• Serum lipase ≤ ULN 
     11. Willing and able to comply with scheduled visits, treatment plan and laboratory tests. 
Patients who are cognitively impaired who may not be able to comply with the oral study 
medication schedule are excluded. 
i) Patients with ER positive (defined at ER>/=10%)breast cancer, must start (or continue) 
an aromatase inhibitor of physician choice during the study duration. In addition, pre-/peri-
menopausal women with ER+ breast cancer will also require ovarian suppression therapy. 
 
     12. Non-English speaking subjects are eligible as long as a translator is available at the treating 
site. 
 
6.2 Exclusion Criteria 
1. Concurrent anticancer therapy within 2 weeks of initiation of study treatment; except: 
i. 
Endocrine therapy (SERM, aromatase inhibitor, fulvestrant, medical ovarian 
suppression therapy) 
ii. 
Palliative radiotherapy for bone metastases < 1 week prior to study treatment 
2. Unstable and symptomatic brain metastasis (Stable disease is defined as CNS 
radiographic study ≥ 4 weeks from completion of radiotherapy and ≥ 2 weeks from 
discontinuation of corticosteroids) 
3. Non-hematologic adverse events from prior anticancer therapy that have not resolved to 
Grade ≤ 1 (CTCAE v 5.0), except for alopecia, vitiligo, pain, constipation if these symptoms 
existed during screening baseline.  
i. 
Grade 3 or above neuropathy induced from prior treatment, that is not resolved to 
grade 2 or below despite best supportive care 
4. Known clinically significant liver disease, including active viral, alcoholic, or other 
hepatitis; cirrhosis 
5. Acute exacerbations of underlying condition within the last 12 months (requiring psoralen 
plus ultraviolet A radiation [PUVA], methotrexate, retinoids, biologic agents, oral 
calcineurin inhibitors; high potency or oral steroids) 
6.  Patients with known HIV infection. Testing for HIV is not required for study screening:  
1) CD4+ count<350 cells/uL; or 2) had AIDS-defining opportunistic infections < 12 months  
7. Known active hepatitis B (chronic or acute) or hepatitis C infection. Testing for hepatitis 
is not required for study screening:  


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i) Patients with past or resolved hepatitis B infection (defined as having a negative 
hepatitis B surface antigen [HbsAg] test and a NEGATIVE anti-HBc [antibody to 
hepatitis B core antigen] antibody test). Patient is eligible if anti-HBc is POSITIVE, but 
should sample for HBV DNA and referral to virologist to monitor for HBV reactivation 
ii) Patients with positive for hepatitis C virus (HCV) antibody and have positive  
polymerase chain reaction (PCR) for HCV RNA. 
8. Severe infections within 4 weeks prior to study treatment, including but not limited 
to hospitalization for complications of infection, bacteremia, or severe pneumonia 
9. Signs or symptoms of infection within 2 weeks prior to study treatment per treating 
physician and PI judgement.   
10. Concurrent oral or IV antibiotics within 5 days prior to study treatment 
* Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract 
infection or chronic obstructive pulmonary disease) are allowed and eligible so long 
as the antibiotic is not prohibited with the study medication (See Tables 8). 
11. Major surgical procedure within 28 days prior to study treatment or anticipation of need 
for a major surgical procedure during the course of the study. 
12. Presence or history of interstitial lung disease or interstitial pneumonitis, including 
clinically significant radiation pneumonitis (i.e., affecting activities of daily living or requiring 
therapeutic intervention). 
13. Long QT syndrome, family history of idiopathic sudden death or congenital long QT 
syndrome. 
14. Clinically significant, uncontrolled heart diseases. 
• Unstable angina within 6 months prior to screening 
• Myocardial infarction within 6 months prior to screening 
• History of documented congestive heart failure (New York Heart Association 
functional classification III-IV) 
• Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥ 160 mm Hg 
and/or Diastolic Blood Pressure (DBP) ≥ 100 mm Hg, with or without 
antihypertensive 
medication. 
Initiation 
or 
adjustment 
of 
antihypertensive 
medication(s) is allowed prior to screening 
• Ventricular arrhythmias 
• Supraventricular and nodal arrhythmias not controlled with medication 
• Other cardiac arrhythmia not controlled with medication 
• QTcF (QT interval corrected by Fridericia’s formula) ≥ 470 ms on the screening 
ECG (as mean of triplicate ECG) 
15. Major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic) within 4 weeks prior 
(2 weeks for resection of brain metastases) to starting study therapy or who have not 
recovered from side effects of such procedure.  


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16. Unable to swallow or absorb study drugs due to impairment of GI function or GI disease 
e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, or malabsorption 
syndrome 
17. Participants receiving treatment with any enzyme-inducing anticonvulsant that cannot be 
discontinued at least 1 week before first dose of capmatinib, and for the duration of the 
study.  
18. Other severe, acute, or chronic medical or psychotic conditions, substance abuse or 
laboratory abnormalities that in the opinion of the investigator may increase the risk 
associated with study participation, or that may interfere with the interpretation of study 
results. 
19. Pregnant or nursing (lactating) women 
20. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing and for one month after stopping treatment. Highly effective contraception 
methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) total hysterectomy, or tubal ligation at least six weeks before taking 
study treatment. In case of oophorectomy alone, only when the reproductive status 
of the woman has been confirmed by follow up hormone level assessment 
• Male sterilization (at least 6 months prior to screening). For female subjects on the 
study, the vasectomized male partner should be the sole partner for that subject 
• Use of injected or implanted hormonal methods of contraception or placement of 
an intrauterine device (IUD) or intrauterine system (IUS), or other forms of 
hormonal contraception that have comparable efficacy (failure rate <1%), for 
example hormone vaginal ring or transdermal hormone contraception. Women are 
considered post-menopausal and not of childbearing potential if they have had 12 
months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g., age appropriate, history of vasomotor symptoms) or have had surgical 
bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least 
six weeks before study entry. In the case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up hormone level 
assessment is she considered not of child-bearing potential. 
21. Sexually active males will not be eligible unless they use a condom during intercourse 
while taking drug and for 3 months after stopping treatment and should not father a child 
in this period. A condom is required for all sexually active male to prevent them from 
fathering a child AND to prevent delivery of study treatment via seminal fluid to partner. 
In addition, male participants must not donate sperm for the time period specified above. 
22. Participants receiving treatment with the following medications that cannot be 
discontinued at least 1 week prior to the start of treatment with study therapy and for the 
duration of the study: 
a. strong inducers of CYP3A 


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b. moderate inducer of CYP3A4 
c. strong CYP3A4 inhibitor 
d. concomitant use of a moderate CYP3A4 and P-gp dual inhibitor (verapamil). 
e. proton pump inhibitor. Neratinib may be taken at least 2 hours before or 10 hours 
after an H2-receptor antagonist, and 3 hours after antacids. 
f. P-gp substrates (such as digoxin, dabigatran, fexofenadine) or strong P-gp inducers 
(such as carbamazepine, phenytoin, rifampicin, and St. John's wort). 
g. Chronic immunosuppressive therapies including systemic corticosteroids. Steroids 
given for physiological replacement, as anti-emetics or inhaled as well as short 
course of oral/topical steroids given for allergic reactions or asthma flares are 
allowed. 
23. No prior treatment with Capmatinib, Neratinib, or other HER2 directed tyrosine kinase       
inhibitor (for phase II patients only). 
 
7.0 Study Procedures 
7.1 Schema
 
Figure 1. Study Schema 
 
7.2 Dosing level and Drug Administration  
All participants will receive two drugs (neratinib and capmatinib) during the study as scheduled 
per Schema.  Capmatinib and neratinib will be provided by Novartis and Puma respectively, and 
not billed to the patient. Additionally, patients with ER+ breast cancer will receive endocrine 
therapy (AI +/- ovarian suppression). Endocrine therapy is standard of care (SOC), not provided 
by the study. 


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The Phase Ib portion of the trial will determine the Maximum Tolerated Dose (MTD) from the 
combination of dosing levels listed in Tables 2 and 3, starting at Dose Level (1,1) (capmatinib 
PO  400 mg twice per day and neratinib PO 120 mg on days 1-7, then 160 mg through end of 
treatment). The maximum accrual for phase Ib is 18 patients (including the possibility of adding 
up to 6 additional ER+/HER2 negative patients in a safety assessment of aromatase inhibitor 
treatment). 
The Phase II portion of the trial will enroll 29 patients treated at the MTD determined from the 
phase Ib portion of the study. 
Total accrual of this study will be up to 47 patients 
Both drugs are oral agents and each study cycle will be 28 days. 
Patient will take study drugs by mouth with or without food per cohort dosing. Neratinib will be 
taken once daily with food.  Capmatinib will be taken twice daily about 12 hours apart (+/-2 
hours)with or without food. Patients will have a medication diary to record daily study drug 
intake information for each cycle. The study manager will collect it at each clinic visit as source 
document. 
Neratinib 
Nertatinib will be supplied as 40 mg tablets, equivalent to 48.31 mg neratinib maleate. Tablets 
are film-coated, red, oval shaped and debossed with ‘W104’ on one side and plain on the other 
side. 3 – 6 tablets daily will be prescribed based on patient’s dose level. Tablets should be 
swallowed whole (tablets should not be chewed, crushed, or split prior to swallowing). 
If a patient misses a dose, it should not be replaced, and the patient should be instructed to 
resume neratinib with the next scheduled daily dose. 
Neratininb should be stored at controlled room temperature, 20°C to 25°C (68°F to 77°F); 
excursions permitted to 15°C to 30°C (59°F to 86°F). 
Capmatinib 
Capmatinib will be supplied at 200 mg and 150 mg tablets. Capmatinib should be taken twice 
daily with or without food. Tablets should be swallowed whole. Do not break, crush or chew the 
tablets. 
If a patient misses or vomits a dose, instruct the patient not to make up the dose, but to take the 
next dose at its scheduled time. 
Capmatinib should be stored at 20 – 25oC (68 – 77oF), excursions permitted between 15oC and 
30oC (59 - 86oF). Protect from moisture. 
Endocrine Therapy (for patients with ER+ breast cancer in Phase 1b and Phase II) 
Patients with ER+ (defined at ER ≥10%)breast cancer will receive (start or continue) continuous 
aromatase inhibitor therapy by mouth dosed once daily. The aromatase inhibitor drug 
administered will be of physician’s choice during the study duration. For pre-/peri-menopausal 


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women with ER+ breast cancer, ovarian suppression therapy of physician’s choice will also be 
administered. 
7.3 General Treatment Guidelines  
If a toxicity is attributed to one of the study drugs, it may be held and the other drug(s) will still 
be given as scheduled. If a toxicity is not clearly linked to a single drug, then both neratinib and 
capmatinib may be held. The treating physician may withhold any of the drugs per their 
discretion and discussion with the principal investigator as needed to maintain patient safety 
while a toxicity is evaluated and treated. The drug should be resumed after appropriate toxicity 
management and dose reduced, if indicated as per Section 10 of the protocol. 
Patients must receive at least 80% of the scheduled doses of each study medication to be 
considered evaluable for DLT. Patients with ER+ breast cancer must receive at least 80% of the 
scheduled dose of AI to be considered evaluable for DLT. However, any patient who experiences 
DLT, will be counted as a DLT regardless of how many doses received.  
As study therapy is given continuously, missed days of treatment will not be made up. A cycle is 
defined as 28 days regardless of the number of days of treatment received. 
In the event the patient experiences intolerable side effect(s) attributed to the endocrine therapy 
agent(s), the treating physician may withhold the agent per their discretion and discussion with 
the principal investigator as needed to maintain patient safety while a toxicity is evaluated and 
treated. The treating physician may change the AI agent administered and prescribe treatment for 
symptom control, as clinically indicated.   
The following delays are allowed except during the DLT assessment period: 
1) Up to 4 weeks due to study related AEs  
2)  Up to 8 weeks due to non-study related AEs 
Unanticipated Dose Interruptions: 
Interruptions due to non-study related issues (logistical, natural disaster, etc) are permitted in the 
case of logistical reasons not related to study therapy, up to 2 cycles of study. 
7.4 Dose Limiting Toxicity (DLT)  
DLT is defined as any of the following possibly, probably, or definitely due to study therapy, 
assessed during the first 2 cycles [56 days]: 
• Any death not clearly due to the underlying disease or extraneous causes 
• Non- hematologic toxicity  
o Grade 3 or higher non-hematologic toxicity, Grade 3 diarrhea will be considered  
a DLT only if it lasts ≥ 2 days despite prophylaxis and optimal standard  
medication and medical management. 


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• Grade 2 diarrhea lasting ≥ 5 days despite prophylaxis and optimal standard medical 
management  
• Pulmonary toxicity 
o Any grade of pneumonitis or ILD confirmed not attributable to infection or 
another etiology.  
• Hy's Law case, defined as a patient meeting all of the following criteria: 
o ALT or AST ≥ 3 x Upper Limit of Normal (ULN) 
o Total bilirubin >2 x ULN 
o Little or no evidence of cholestasis (alkaline phosphatase <2 x ULN) 
o No other identified explanation for the injury (such as hepatitis A, B, C, or other 
viral hepatic injury, alcohol ingestion, congestive heart failure).  
• Neutropenic fever, defined as per CTCAE version 5.0:  
ANC <1000/mm3 and a single temperature of >38.3 degrees C (101 degrees F) or a 
sustained temperature of >=38 degrees C (100.4 degrees F) for more than one hour.  
• Hematologic toxicity  
o Grade 4 neutropenia or thrombocytopenia >7 days 
o Grade 3 thrombocytopenia with bleeding  
o Grade 4 anemia 
The targeted maximum DLT rate is 25%, and we will enroll patients in cohorts of size 3.  
 
Table 4.  Capmatinib and Neratinib overlapping toxicities 
SOC 
Capmatinib toxicity (Ref: CDS) 
Neratinib toxicity (Ref: USPI and 
SmPC) 
Congenital, familial and genetic 
disorders 
Embryo-Fetal Toxicity 
Embryo-Fetal Toxicity 
Gastrointestinal disorders 
Diarrhoea 
Diarrhoea 
Vomiting 
Vomiting 
Nausea 
Nausea 
Constipation 
Abdominal pain* 
Amylase increased 
Stomatitis** 
Lipase increased 
Dyspepsia 
Acute pancreatitis 
Abdominal distension 
 
Dry mouth 


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General disorders and 
administration site conditions 
Fatigue1 
Fatigue 
 
Weight decreased 
Weight decreased 
Back pain 
 
Oedema peripheral2 
Non-cardiac chest pain3 
Pyrexia4 
Hepatobiliary disorders 
Alanine aminotransferase 
increased 
Alanine aminotransferase 
increased 
 
Aspartate aminotransferase 
increased 
Aspartate aminotransferase 
increased 
Blood bilirubin increased 
Blood bilirubin increased 
Hypoalbuminemia 
 
Infections and infestations 
Cellulitis 
Urinary tract infection 
Metabolism and nutrition 
disorders 
Decreased appetite 
Decreased appetite 
Hyponatremia 
Dehydration 
Hypophosphataemia 
 
Respiratory, thoracic and 
mediastinal disorders 
Pneumonitis/ILD 
Epistaxis 
Dyspnoea 
 
Cough 
 
Skin and subcutaneous tissue 
disorders 
Urticaria 
Rash*** 
Pruritus5 
Dry skin 
  
Nail Disorder**** 
Skin fissures 
Renal and urinary disorders 
Blood creatinine increased 
Blood creatinine increased 
 
Acute kidney injury6 
Renal failure 
Musculoskeletal and Connective 
Tissue Disorders 
 
Muscle spasms 
1Includes fatigue and asthenia 
2 Includes peripheral swelling, oedema peripheral, and fluid overload 
3 Includes chest discomfort, musculoskeletal chest pain, non-cardiac chest pain, and chest pain 
4 Includes pyrexia and body temperature increased 
5 Includes pruritus, pruritus allergic, and pruritus generalized 
6 Includes acute kidney injury and renal failure. 
 
* Includes abdominal pain, abdominal pain upper, and abdominal pain lower 
** Includes stomatitis, aphthous stomatitis, mouth ulceration, oral mucosal blistering, mucosal inflammation, oropharyngeal pain, oral 
pain, glossodynia, glossitis, and cheilitis 
*** Includes rash, rash erythematous, rash follicular, rash generalized, rash pruritic, rash pustular, rash maculo-papular, rash 
papular, dermatitis, dermatitis acneiform, and toxic skin eruption  
**** Includes nail disorder, paronychia, onychoclasis, nail discoloration, nail toxicity, nail growth abnormal, and nail dystrophy 
 


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7.5 Duration of therapy 
In the absence of treatment delays due to AEs, the treatment will continue up to 3 years or until 
disease progression, death of patient for any cause or meeting the treatment discontinuation 
criteria, whichever comes first. 
7.6 Study Discontinuation 
Patient will stop receiving the study treatment if any of the following criteria are met: 
1) 
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). 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). 
2) 
Noncompliance 
If the patient is not able to be compliant with the treatment schedule in the absence of toxicity, 
missing medications by non-medical reasons that are reported to the research staff more than 14 
days, the study treatment should be discontinued for the patient. 
3) 
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 8 weeks. 
4) 
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. 
5) 
Patient withdraws consent 
Patients have the right to voluntarily withdraw from the study at any time for any reason. Every 
effort should be made to obtain information on patients who withdraw from the study.  The 
primary reason for withdrawal from the study should be documented on the appropriate Case 
Report Form (CRF) in the RedCap database.  However, patients will not be followed for any 
reason after consent has been withdrawn  
6) 
Any medical condition that the investigator, IND medical monitor or Novartis and 
PUMA determines may jeopardize the patient’s safety if he or she continues in the study 
7) 
Intolerable toxicity related to study treatment determined by the investigator to be 
unacceptable given the individual patient’s potential response to therapy and severity of the 
event 


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8) 
Pregnancy 
9) 
Symptomatic deterioration attributed to disease progression 
7.7 Follow up 
Patients will be followed for safety for 30 days following the last dose of study drug, or until 
receipt 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 6 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 study is terminated). 
7.8 End of Study 
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs or the 
date at which the last data point required for statistical analysis (i.e., OS) or safety follow-up is 
received from the last patient, whichever occurs later. LPLV is expected to occur 3 years after 
the first patient is enrolled. 
7.9 Correlative Research 
Blood: Research blood, approximately 30 ml, will be collected at baseline and then every 2 
cycles until the end of study treatment. Each blood collection will consist of 1x10mL red top 
tube (for serum) and 2x10mL EDTA tubes (for plasma and PBMC isolation). Samples will be 
processed and aliquots banked in the MDA IBC translational lab for future research. Samples 
will be stored in the short term at -80C (serum and plasma, Z12.4041) and LN2 dewar (for 
PBMCs) in the Zayed laboratory and transferred to off-site storage at Cryogene per routine 
laboratory procedures. Samples will be coded by a de-identification number and a key will be 
maintained by the research staff to associate each sample with the related clinical data. For any 
visits performed outside of MD Anderson, research blood will not be collected.   
 
Tissue: Fresh tissue samples from breast/chest wall, or a metastatic site including lung, liver or 
lytic lesions of the bone that may be safely accessed, will be collected via image-guided core 
biopsy. Tissue should be from a viable section of the tumor. Core needle biopsy specimen 
diameter should not be smaller than 16 gauge with 2 or more cores preferred. Viable tumor 
resection biopsies should not be less than 25 mg. Fine needle aspirates are not acceptable. 
Samples will be collected using a Celcuity provided specimen collection kit and then delivered 
directly to Celcuity’s CLIA-certified and CAP-accredited laboratory where the CELsignia MP 
test (HER2, EGFR, HER3, c-MET etc.) is performed. Additional details regarding sample 
collection and processing are included in Appendix 2, “CELsignia Collection Kit User 
Instructions Card”.  Please also see Appendix 3 for the “CELsignia Specimen Collection 
Requisition” form. 


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In addition to the CELsignia MP test, remaining tissue will be banked inthe MDA IBC Lab for 
future research and to perform companion genomic testing to include major relevant pathways 
affected by the combination treatment.  A total of 4-6 cores will be obtained from each patient, 
2-4 of which will be sent to Celcuity for the CELsignia assay. The remaining cores will be 
preserved in OCT in order to preserve morphology, for further research on biomarkers of 
response/resistance to the therapy. IHC for c-MET will not be used for patient selection for the 
clinical trial given lack of validated clinical data.  
 
Future studies performed on tissue and/or blood may include, but will not be limited to analysis 
of genomics, RNA, protein expression, or other analytes to study biomarkers, mechanisms of 
action, mechanisms of response/resistance, and pathways of interest. 
 
In addition, we will perform mandatory collection of available data on cancer genomics that has 
been performed on the cancers of study participants for purposes outside of this study. 
 
7.10. Study Calendar 
Trial Period: 
Screening  
Phase 
Treatment Cycles 
 1 cycle=28 days a 
End of 
Treatment Post-Treatment 
 
Screening 
/Baseline 
1 2 3 4 5 6 7 8+  
Safety 
F/U f 
F/U g 
Scheduling Window (Days): 
Within 28 days 
+/- 3 days 
± 
3 
± 
3 
± 
3 
± 
3 
± 
3 
± 
3 
± 
3 
± 
3 
 
1  
month 
2 years  
 
Informed Consent 
x 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam b, V/S, 
concomittent medications, 
ECOGb  
x 
x x x x x x x x 
xl 
 
 
Adverse Events b 
x 
x x x x x x x x 
xl 
x 
x 
Pregnancy Test – Urine or Serum 
β-HCG (for women with 
childbearing potential) 
x 
x x x x x x x x 
xl 
 
 
CBC and Biochemical Profiles c 
x 
x x x x x x x x 
xl 
 
 
Urine analysis  c 
x 
x x x x x x x x 
xl 
 
 
EKG, MUGA or ECHO as SOC i 
x 
 
 
 x  
 x 
 
 
 
 
Radiological Evaluation as 
clinically indicated and as SOC d 
x 
 
 x  x  x 
 
xl 
 
 
Correlative Studies Blood 
Collection e 
x 
 
 x  
x  x 
 
 
 
 
Biopsy h  
x 
 
 
 
 
 
 
 
 
 
 
 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
x 
Neratinib j 
 
x x x x x x x x 
 
 
 
Capmatinib j 
 
x x x x x x x x 
 
 
 
Endocrine Therapy K 
 
x x x x x x x x 
x 
 
 


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a. 
Study treatment can be up to 3 years until the treatment is discontinued. 
b. 
Complete physical exam during the screening period. This will not be repeated if done within 8 (+/- 3 days) days before 
the start of treatment. During treatment Physical Exam as clinically indicated prior to trial treatment administration.  Adverse 
events and ECOG performance status assessment can be done within 8 (+/- 3 days) days before the start of treatment. If a virtual 
visit is required, then physical exam and VS will not be obtained. 
c. 
Hematologic and biochemical profiles (CBC, albumin, alkaline phosphatase, ALT, AST, LDH, amylase,  lipase, uric 
acid, calcium, glucose, phosphorus, potassium, sodium, magnesium, total bilirubin, total protein, BUN, creatinine, as standard of 
care (will not be repeated if done within 8 (+/- 3 days) days before the start of treatment). During treatment, an earlier evaluation 
will be performed if clinically indicated. 
d. 
Radiological evaluation will be performed every 2 cycles as standard of care and may include CT of the chest and 
abdomen, Ultrasound, bone Scan and X-Rays, brain MRI as clinically indicated for standard of care. PET/CT, Chest wall/breast 
photos may also be performed as indicated for standard of care. During treatment, an earlier evaluation will be performed if 
clinically indicated. The same method of evaluation, specific to the subject's condition, will be performed according to the time 
points. 
e. 
Blood (EDTA tube) and serum (red tube) for correlative studies. Approximately 30cc of blood will be drawn at 
baseline, and every 2 cycles (i.e. 3th, 5th, 7th, etc.). For any visits performed outside of MD Anderson, research blood will not be 
collected. Correlative research blood is mandatory.    
f. 
The Safety Follow-Up Visit should be conducted approximately 30 days after the last dose of trial treatment or before 
the initiation of a new anti-cancer treatment, whichever comes first.  All AEs that occur prior to the Safety Follow-Up Visit 
should be recorded. Safety Follow-Up Visit can be done in the clinic, or by phone/video if patient is not willing to come to the 
clinic for follow up.   
g. 
2 years follow up can be performed every 6 months in the clinic, or by phone/video if patient is not willing to come to 
the clinic for follow up.   
h. 
Mandatory to Phase II patients only. Biopsy at baseline can be combined with the primary diagnosis biopsy, or any 
time before the initiation of this trial to confirm the Celcuity assay score.  
i.          EKG, MUGA or ECHO will be performed every 3 cycles as standard of care. 
j.          Participants may follow Study Medication Disposal Guide of MDA to dispose of study medications locally when 
participants cannot come back to study site to return remaining study medications and medication bottles. Participants may also 
capture pictures of the pill diaries and send them to research staff, if needed. 
k.          ER+ breast cancer patients only (defined at ER ≥10%) will receive continuous aromatase inhibitor therapy (of 
physician’s choice) by mouth dosed once daily. In addition, for pre-/peri-menopausal women with ER+ breast cancer, ovarian 
suppression therapy will also be administered.  
l.        If applicable; can be combined with post 1 month follow up.  
 
7.11. Remote Procedures  
In case of any unexpected incidents resulting in the inability to return to MD Anderson Cancer 
Center for study treatment and assessments, remote procedures can be applied for this trial 
conduction, including remote consent, remote toxicity assessment via phone calls, virtual visit, 
etc., with compliance with institutional policies. Patients may have routine lab work and 
additional labs performed at a local facility for toxicity management as needed. Lab certificates 
(CLIA/CAP) of the local lab will be obtained for regulatory compliance.  Laboratory work done 
at an outside facility is to be forwarded to the subject's attending physician at MDACC or the PI 
of the study, who will date and sign off on the labs to verify the results were reviewed. If the 
patient’s outside records are available to review in MDACC’s EMR ( i.e. EPIC ‘Care 
Everywhere’), then it will be documented in either the physician’s note and/or the study 
coordinator’s note (attested by the physician) that the outside labs were reviewed by the MDA 
attending physician. Remote monitoring (virtual video or telephone visit) can be applied as 
needed. Study drug may be mailed to the patient per institutional guidelines/approval. Physician 
exam and VS assessment may be omitted if a virtual visit is necessary. 
7.12. Drug Accountibility and Reconcilation 
At completion of the study, to satisfy regulatory requirements regarding drug accountability, 
accurate records of of the amount dispensed to and returned by the subjects and the amount 


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remaining at the conclusion of the trial will be documentated, all unused and/or partially used 
investigational products Neratinib and Capmatinib will be reconciled and destroyed in 
accordance with applicable state and federal regulations and in accordance to MD Anderson 
institutional policies and procedures for drug destruction, and appropriate records of disposal are 
kept. 
8.0 Clinical Safety Information for Study Drugs 
8.1 Neratinib: 
As of 01-MAY-2019, the total safety population from 37 completed and ongoing neratinib 
clinical studies consist of 6574 subjects; out of these, 2686 subjects with early-stage HER2- 
positive, or locally advanced, or metastatic solid malignancies have received at least 1 dose of 
single-agent neratinib administered subjects with cancer are known to have received neratinib in 
combination with other drugs. once a day; and 1317 subjects with cancer are known to have 
received neratinib in combination with other drugs. 
 
Safety results from the completed and ongoing studies show that neratinib is generally well 
tolerated and with a consistent safety profile for subjects with breast cancer or other solid tumors. 
GI disorders accounted for the most frequently reported TEAEs. An updated prophylactic 
diarrhea management plan has shown promise in reducing the incidence and severity of diarrhea 
resulting from neratinib treatment.  Please see details in the Investigator’s Brochure.  
 
8.1.1 Incidence of Treatment-emergent Adverse Events of Single-agent Studies 
Safety data is available for 2686 subjects with early-stage HER2-positive, or locally advanced, or 
metastatic solid malignancies who received at least 1 dose of single-agent neratinib administered 
once a day in 9 studies. Six (6) of these studies have been completed. The most frequently 
reported SAEs in neratinib monotherapy studies were diarrhea, vomiting, anddehydration. 
 
Table 5: Incidence of Treatment-emergent Adverse Events Reported in ≥10% of Subjects, 
by Treatment Arm, Maximum CTCAE Grades 1-4 by System Organ Class and Preferred 
Term (Safety Population); Study 3144A2-3004-WW/B1891004 


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8.1.2 Adverse Drug Reactions with Neratinib Monotherapy  
The ADRs occurring in subjects receiving neratinib monotherapy is based on the safety data 
from Study 3144A2-3004-WW/B1891004, a large randomized, double-blind, placebo-controlled 
Phase 3 study in women with early-stage HER2-positive breast cancer who received neratinib 
240 mg monotherapy in the extended adjuvant setting (Table 6). In this study, 1408 subjects 
received neratinib monotherapy; diarrhea management with prophylactic use of loperamide was 
not implemented.  
Table 6: Adverse Drug Reactions Occurring in Subjects Receiving Neratinib Monotherapy 
(N=1408) 


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8.1.3 Reference Safety Information for Assessment of Expectedness of Serious Adverse  
Table 6 is based on data from n=1408 subjects who received neratinib monotherapy in 
Study 3144A2-3004-WW/B1891004. Diarrhea management with prophylactic use of loperamide 


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was not implemented in this study. For the purpose of safety reporting in clinical trials, only 
SARs listed in Table 7. should be considered expected in subjects receiving neratinib 
monotherapy.  
 
Table 7: Serious Adverse Reactions for Neratinib Monotherapy Considered Expected 
for Safety Reporting Purposes (N=1408 Subjects Exposed) 
 
 
8.1.4 Interaction With Other Medicinal Products and Other Forms of Interaction 
 


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Table 8: Drug Interactions That Affect Neratinib (NERLYNX) 
 
Certain P-glycoprotein (P-gp) Substrates  
Concomitant use of NERLYNX increased concentrations of a P-gp substrate, which may 
increase the risk of adverse reactions of these substrates. Monitor for adverse reactions of certain 
P-gp substrates for which minimal concentration changes may lead to serious adverse reactions. 
  
8.1.5. Adverse Events of Special Interest 
•    Pulmonary Toxicity:  
Interstitial lung disease (ILD) or pneumonitis, a diffuse parenchymal lung disease, is a 
group of fibrotic lung disorders that affect the alveoli of the lung. In theory, neratinib 
may induce interstitial lung disease as this risk was identified for similar compound(class 
effect). 
•    Cardiac Toxicity (Left Ventricular Ejection Fraction Decreased): 


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Small-molecule TKIs have been shown to be associated with a certain degree of 
cardiovascular side effects that are often reversible. In theory, neratinib may decrease left 
ventricular ejection fraction (LVEF) as this risk was identified for similar compounds 
(class effect). 
8.1.6. Special Precautions 
•    Pregnancy and Lactation 
The potential effects of neratinib on pregnancy and lactation have not been investigated 
in humans. Safety for women of childbearing capacity cannot be implied from the 
existing data. If a woman becomes pregnant within 1 month of her being exposed to 
neratinib or within 3 months of her partner’s being exposed to neratinib, the pregnancy 
should be followed to its outcome.  
•    Risk to Unborn Children 
It is not known whether neratinib may cause side effects to pregnant women, to an 
unborn child (an embryo or a fetus), or to children of nursing women. In a study with 
pregnant animals, administration of neratinib caused harm, including birth defects and 
death, to the fetuses. 
•    Effects on Ability to Drive and Use Machines 
In Study 3144A2-3004-WW/B1891004, the incidence of dizziness was similar between 
the neratinib arm and placebo arm, and the incidence of hypotension was <1% in both 
arms. Subjects should be instructed that if they experience dizziness, they should avoid 
potentially hazardous tasks such as driving or operating machinery. 
•    Overdose 
No specific antidotes exist for the treatment of neratinib overdoses, and the benefit of 
hemodialysis in the treatment of neratinib overdose is unknown. General supportive care 
is recommended. 
 
8.2 Capmatinib 
Capmatinib has been extensively tested in both healthy volunteers and cancer patients (majority 
with NSCLC). As of the safety cut-off date of 28-Sep-2023, more than 800 participants with 
solid tumors have been treated with capmatinib as a single agent, and 845 participants have 
received capmatinib in combination with other therapies. The recommended phase II dose 
(RP2D) for capmatinib as a single agent has been determined to be 400 mg b.i.d. in tablet 
formulation. See detailed data in Investigator Brochure (IB). 
8.2.1  Reference Safety Information for Capmatinib  
The reference safety information (RSI) tables are based upon evaluation of the available clinical 
safety information, including data from all capmatinib global clinical trials sponsored by 
Novartis (and the Novartis safety database Argus (cut-off date: 28-Sep-2023). Only suspected 
serious adverse reactions (SARs) are included into the RSI tables, and are used for determination 
of “expectedness” for single case SAE reporting. Table 9 constitutes the Reference Safety 
Information used for determination of “expectedness” for single case SAE reporting. For the 
purpose of individual case safety reporting in clinical trials, fatal and life-threatening SARs will 
always be considered unexpected. The safety profile may change as more data becomes available 


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Capmatinib monotherapy reference safety information 
Serious suspected adverse reactions considered expected for reporting purposes in the 
capmatinib trials were identified based on the review of the capmatinib monotherapy data from 
the pooled safety data from six studies (CINC280A2201, CINC280X1101, CINC280X2102, 
CINC280A2103, CINC280A2105 and CINC280A2108) which includes a total of 580 patients 
treated at the recommended capmatinib dose. 
 
Table 9: Serious Adverse Drug Reactions for Treatment With Capmatinib As Single Agent 
Considered Expected for Safety Reporting Purposes 
 
 
 
 
 


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Capmatinib combination trials reference safety information  
Based on a review of the available safety data at the time of capmatinib IB data cut-off, no SAR 
expected for reporting purposes has been identified for capmatinib administered in combination 
with EGF816, nivolumab, PDR001 and pembrolizumab. Therefore, no combination therapy RSI 
table was generated. Please refer to the respective IBs for single agent RSI of compounds used in 
combination studies. 
 
8.2.2 Summary of clinical safety for capmatinib administered as single agent  
As of 28-Sep-2023, a total of 1731 cancer patients and 236 non-cancer subjects have received 
capmatinib. A total of 1122 subjects, including healthy volunteers, have been treated with 
capmatinib as a single agent at different doses. The MTD for capmatinib as single agent was not 
reached. The RP2D for capmatinib as a single agent has been determined to be 400 mg BID in 
tablet formulation. 
 
Overall, capmatinib has been well tolerated by patients and the majority of the adverse events 
(AEs) reported with capmatinib single agent have been of mild or moderate severity. See 
detailed data in current version of Investigator’s Brochure.  
 
Clinical safety monitoring  
Clinical safety findings while on treatment with capmatinib may vary. The more frequent 
adverse events could include peripheral edema, nausea, blood creatinine increased, vomiting, 
decreased appetite, fatigue and diarrhoea. Onset or worsening of any of these events should be 
reported to the treating physician.  
 
Precautions and management of potential risks  
While the available clinical experience with capmatinib is increasing, the sponsor strongly 
suggests that the treating physician continues to inform the Novartis medical monitor if, during 
the treatment period, any signs or symptoms are observed that are not consistent with the 
toxicities discussed within IB. The potential risks associated with capmatinib will be carefully 
assessed and monitored following the procedure defined in the protocol.  
 
Hepatic effects  
Capmatinib is primarily metabolized by liver enzymes. Liver function test alterations (ALT 
and/or AST and/or bilirubin increase) have been observed in a number of patients. Overall, when 
capmatinib is administered as a single agent, liver function test alterations appear to be limited.  
Progressive liver disease or underlying primary malignancies could not be fully ruled out as 
causally related to the liver function test alterations in a number of patients. Caution is 
recommended when capmatinib is administered in combination with other anticancer drugs with 
known risk of hepatotoxicity.  
 
Renal dysfunction  


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Capmatinib inhibits renal transporter MATE1 and MATE2K with a Ki of 0.28 μM in vitro. It has 
been reported that a small portion of creatinine could be cleared via active tubular secretion by 
these renal transporters such as MATE and OAT.  
 
In HV DDI study (A2102), both creatinine and cystatin C levels were evaluated following single 
dose of capmatinib. The results showed that cystatin C levels did not change while serum 
creatinine levels increased slightly. Creatinine mainly cleared by passive glomerular filtration, 
but 10-40% could be active tubular secretion. Cystatin C is 100% through glomerular filtration. 
So it is likely that the transient increase of creatinine is caused by transporter inhibition.  
 
In the [CINC280A2201] study, 101 patients (27.1%) experienced events of blood creatinine 
increased of which except for 1 patient with Grade 3 blood creatinine increased all other patients 
had Grade 1/2 events. Three Grade 1/2 events of renal failure (0.8%) suspected to be related to 
capmatinib were reported (with no Grade 3/4 events of renal failure). There was one Grade 3 
event of acute kidney injury reported as suspected to be related to capmatinib. None of the 
events were fatal. 
 
Effects on pancreas  
When capmatinib is administered as a single agent, pancreatic events are reported in a number of 
patients; in [CINC280A2201] study 52 patients (13.9%) experienced amylase increase and lipase 
increase, respectively, of any grade suspected to be related to capmatinib. Grade 3/4 AEs of 
increased amylase/lipase suspected to be related to study treatment have been reported in 32 
patients (8.6%), and one patient experienced acute pancreatitis (0.3%) suspected to be related to 
the study treatment. Based on the current available data, a direct toxic effect of capmatinib on 
pancreas cannot be definitively identified. 
 
Pneumonitis/ILD  
In preclinical studies, capmatinib did not show any toxic effect on lung tissue.  
In capmatinib single agent study [CINC280A2201], any grade ILD/pneumonitis was reported in 
17 of 373 patients (4.6%) treated with capmatinib. Grade 3 ILD/pneumonitis was reported in 7 
patients (1.9%), with a fatal event of pneumonitis reported in 1 patient (0.3%).  
Most of these subjects had previous treatment with immunotherapy (nivolumab and 
pembrolizumab) or radiotherapy to the lung as confounding factors and had progressive disease 
at the onset of ILD/pneumonitis.  
 
Eight patients (2.1%) discontinued capmatinib due to ILD/pneumonitis. ILD/pneumonitis mostly 
occurred within approximately the first 3 months of treatment. The median time-to-onset of 
Grade 3 or higher ILD/pneumonitis was 7.9 weeks (range: 0.7 to 88.4 weeks).  
Investigators are advised to carefully monitor patients for signs and symptoms of pneumonitis in 
all capmatinib studies, both single agent and especially in combination studies with EGFR TKIs.  
 
Hypersensitivity reactions 


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No cases of serious hypersensitivity have been reported in patients treated with capmatinib in 
capmatinib single-agent study [CIN280A2201]. In other clinical studies, cases of serious 
hypersensitivity (Uncommon frequency) were reported in patients treated with capmatinib. 
Clinical symptoms included pyrexia, chills, pruritus, rash, blood pressure decreased, nausea and 
vomiting. 
 
Based on the severity of the hypersensitivity reaction, investigators are advised to temporarily 
withhold or permanently discontinue capmatinib and institute appropriate treatment for 
hypersensitivity reactions. 
 
Photosensitivity  
Capmatinib has shown photosensitization potential in in vitro and in vivo assays. Clinical 
protocol provisions advise against ultraviolet exposure while taking capmatinib.  
In capmatinib single agent study [CINC280A2201], there was only 1 subject (0.3%) who 
experienced an event of phototoxicity (Grade 1) and did not lead to discontinuation of treatment. 
The subject had psoriasis at baseline which was a confounding factor.  
 
Teratogenicity  
Capmatinib should be considered potentially teratogenic to humans. Male patients must be 
willing to abide by protocol permitted methods to avoid fathering a child from the time of 
creening through follow-up. Women of child-bearing potential who agree to participate in initial 
clinical studies must agree to abide by permitted methods defined in the clinical protocol to 
avoid pregnancy and lactation from screening through follow-up.  
 
Pregnancy testing  
The pregnancy status of females of reproductive potential should be verified prior to starting 
treatment with capmatinib.  
 
Contraception  
Females  
Sexually-active females of reproductive potential should use effective contraception (methods 
that result in less than 1% pregnancy rates) during treatment with capmatinib and for at least one 
month after the last dose.  
Males  
Male patients with sexual partners who are pregnant, possibly pregnant, or who could become 
pregnant should use condoms during treatment with capmatinib and for at least 3 months after 
the last dose. 
 
Safety assessments  
Safety will be monitored using the following assessments: hematology, chemistry, coagulation 
parameters, urinalysis, 12-lead ECG, physical (including neurological) exam, vital signs, height, 
weight, performance status, radiology examinations, and cardiac assessment. In addition, AEs, 


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pregnancy tests and concomitant medications will also be collected at every visit. Pregnancy 
tests will be obtained in women of childbearing potential prior to each cycle of therapy. 
 
9.0 Concomitant and Prohibited Therapy 
Concomitant therapy includes any prescription medications or over the counter preparations used 
by a patient between the 7 days preceding the screening evaluation and the treatment 
discontinuation visit. If the patient is taking any prohibited medications as of the day of consent, 
alternatives will be discussed with the patients prior to initiating treatment on study. For agents 
known to prolong QT interval, if the principal investigator and/or attending physician deems the 
risk for QT prolongation to be low, continuation may be allowed if it is considered in the 
patient’s best interest.  Increased cardiac monitoring may be done in these circumstances for 
patient safety per physician’s discretion as standard of care. 
Patients who use hormone-replacement therapy, prophylactic or therapeutic anticoagulation 
therapy (such as low-molecular-weight heparin or warfarin at a stable dose level) should 
continue their use.  However, hormone-replacement therapy should be discontinued if the patient 
is HR-positive. 
All concomitant medications will be documented in medical record as standard of care only, and 
will not be collected for this study. 
Any other anti-cancer agents and agents listed below are prohibited. 
9.1 Prohibited Concomitant Therapy and Cautions for Capmatinib Use:  
There is no contraindication for the use of Capmatinib. But there are some drug interactions 
identified:  
• P-gp Inducers 
Capmatinib is a substrate for P-gp. Strong P-gp inducers may have the potential to 
decrease Capmatinib exposure. Concomitant use of strong P-gp inducers (e.g., 
carbamazepine, phenytoin, rifampicin, and St. John's wort) should be avoided. 
• P-gp Substrates 
Multiple administrations of Capmatinib HCl hydrate 500 mg once daily for 8 days had a 
mild effect on the PK of the sensitive P-gp substrate dabigatran etexilate, increasing its 
exposure by approximately 50% based on the AUC. Monitoring the clinical effects of P 
gp-dependent substances with a narrow therapeutic index (e.g., digoxin) is 
recommended during co-administration with Capmatinib. 
• BCRP Substrates 
Capmatinib can inhibit the transport of sensitive substrates of BCRP. Monitoring the 
clinical effects of sensitive BCRP substrates is recommended during co-administration 
with  Capmatinib. 
• Metformin 
Based on in vitro data, Capmatinib and its metabolite may have the potential to increase 
the AUC of co-administered metformin in humans, through inhibition of its renal 
excretion mediated via OCT1 and OCT2, and MATE1 and MATE2. Monitoring of the 


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effect of metformin is recommended during co-administration with Capmatinib, which 
not contraindicated. 
• Proton Pump Inhibitor 
The solubility of capmatinib is pH-dependent. The [CINC280A2101] study was a 
clinical drug-drug interaction study investigating the effect of the proton pump inhibitor, 
rabeprazole, on a single dose of 600 mg capmatinib tablet in healthy subjects. 
Rabeprazole treatment resulted in a modest reduction in the extent of capmatinib 
absorption with a 37.5% decrease in Cmax and a 25.2% decrease in AUCinf. 
 
9.2 Prohibited Concomitant Therapy for Neratinib use: 
         1.   Agents known to be strong cytochrome P450 (CYP) 3A4 inducers or inhibitors, such 
as: phenobarbital, phenytoin, primidone, rifampin, dexamethasone, and oral 
contraceptives.  
Patients should also avoid grapefruit and herbal remedies, including, but not limited to St. 
John's Wort. 
2. Chronic immunosuppressive therapies including systemic corticosteroids. Steroids given 
for physiological replacement, as anti-emetics or inhaled as well as short course of 
oral/topical steroids given for allergic reactions or asthma flares are allowed.  
3. 
P-glycoprotein (P-gp) Substrates: Concomitant use of neratinib with digoxin, a P-gp 
substrate, increased digoxin concentrations. Increased concentrations of digoxin may 
lead to increased risk of adverse reactions including cardiac toxicity. Refer to the 
digoxin prescribing information for dosage adjustment recommendations due to drug 
interactions. Neratinib may inhibit the transport of other P-gp substrates (e.g., 
dabigatran, fexofenadine). 
4. 
Drugs that have interactions that affect neratinib (see Table 8 Drug Interactions That 
Affect Neratinib). 
10.0 Common Toxicity and Dose Modification 
10.1 Neratinib Dose Modifications and Management – General Toxicities 
For toxicities deemed to be related to neratinib, follow Table 10. 
Table 10: Neratinib Dose Modifications and Management – General Toxicities* 
 
* Refer to Tables 13, 14 below for management of diarrhea and hepatotoxicity 
† Per CTCAE v5.0 
10.2 Management of Diarrhea 
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 


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earlier. For the majority of patients, diarrhea subsides after about 2 weeks. Therefore, intensive 
prophylactic measures begin at the start of therapy. If diarrhea occurs despite prophylaxis, treat 
with additional antidiarrheals, fluids and electrolytes as clinically indicated. Additionally, based 
on results from the CONTROL clinical trial, the neratinib dose will be escalated to the assigned 
target dose during the 1st cycle of treatment (29).  
 
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. Anti-
diarrheal medication may be held for constipation at the discretion of the treating physician, 
but should be resumed if diarrhea recurs.  
Intensive primary prophylaxis  
Antidiarrheal medication (loperamide) must begin with the first dose of neratinib.  Patients must 
take an initial dose of loperamide 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 loperamide PO 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, not to exceed 16 mg per day.   
 
Table 11: Suggested Dosing Time 
 
7am 
 
2pm 
7pm 
9pm 
C1D1  
through  
28 days 
Neratinib & 
 Capmatinib  
with food** 
 
        
Capmatinib      
 
Loperamide 
4mg*** 
 
Loperamide 
4mg*** 
 
Loperamide 
    4mg***      
** Neratinib and Capmatinib dose will be as assigned  
*** After the first 14 days, loperamide 4 mg is to be taken twice a day through the first two cycle only of therapy 
(Day 56). Daily dose as needed (not to exceed 16 mg per day) for Days 56+ (Cycle 3 and beyond). 
 
For Grade 2 diarrhea lasting ≥ 5 days despite prophylactic medication, and higher grade (Grade 3 
and 4), we recommend following the guideline as noted in below Table 12.  
 
Table 12:  Management Guideline for Neratinib-related Diarrhea 


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Note: Antidiarrheal treatment adjustment will be per physician’s discretion. Examples of 
antidiarrheal treatment include but not limited to: 
• Diphenoxylate 5 mg/Atropine Sulfate 0.05 mg (Lomotil): 2 tablets or 10 mL by mouth, 4 
times per day, as needed. Maximum 8 tablets, or 40 mL per day. 
• Colestipol: 2 grams by mouth twice per day. Colestipol should be taken at least 1 hour 
after and at least 4 hours before other oral medications. 
• Tincture of Opium, 10 mg/mL: 6 mg (0.6 mL) 4 times per day, as needed. 
Note: If grade 3 diarrhea reoccurs, the patient patient maymaintain  the same dose level of 
Neratinib or have dose reduced to the next lower dose(120 mg is the lowest dose level of 
Neratinib), per physician discretion. The patient may voluntarly come off the study at any time. 
 
* Per CTCAE v5.0  
† Complicated features include dehydration, fever, hypotension, renal failure, or Grade 3 or 4 neutropenia  
‡ Despite being treated with optimal medical therapy 
 
Stop Loperamide if no bowel movement for >/= 2 days per attending physician’s discretion and 
resume the Loperamide as instructed if any signs and symptoms of abdominal cramping, loose 
stool and diarrhea occurs: take 2 pills of Loperamide immediately, then 1 pill of Loperamide 
with each subsequent episode of diarrhea, which is not to exceed 8 pills of Loperamide in 24 


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hours. If diarrhea persists, take Lomotil and/or other antidiarrheal medications as needed per 
standard of care per attending physician’s discretion. Resume adjusted dosage of Loperamide as 
per attending physician’s discretion to manage the diarrhea and Loperamide induced 
constipation.  
 
10.3 Management of Cardiac Left Ventricular Dysfunction 
Neratinib 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 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, neratinib must be permanently 
discontinued.  
• Severe refractory/poorly controlled CHF (grade 4):  
Neratinib should be discontinued if the patient develops severe refractory/poorly controlled CHF. 
 
For asymptomatic patients, the decision to continue or stop neratinib 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.  
 
10.4 Neratinib Dose Modifications for Hepatic Impairment 
Guidelines for dose adjustment of neratinib in the event of liver toxicity are shown in Table 13. 
Patients who experience ≥Grade 3 diarrhea requiring IV fluid treatment or any signs or 
symptoms of hepatotoxicity, such as worsening of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, or eosinophilia, should be evaluated for changes in liver 
function tests. Fractionated bilirubin and prothrombin time should also be collected during 
hepatotoxicity evaluation. 
Table 13: Dose Modifications for Hepatotoxicity 


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ALT=Alanine Aminotransferase; AST=Aspartate Aminotransferase; ULN=Upper Limit Normal 
* Per CTCAE v5.0 
 
10.5 Capmatinib Dose Reduction and Toxicity Management 
 
10.5.1 Capmatinib Dose Reduction Levels 
 
Table 14:  Dose Reduction Steps for Capmatinib PO  
  
Starting dose level 1 
Dose level -1 
Dose level -2 
capmatinib 
400 mg  b.i.d. 
300 mg  b.i.d. 
200 mg  b.i.d. 
Note: dose reduction should be based on the worst toxicity demonstrated at the last dose. 
Dose reduction below 200 mg is not allowed 
 
10.5.2 Capmatinib Treatment Interrruption and Dose Reduction Guidance 
Table 15.  Criteria for Dose Reduction/Interruption And Re-initiation of Capmatinib 
Treatment for Adverse Drug Reactions 
To be considered recommended dose modifications, unless otherwise specified as mandatory in 
this Table 15. Refer to Table 16 for follow-up evaluations as applicable. 
 
Worst toxicity CTCAE Gradea during a cycle of therapy 
No toxicity 
Maintain dose level 
HEMATOLOGICAL 
Neutrophil count decreased (ANC) Neutropenia 
Grade 1 (ANC < LLN - 1500/mm3; < LLN - 1.5 x 109/L) 
Maintain dose level 
Grade 2 (ANC < 1500 - 1000/mm3; < 1.5 - 1.0 x 109/L) 
Maintain dose level 
Grade 3 (ANC < 1000 - 500/mm3; < 1.0 - 0.5 x 109/L) 
Omit dose until resolved to ≤ grade 2, then: 
If resolved in ≤ 7 days, resume treatment at the same 
dose level 
If resolved in > 7 days, then ↓ 1 dose level 
Grade 4 (ANC < 500/mm3; < 0.5 x 109/L) 
Omit dose until resolved to ≤ grade 2 and then ↓ 1 dose 
level 


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Febrile neutropenia 
(ANC < 1000/mm3 (< 1.0 x 109/L), fever > 38.3°C) 
Omit dose, then: 
If resolved in ≤ 7 days, resume treatment at ↓ 1 dose 
level 
If resolved in > 7 days, permanently discontinue 
participant from capmatinib treatment 
Platelet count decreased (Thrombocytopenia) 
Grade 1 (PLT < LLN - 75,000/mm3; < LLN - 75 x 109/L) Maintain dose level 
Grade 2 (PLT < 75,000 - 50,000/mm3; < 75 - 50 x 109/L) 
Maintain dose level 
Grade 3 (PLT < 50,000 - 25,000/mm3; < 50 - 25 x 109/L) 
Omit dose until resolved to ≤ grade 2, then: 
If resolved in ≤ 7 days, then maintain dose level 
If resolved in > 7 days, then ↓ 1 dose level 
Grade 4 (PLT < 25,000/mm3; < 25 x 109/L) 
Omit dose until resolved to ≤ grade 2, then ↓ 1 dose 
level 
Hemoglobin decreased (Anemia) 
Grade 1 (Hemoglobin [Hgb] < LLN - 10.0 g/dL; < LLN - 
6.2 mmol/L; < LLN - 100 g/L) 
Maintain dose level 
Grade 2 (Hgb < 10.0 - 8.0 g/dL; < 6.2 – 4.9 mmol/L; < 
100 - 80 g/L) 
Maintain dose level 
Grade 3 (Hgb < 8.0 g/dL; < 4.9 mmol/L; < 80 g/L; 
transfusion indicated) 
Omit dose until resolved to ≤ grade 2, then: 
If resolved in ≤ 7 days, resume treatment at the same 
dose level 
If resolved in > 7 days, then ↓ 1 dose level 
Grade 
4 
(Life-threatening 
consequences; 
urgent 
intervention indicated) 
Omit dose until resolved to ≤ grade 2 and then ↓ 1 dose 
level 
If toxicity recurs, permanently discontinue participant 
from capmatinib treatment. 
RENAL 
Serum creatinine 
Grade 1 (> ULN - 1.5 x ULN) 
Maintain dose level 
Grade 2 (> 1.5 - 3.0 x ULN) 
Omit dose until resolved to ≤ grade 1 or baseline, then 
resume treatment at the same dose level. 
Grade 3 (> 3.0 - 6.0 x ULN) 
Omit dose until resolved to ≤ grade 1 or baseline, then 
resume treatment at ↓ 1 dose level. 
Grade 4 (> 6.0 x ULN) 
Permanently discontinue participant from capmatinib 
treatment 
HEPATIC 
Isolated Total Bilirubin elevation* 
Grade 1 (> ULN - 1.5 x ULN) 
Maintain dose level 


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Grade 2 (> 1.5 - 3.0 x ULN) 
Omit dose until resolved to ≤ grade 1, then 
If resolved in ≤ 7 days, maintain dose level. 
If resolved in > 7 days, ↓1 dose level 
Grade 3 (> 3.0 - 10.0 x ULN) 
Omit dose until resolved to ≤ grade 1, then 
If resolved in ≤ 7 days, ↓ 1 dose level 
If resolved in > 7 days, permanently discontinue 
participant from capmatinib treatment 
Grade 4 (> 10.0 x ULN) 
Mandatory: Permanently discontinue participant from 
capmatinib treatment 
Isolated AST or ALT elevation 
Grade 1 (> ULN - 3 x ULN) 
Maintain dose level 
Grade 2 (> 3.0 - 5.0 x ULN) 
Maintain dose level 
Grade 3 (> 5.0 - 20.0 x ULN) 
Omit dose until resolved to ≤ grade 1 (or ≤ grade 2 if 
grade 2 elevation at baseline) then 
If resolved in ≤ 7 days, then resume treatment at the 
same dose level 
If resolved in > 7 days, resume treatment at ↓ 1 dose 
level 
Grade 4 (> 20.0 x ULN) 
Mandatory: Permanently discontinue participant from 
capmatinib treatment 
Combined elevations of AST or ALT and Total Bilirubin b,c,d 
For participants with normal baseline ALT and AST and 
total bilirubin value: 
AST or ALT > 3.0 x ULN combined with total bilirubin > 
2.0 x ULN without evidence of cholestasis or hemolysis 
OR 
For participants with elevated baseline AST or ALT or 
total bilirubin value: 
[AST or ALT > 3 x baseline] OR [AST or ALT > 8.0 x 
ULN], whichever is lower, combined with [total 
bilirubin > 2 x baseline AND > 2.0 x ULN] without 
evidence of cholestasis or hemolysis 
Mandatory: Permanently discontinue participant from 
capmatinib treatment 
METABOLIC 
Amylase and/or lipase elevation 
Grade 1 (> ULN - 1.5 x ULN) 
Maintain dose level 
Grade 2 (> 1.5 - 2.0 x ULN; > 2.0 - 5.0 x ULN and 
asymptomatic) 
Maintain dose level 
Grade 3 (> 2.0 - 5.0 x ULN with signs or symptoms; > 5.0 
x ULN and asymptomatic) 
Omit the dose until resolved to ≤ grade 2, then 
If resolved in ≤ 14 days, resume treatment at the same 
dose level 


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If resolved in > 14 days, then ↓ 1 dose level 
Grade 4 (> 5.0 x ULN with signs or symptoms) 
Permanently discontinue participant from capmatinib 
treatment 
CARDIAC 
Electrocardiogram QT corrected (QTc) interval prolonged 
Grade 1 (QTcF 450-480 ms) 
Maintain dose level 
Grade 2 (QTcF 481-500 ms) 
Maintain dose level 
Grade 3 (QTcF ≥ 501 ms on at least two separate ECGs) 
Omit dose until resolved to ≤ grade 2, then: 
If resolved in ≤ 7 days, resume treatment at the same 
dose level 
If resolved in > 7 days, then ↓ 1 dose level 
Grade 4 (QTcF ≥ 501 or > 60 ms change from baseline 
and Torsades de pointes or polymorphic ventricular 
tachycardia or signs/symptoms of serious arrhythmia) 
Permanently discontinue participant from capmatinib 
treatment 
GASTROINTESTINAL 
Pancreatitis 
Grade 2 
Maintain dose level 
Grade ≥ 3 
Mandatory: Permanently discontinue participant from 
capmatinib treatment 
Diarrhea**  
Grade 1 (despite appropriate anti-diarrheal medication) 
Maintain dose level 
Grade 2 (despite maximal anti-diarrheal medication) 
Omit dose until resolved to ≤ grade 1, then maintain 
dose level. 
If diarrhea returns as ≥ grade 2, then omit dose until 
resolved to ≤ grade 1, then resume treatment at ↓ 1 
dose level 
Grade 3 or 4 (despite appropriate anti-diarrheal 
medication) 
Omit dose until resolved to ≤ grade 1, then resume 
treatment at ↓ 1 dose level 
Vomiting 
Grade 1 (despite appropriate anti-emetics) 
Maintain dose level 
Grade 2 (despite appropriate anti-emetics) 
Omit dose until resolved to ≤ grade 1, then maintain 
dose level. 
If vomiting returns as ≥ grade 2, then omit dose until 
resolved to ≤ grade 1, then ↓ 1 dose level. 
Grade 3 (despite appropriate anti-emetics) 
Omit dose until resolved to ≤ grade 1, then ↓ 1 dose 
level 
Grade 4 (despite appropriate anti-emetics) 
Omit dose until resolved to ≤ grade 1, then ↓ 1 dose 
level 
Nausea 
Grade 1 or 2 (despite appropriate anti-emetics) 
Maintain dose level 


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Grade 3 (despite appropriate anti-emetics) 
Omit dose until resolved to ≤ grade 1, then ↓ 1 dose 
level 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
Rash/photosensitivity*** 
Grade 1 
Maintain dose level 
Grade 2 
Maintain dose level 
Grade 3, despite skin toxicity therapy 
Omit dose until resolved to grade ≤ 1, then: 
If resolved in ≤ 7 days, then resume treatment at ↓ 1 
dose level 
If resolved in > 7 days (despite appropriate skin 
toxicity therapy), then permanently discontinue 
participant from capmatinib treatment 
Grade 4, despite skin toxicity therapy 
Omit dose and permanently discontinue participant 
from capmatinib treatment 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
ILD /Pneumonitis 
Monitor participants for pulmonary symptoms indicative of ILD/pneumonitis. In addition, withhold capmatinib for 
acute onset of new or progressive unexplained pulmonary symptoms, such as dyspnea, cough and fever and during 
diagnostic workup for ILD/pneumonitis to exclude alternative causes such as, but not limited to infections, 
lymphangitic carcinomatosis, cardiogenic edema, or pulmonary hemorrhage. 
Grade 1 
Interrupt capmatinib during diagnostic workup for 
ILD/Pneumonitis. Exclude infections and other 
etiologies. 
In presence of diagnosis of ILD/Pneumonitis after 
diagnostic workup, it is mandatory to permanently 
discontinue capmatinib. 
Only 
in 
the 
absence 
of 
a 
diagnosis 
of 
ILD/Pneumonitis, capmatinib may be restarted at the 
same dose. 
If it recurs after resumption of study drug, permanently 
discontinue capmatinib. 
Grade 2 
Mandatory: 
Interrupt 
capmatinib 
dose 
during 
diagnostic 
workup 
for 
ILD/pneumonitis 
until 
improvement to ≤ Grade 1. Exclude infections and 
other etiologies. 
In presence of diagnosis of ILD/Pneumonitis after 
diagnostic workup, it is mandatory to permanently 
discontinue capmatinib. 
Only 
in 
the 
absence 
of 
a 
diagnosis 
of 
ILD/Pneumonitis, capmatinib may be restarted 
following these guidelines: 
· If resolves to ≤ Grade 1 in ≤ 7 days reduce study drug 
by 1 dose level 


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· If fails to resolve to ≤ Grade 1 within 7 days or recur 
after resumption of study drug at decreased dose, 
permanently discontinue capmatinib 
Grade 3 and Grade 4 
Mandatory: Permanently discontinue capmatinib. 
Treat with IV steroids as clinically indicated. Oxygen 
therapy as indicated 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
Fatigue/ Asthenia  
Grade 1 or 2 
Maintain dose level 
Grade 3 
Omit dose until resolved to ≤ grade 1, then: 
If resolved in ≤ 7 days, resume treatment at same dose 
level 
If resolved in > 7 days, resume treatment at ↓ 1 dose 
level 
Peripheral edema  
Grade 1 or 2 
Maintain dose level. 
Grade 3 
Omit dose until resolved to ≤ Grade 1, then ↓1 dose 
level 
Grade 4 
Permanently discontinue capmatinib 
Other adverse events 
Grade 1 or 2 
Maintain dose level, consider to initiate appropriate 
support medication. 
For any intolerable grade 2 (e.g. limiting instrumental 
ADL), consider omitting the dose until resolved to ≤ 
grade 1, then then restart either at same dose or ↓ 1 
dose level. 
Grade 3 
Omit dose until resolved to ≤ grade 1, then↓ 1 dose 
level 
Grade 4 
Permanently discontinue capmatinib 
All dose modifications should be based on the worst preceding toxicity. 
a Common Toxicity Criteria for Adverse Events (CTCAE version 5.0). 
b “Combined” defined as: total bilirubin increase to the defined threshold concurrently with ALT/AST increase to 
the defined threshold 
c “Cholestasis” defined as: ALP elevation (> 2.0 x ULN and R value (ALT/ALP in x ULN) < 2.0) in participants 
without bone metastases, or elevation of ALP liver fraction in participants with bone metastases 
d If combined elevations of AST or ALT and total bilirubin do not meet the defined thresholds, please follow the 
instructions for isolated elevation of total bilirubin and isolated elevation of AST/ALT, and take a conservative 
action based on the degree of the elevations (e.g. discontinue treatment at the situation when omit dose is needed 
for one parameter and discontinue treatment is required for another parameter). After all elevations resolve to the 
defined thresholds that allow treatment re-initiation, re-start the treatment either at the same dose or at one dose 
lower if meeting a criterion for dose reduction 


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* Note: If total bilirubin > 3.0 x ULN is due to the indirect (non-conjugated) component only, and hemolysis as the 
etiology has been ruled out as per institutional guidelines (e.g., review of peripheral blood smear and haptoglobin 
determination), then ↓ 1 dose level and continue treatment at the discretion of the investigator. 
** Note: antidiarrheal medication is recommended at the first sign of abdominal cramping, loose stools or overt 
diarrhea 
*** During the whole duration of treatment with capmatinib, the participant is recommended to use precautionary 
measures against ultraviolet exposure (e.g., use of sunscreen, protective clothing and avoid sunbathing or using a 
solarium intensively). 
These dose changes must be recorded on the appropriate eCRF. 
 
10.5.3 Toxicity Follow-up 
 
Follow-up for toxicities 
All participants will be followed for safety until 30 days after the last dose of neratinib and 
capmatinib . Participants whose treatment is temporarily interrupted or permanently discontinued 
due to an AE or abnormal laboratory value must be followed until resolution or stabilization of the 
event, whichever comes first, including all study assessments appropriate to monitor the event. 
An unscheduled assessment should be performed in all cases below where toxicity monitoring is 
recommended more frequently than defined by the schedule of assessments. Subsequent 
monitoring must be performed as per the regular visit schedule. 
 
Table 16.  Follow-up Evaluations for Selected Toxicities* 
TOXICITY 
FOLLOW-UP EVALUATION 
HEMATOLOGICAL 
Febrile neutropenia, 
Neutropenia ≥ CTCAE grade 3 
Thrombocytopenia ≥ CTCAE grade 3 
Anemia ≥ CTCAE grade 3 
Test weekly (or more frequently if clinically indicated) until ≤ 
CTCAE grade 2. 
Perform physical exam for check on bruising in case of major 
thrombocytopenia. 
RENAL 
Serum creatinine ≥ CTCAE grade 2 
Test weekly (or more frequently if clinically indicated) until ≤ 
CTCAE grade 1 or baseline. 
Participants will be instructed to increase hydration until 
resolution to ≤ CTCAE grade 1 or baseline. 
HEPATIC 
Isolated total bilirubin elevation 
Total bilirubin CTCAE Grade 1: 
Monitor LFTs per protocol or more frequently if clinically 
indicated 
Total bilirubin CTCAE Grade 2: 


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TOXICITY 
FOLLOW-UP EVALUATION 
Weekly monitoring of LFTs, or more frequently if clinically 
indicated, until resolved to ≤ 1.5 x ULN 
Total bilirubin CTCAE Grade 3: 
Weekly monitoring of LFTs, or more frequently if clinically 
indicated, until resolved to ≤ 1.5 x ULN. If resolved in > 7 days, 
after discontinuing the participant from capmatinib permanently, 
the participant should be monitored weekly (including LFTs), or 
more frequently if clinically indicated, until total bilirubin have 
resolved to baseline or stabilization over 4 weeks 
Total bilirubin CTCAE Grade 4: 
After discontinuing the participant from capmatinib permanently, 
the participant should be monitored weekly (including LFTs), or 
more frequently if clinically indicated, until total bilirubin have 
resolved to baseline or stabilization over 4 weeks 
Isolated AST/ALT elevation 
AST/ALT CTCAE Grade 2 elevation: 
For participants with baseline value ≤ 3.0 x ULN: repeat LFTs as 
soon as possible, preferably within 48-72 hr from awareness of the 
abnormal results; if abnormal lab values are confirmed upon the 
repeat test, then monitor LFTs weekly, or more frequently if 
clinically indicated, until resolved to ≤ 3.0 x ULN 
For participants with baseline value > 3.0 x ULN: monitor LFTs 
per protocol or more frequently if clinically indicated 
AST/ALT CTCAE Grade 3 elevation: 
For AST/ALT elevation > 5.0 - 10.0 x ULN: 
• 
For participants with baseline value ≤ 3.0 x 
ULN: repeat LFTs as soon as possible, 
preferably within 48-72 hr from awareness of 
the abnormal results; monitor LFTs weekly, or 
more frequently if clinically indicated, until 
resolved to ≤ 3.0 x ULN 
• 
For participants with baseline value > 3.0 x 
ULN: repeat LFTs as soon as possible, 
preferably within 48-72 hr from awareness of 
the abnormal results; if abnormal lab values are 
confirmed upon the repeat test, then monitor 
LFTs, weekly, or more frequently if clinically 
indicated, until resolved to ≤ 5.0 x ULN 
 
 
For AST/ALT elevation > 10.0 - 20.0 x ULN: 
• 
Repeat LFTs as soon as possible, preferably 
within 48-72 hr from awareness of the abnormal 
results; monitor LFTs weekly, or more 
frequently if clinically indicated, until resolved 
to ≤ baseline 


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TOXICITY 
FOLLOW-UP EVALUATION 
AST/ALT CTCAE Grade 4 elevation: 
Repeat LFTs as soon as possible, preferably within 48-72 hr from 
awareness of the abnormal results; monitor LFTs weekly, or more 
frequently if clinically indicated, until resolved to baseline or 
stabilization over 4 weeks. 
Combined elevations in ALT and/or AST with 
concurrent total bilirubin increase, in the 
absence of cholestasis or hemolysis 
Combined elevations of AST or ALT and total bilirubin: 
After discontinuing the participant from capmatinib permanently, 
repeat LFTs as soon as possible, preferably within 48 hr from 
awareness of the abnormal results, then with weekly monitoring 
of LFTs, or more frequently if clinically indicated, until AST, 
ALT, or bilirubin have resolved to baseline or stabilization over 4 
weeks. 
Core LFTs consist of ALT, AST, GGT, total bilirubin 
(fractionated [direct and indirect], if total bilirubin > 2.0 x ULN), 
and alkaline phosphatase (fractionated [quantification of 
isoforms], if alkaline phosphatase > 2.0 x ULN.) 
METABOLIC 
Asymptomatic amylase or lipase ≥ CTCAE 
grade 3 
Test weekly (or more frequently) until ≤ CTCAE grade 2. 
A CT scan or equivalent imaging procedure to assess the pancreas, 
liver, and gallbladder is recommended within 7 days of the first 
occurrence of any ≥ CTCAE grade 3 result, to exclude disease 
progression or potential other liver or pancreatic disease. 
CARDIAC 
≥ CTCAE grade 3 
Test weekly (or more frequently) until ≤ CTCAE grade 2. 
QTcF ≥ 501 ms (CTCAE grade 3) 
When QTcF ≥ 501 ms (CTCAE grade 3), perform the following: 
Perform an analysis of serum potassium, calcium, phosphorus, 
and magnesium, and if below lower limit of normal, correct with 
supplements to within normal limits. 
Review concomitant medication usage for the potential to prolong 
the QT-interval. 
Check compliance with correct dose and administration of 
capmatinib. 
Perform a repeat ECG within one hour of the first QTcF of ≥501 
ms. 
If QTcF remains ≥ 501 ms, repeat ECG as clinically indicated, but 
at least once daily until the QTcF returns to < 501 ms. 
Repeat ECGs 7 days and 14 days (and then every 21 days) after 
dose resumption for all participants who had therapy interrupted 
due to QTcF ≥ 501 ms. 
If QTcF of ≥ 501 ms recurs, repeat ECGs as described above. 
Notes: 
Call the study’s central ECG review laboratory immediately and 
request an immediate manual read of the ECG” 


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TOXICITY 
FOLLOW-UP EVALUATION 
The investigator should contact the Novartis Medical Lead or 
designee regarding any questions that arise if a participant with 
QTcF prolongation should be maintained on study. 
GASTROINTESTINAL 
Diarrhea 
Investigate potential concomitant medication, food or comorbidity 
driven causes of diarrhea (including infectious causes) and 
remedy these causes if possible (e.g. discontinuation of 
concomitant medication, dietary modification, treatment of 
comorbidity). 
The participant should be monitored for signs of dehydration and 
instructed to take preventive measures against dehydration as soon 
as diarrhea occurs. Antidiarrheal medication must be initiated at 
the first sign of abdominal cramping, loose stools or overt 
diarrhea. Concomitant medication for the treatment of diarrhea 
should follow local practice and the investigator’s best judgment 
and may follow “the recommended guidelines for the treatment of 
cancer treatment-induced diarrhea” (Benson et al 2004). For 
example: 
For uncomplicated diarrhea (grade 1 or 2 without complicating 
signs or symptoms), loperamide given at a standard dose (e.g. 
initial administration of 4 mg, then 2 mg every 2-4 hr, maximum 
of 16 mg/day), along with oral hydration and dietetic measures 
should be considered. Note: complicating signs or symptoms 
include moderate to severe cramping, decreased performance 
status, fever, neutropenia, frank bleeding or dehydration. 
For complicated diarrhea (all grade 3 or 4, grade 1-2 with 
complicating signs or symptoms), management should involve 
intravenous (IV) fluids, and consider treatment with octreotide (at 
starting dose of 100 to 150 µg sub-cutaneous tid or 25 to 50 µg 
IV) and antibiotics (e.g. fluoroquinolone) should be given 
Nausea and Vomiting 
The 
investigator 
should 
consider/investigate 
potential 
concomitant medication, food or comorbidity driven causes of 
nausea and/or vomiting and remedy these causes if possible (e.g. 
discontinuation of concomitant medication, dietary modification, 
treatment of comorbidity). 
Individualized supportive and anti-emetic treatment should be 
initiated, as appropriate, at the first signs and/or symptoms of these 
AEs. In participants with vomiting, the participant should be 
monitored for signs of dehydration and instructed to take 
preventive measures against dehydration. 
Concomitant medication for the treatment of nausea and/or 
vomiting should follow local practice and the investigator’s best 
judgment. 
SKIN TOXICITY 
Rash and Photosensitivity 


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TOXICITY 
FOLLOW-UP EVALUATION 
CTCAE grade 1 
Consider to initiate institute appropriate skin toxicity therapy 
(such as antihistamines, topical corticosteroids and low-dose 
systemic corticosteroids) 
CTCAE grade 2 
Initiate/intensify appropriate skin toxicity therapy (such as 
antihistamines, topical corticosteroids and low-dose systemic 
corticosteroids). 
≥ CTCAE grade 3 
Intensify appropriate skin toxicity therapy and monitor weekly or 
more frequently until resolved to grade ≤ 2 
Peripheral edema 
CTCAE grade≤2 
Consider to initiate conservative measures such as leg elevation, 
compression stockings, and dietary salt modification as clinically 
indicated. 
CTCAE grade≥3 
Initiate/intensify conservative measures 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
ILD/Pneumonitis 
CTCAE Grade 1 
CT scan (high-resolution with lung windows) recommended, with 
serial imaging to monitor for resolution or progression- re-image 
at least every 3 weeks 
Monitor for symptoms every 2-3 days - Clinical evaluation and 
laboratory work-up for infection 
Monitoring of oxygenation via pulse oximetry recommended 
Consultation of pulmonologist recommended 
CTCAE Grade 2 
CT scan (high-resolution with lung windows) 
• Monitor symptoms daily, consider hospitalization 
• Clinical evaluation and laboratory work up for infection 
• Consult pulmonologist 
• Pulmonary function tests a - if normal at baseline, repeat every 
8 weeks 
• Bronchoscopy with biopsy and/or BAL recommended c 
Symptomatic therapy including corticosteroids if clinically 
indicated (1 to 2 mg/kg/day prednisone or equivalent as clinically 
indicated) b 
CTCAE Grade 3 and Grade 4 
CT scan (high-resolution with lung windows) 
Clinical evaluation and laboratory work-up for infection 
Consult pulmonologist 
Pulmonary function testsa-if < normal, repeat every 8 weeks until 
≥ normal 
Bronchoscopy with biopsy and/or BAL if possiblec 
Treat with IV steroids (methylprednisolone 125 mg) as indicated. 
When symptoms improve to ≤ Grade 1, a high dose oral steroid 


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TOXICITY 
FOLLOW-UP EVALUATION 
(prednisone 1 to 2 mg/kg once per day or dexamethasone 4 mg 
every 4 hr)b. 
If IV steroids followed by high dose oral steroids does not reduce 
initial symptoms within 48 to 72 hours, consider non-
corticosteroid immunosuppressive medication 
a PFT (Pulmonary function tests) to include: diffusing capacity corrected for hemoglobin (DLCO); spirometry; 
resting oxygen saturation 
Guideline for significant deterioration in lung function: Decrease in spirometry and/or DLCO of 30% and/or O2 
saturation ≤ 88% at rest on room air. 
b Duration and dose of course of corticosteroids will vary according to circumstances but should be as limited as 
possible. Consider tapering dosage at end. 
c If bronchoscopy is performed, bronchoalveolar lavage (BAL) should be done where possible to exclude alveolar 
hemorrhage, opportunistic infections, cell count + determination lymphocyte CD4/8 count where possible. 
Follow-up on potential drug-induced liver injury (DILI) cases 
Participants with transaminase increase combined with total bilirubin increase may be indicative 
of potentially severe drug- induced liver injury (DILI) and should be considered as clinically 
important events and assessed appropriately to establish the diagnosis. The required clinical 
information, as detailed below, should be sought to obtain the medical diagnosis of the most likely 
cause of the observed laboratory abnormalities. 
The threshold for potential DILI may depend on the participant’s baseline AST/ALT and total 
bilirubin value; participants meeting any of the following criteria will require further follow-up as 
outlined below: 
• For participants with normal ALT and AST and total bilirubin value at baseline: AST or ALT > 
3.0 x ULN combined with total bilirubin > 2.0 x ULN 
• For participants with elevated AST or ALT or total bilirubin value at baseline: [AST or 
ALT >3.0 x baseline] OR [ALT or AST > 8.0 x ULN], whichever is lower, combined with 
[total bilirubin > 2.0 x baseline AND > 2.0 x ULN] 
As DILI is essentially a diagnosis of exclusion, other causes of abnormal liver tests should be 
considered and their role clarified before DILI is assumed as the cause of liver injury. 
A detailed history, including relevant information such as review of ethanol consumption, 
concomitant medications, herbal remedies, supplement consumption, history of any pre-existing 
liver conditions or risk factors, should be collected. 
Laboratory tests should include ALT, AST, total bilirubin, direct and indirect bilirubin, GGT, 
GLDH, prothrombin time (PT)/ International normalized ratio (INR), alkaline phosphatase, 
albumin, and creatine kinase. 
Evaluate status of liver metastases (new or exacerbation) or vascular occlusion – e.g. using CT, 
MRI, or duplex sonography. 
Perform relevant examinations (Ultrasound or MRI, ERCP) as appropriate, to rule out an 
extrahepatic cause of cholestasis. Cholestasis (is defined as an ALP elevation > 2.0 x ULN with R 
value < 2 in participants without bone metastases, or elevation of the liver-specific ALP isoenzyme 
in participants with bone metastases). 


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Note: The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN for 
both values. It denotes whether the relative pattern of ALT and/or ALP elevation is due to 
cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R >2 and < 5) liver injury. In clinical 
situations where it is suspected that ALP elevations are from an extrahepatic source, the GGT can 
be used if available. GGT may be less specific than ALP as a marker of cholestatic injury, since 
GGT can also be elevated by enzyme induction or by ethanol consumption. It is more sensitive 
than ALP for detecting bile duct injury (livertox.nih.gov/rucam.html). 
Table 17 provides guidance on specific clinical and diagnostic assessments which can be 
performed to rule out possible alternative causes of observed LFT abnormalities. 
 
Table 17.  Clinical And Diagnostic Assessments for LFT Abnormalities 
Disease 
Assessment 
Hepatitis A, B, C, E 
IgM anti-HAV; HBsAg, IgM & IgG anti-HBc, HBV DNA; anti-HCV, HCV 
RNA, IgM & IgG anti-HEV, HEV RNA 
CMV, HSV, EBV infection 
IgM & IgG anti-CMV, IgM & IgG anti-HSV; IgM & IgG anti-EBV 
Autoimmune hepatitis 
ANA & ASMA titers, total IgM, IgG, IgE, IgA 
Alcoholic hepatitis 
Ethanol history, GGT, MCV, CD-transferrin 
Nonalcoholic steatohepatitis 
Ultrasound or MRI 
Hypoxic/ischemic hepatopathy 
Medical history: acute or chronic CHF, hypotension, hypoxia, hepatic 
venous occlusion. Ultrasound or MRI. 
Biliary tract disease 
Ultrasound or MRI, ERCP as appropriate. 
Wilson disease (if <40 yrs old) 
Ceruloplasmin 
Hemochromatosis 
Ferritin, transferrin 
Alpha-1-antitrypsin deficiency 
Alpha-1-antitrypsin 
Other causes should also be considered based upon participants’ medical history (hyperthyroidism 
/ thyrotoxic hepatitis – T3, T4, TSH; CVD / ischemic hepatitis – ECG, prior hypotensive episodes; 
T1D / glycogenic hepatitis). 
Obtain PK sample to determine exposure to study treatment and metabolites. 
Following appropriate causality assessments, as outlined above, the causality of the treatment is 
estimated as “probable” i.e. >50% likely, if it appears greater than all other possible causes of liver 
injury combined. The term “treatment-induced” indicates probably caused by the treatment, not 
by something else, and only such a case can be considered a DILI case and should be reported as 
an SAE. 
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no other 
alternative cause for LFT abnormalities identified, should be considered as “medically 
significant,” and thus, meet the definition of SAE and should be reported as SAE using the term 
“potential treatment-induced liver injury.” All events should be followed up with the outcome 
clearly documented. 
 


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11.0 Tumor Response Evaluation Criteria 
11.1 Evaluation of Target Lesions 
This section provides the definitions of the criteria used to determine objective tumor response 
for target lesions. 
• Complete response (CR):  disappearance of all target lesions 
Any pathological lymph nodes (whether target or non-target) must have reduction in 
short axis to < 10 mm. 
• Partial response (PR):  at least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum of diameters 
• Progressive disease (PD):  at least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (nadir), including baseline 
In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. 
The appearance of one or more new lesions is also considered progression. 
• Stable disease (SD):  neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum on study 
11.2 Evaluation of Non-Target Lesions 
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions.  While some non-target lesions may actually be measurable, they 
need not be measured and, instead, should be assessed only qualitatively at the time points 
specified in the protocol. 
• CR:  disappearance of all non-target lesions and (if applicable) normalization of tumor 
marker level) 
All lymph nodes must be non-pathological in size (< 10 mm short axis). 
• Non-CR/Non-PD:  persistence of one or more non-target lesion(s) and/or (if applicable) 
maintenance of tumor marker level above the normal limits 
• PD:  unequivocal the appearance of one or more new lesions is also considered 
progression. 
12.0 Safety Monitoring and Reporting 
All study patients who have received neratinib and capmatinib as combination therapy will be 
evaluable for safety. The ongoing review of safety data will include review of clinical AEs and 
SAEs. 
12.1 Adverse Event 
12.1.1 Adverse Event Definition 
An Adverse Event is defined as any untoward medical occurrence in a patient regardless of its 
causal relationship to study treatment. An AE can be any unfavorable and unintended sign 


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(including any clinically significant abnormal laboratory test result), symptom, or disease 
temporally associated with the use of the study treatment, whether or not it is considered to be 
study drug(s) related. Included in this definition are any newly occurring events and any previous 
condition that has increased in severity or frequency since the administration of study 
12.1.2 Adverse Event Attribution 
Attribution is the determination of whether an adverse event is related to a medical treatment or 
procedure.  
Definite - the adverse event is clearly related to the investigational agent(s). 
Probable - the adverse event is likely related to the investigational agent(s). 
Possible - the adverse event may be related to the investigational agent(s). 
Unlikely - The adverse event is doubtfully related to the investigational agent(s). 
Unrelated - The adverse event is clearly NOT related to the investigational agent(s). 
The Study PI or designee will be responsible for assigning attribution of adverse events to the 
study agent and signing the case report form. 
12.1.3 Adverse Event Severity 
The severity of the adverse events (AEs) will be graded according to the National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 5.0.  Events not 
included in the NCI CTCAE will be scored as follows: 
General grading: 
Grade 1: Mild: discomfort present with no disruption of daily activity, no treatment required 
beyond prophylaxis. 
Grade 2: Moderate: discomfort present with some disruption of daily activity, require treatment. 
Grade 3: Severe: discomfort that interrupts normal daily activity, not responding to first line 
treatment.  
Grade 4: Life Threatening: discomfort that represents immediate risk of death 
Grade 5: Fatal    
12.1.4 Adverse Event Recording 
Adverse events and Serious Adverse Events will be captured in the study database REDCap. 
All AEs and SAEs will be captured during the study Phase 1b portion. For the Phase II portion of 
the study, only AEs >/= grade 2 non-hematological and >/= grade 3 hematological AEs, 
occurring after first protocol intervention 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. Baseline toxicities will be documented in the patients’ medical record.  


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Abnormal laboratory values will not be reported as AEs; however,  the abnormal laboratory 
value is considered to be an AE if the abnormality:  
o Results in discontinuation from the study 
o Requires treatment, modification/interruption of study treatment dose, or any other 
therapeutic intervention  
o Is judged to be of significant clinical importance  
o If a laboratory abnormality is one component of a diagnosis or syndrome, then only the 
diagnosis or syndrome should be recorded on the AE page of the eCRF. If the abnormality 
was not a part of a diagnosis or syndrome, then the laboratory abnormality should be 
recorded as the AE.  
 
12.2 Serious Adverse Event Reporting (SAE)  
12.2.1 Internal SAE reporting to Investigational New Drug (IND) Office 
Serious Adverse Event (SAE) Reporting Requirements for M D Anderson Sponsor Single 
Site IND Protocols 
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 event 
• 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 (21 CFR 312.32). 
• 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, IND Office. 
• 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 on Reporting Adverse Events for Drugs and Devices”. 


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• Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 30 days after the last dose, 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. 
• All SAEs, expected or unexpected/ initial or follow up, must be reported to the IND 
Office within 5 working days of knowledge of the event regardless of the attribution. 
• Death or life-threatening events that are unexpected, possibly, probably or definitely 
related to drug must be reported (initial or follow up) to the IND Office within 24 hours 
of knowledge 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. 
• The electronic SAE application (eSAE) will be utilized for safety reporting to the IND 
Office and MD Anderson IRB.  
• All events reported to the supporting company must also be reported to the IND Office  
Reporting to FDA: 
• Serious adverse events will be forwarded to FDA by the IND Sponsor 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. 
 
12.2.3 Investigator Communication with Supporting Company 
The MDACC Internal SAE Report Form will be used for reporting to Puma Biotechnology Inc. 
and Novartis and reporting timeline is as below: 
• 
Death that is unanticipated and definitely, probably or possibly related to study 
intervention that occur any time from the first protocol-specific intervention, until 30-
days after the last day of active study intervention will be reported to Puma 
Biotechnology Inc. and Novartis within 24 working hours, not including holidays. 
• 
All other SAEs  regardless of suspected causality (unanticipated, and definitely, 
probably or possibly related to study drugs) will be reported to Puma Biotechnology 
Inc. and Novartis within 24 working hours, not including holidays. The investigator 
must assess and record the relationship of each SAE to each specific study treatment (if 
there is more than one study treatment), and submit the completed form to Puma via 
email to PumaSAE@parexel.com and to Novartis via email to 
clinicalsafetyop.phuseh@novartis.com (Fax: + 1 877 778 9739). 


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• Any additional information for the SAE including complications, progression of the 
initial SAE, and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE 
occurring at a different time interval or otherwise considered completely unrelated to a 
previously reported one should be reported separately as a new event. 
• Any SAEs experienced after the 30-day safety follow-up period should only be reported 
to Novartis if the investigator suspects a causal relationship to the study treatment. 
• Follow-up information is submitted in the same way as the original SAE Report. Each 
re-occurrence, complication, or progression of the original event should be reported as a 
follow-up to that event regardless of when it occurs. The follow-up information should 
describe whether the event has resolved or continues, if and how it was treated, whether 
the blind was broken or not, and whether the subject continued or withdrew from study 
participation. 
• If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the Novartis study treatment, an 
oncology Novartis Chief Medical Office and Patient Safety (CMO&PS) department 
associate may urgently require further information from the investigator for Health 
Authority reporting. Novartis may need to issue an Investigator Notification (IN), to 
inform all investigators involved in any study with the same drug that this SAE has been 
reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected 
and reported to the competent authorities and relevant ethics committees in accordance 
with Directive 2001/20/EC or as per national regulatory requirements in participating 
countries. 
• Other events requiring reporting - Pregnancy 
To ensure subject safety, each pregnancy occurring while the subject is on study 
treatment must be reported to Novartis within 24 hours of learning of its occurrence. 
The pregnancy should be followed up to determine outcome, including spontaneous or 
voluntary termination, details of the birth, and the presence or absence of any birth 
defects, congenital abnormalities, or maternal and/or newborn complications.  
 
13.0 Statistical Consideration 
Safety will be evaluated in this study through the monitoring of adverse events and serious 
adverse events defined as Section 12.1. This is an IND study and will be monitored by MD 
Anderson IND office. 
13.1 Phase 1b Dose-Finding Design 
We will employ the Bayesian optimal interval (BOIN) design (Liu and Yuan, 2015; Yuan et al., 
2016) (24, 25), with the 3+3 design run-in, to find the MTD (see Appendix 1 for design 
parameters). The BOIN design is implemented in a simple way similar to the traditional 3+3 
design, but is more flexible and possesses superior operating characteristics that are comparable 
to those of the more complex model-based designs, such as the continual reassessment method 
(CRM) (Zhou et al., 2018)(26). 


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The target toxicity rate for the MTD is 𝜙𝜙= 0.25 and the maximum sample size for dose 
escalation is 18. We will enroll and treat patients in cohorts of size 3. DLTs are defined in 
Section 7.4 and only those DLTs that occur within the first 2 cycles (56 days) will be used for 
dose finding. As shown in Figure 2, the BOIN design uses the following rule, optimized to 
minimize the probability of incorrect dose assignment, to guide dose escalation/de-escalation: 
• 
if the observed DLT rate at the current dose is ≤ 0.197, escalate the dose to the next higher 
dose level; 
• 
if the observed DLT rate at the current dose is > 0.298, de-escalate the dose to the next 
lower dose level; 
• 
otherwise, stay at the current dose. 
The 3+3 design run-in will be applied to override the above decision rule when the number of 
patients treated at the current dose is 3. That is, we will escalate the dose if 0/3 DLT, stay at the 
current dose if 1/3 DLT, and de-escalate the dose if >= 2/3 DLTs. For the purpose of overdose 
control, doses 𝑗𝑗 and higher levels will be eliminated from further examination if Pr(𝑝𝑝𝑗𝑗> 0.25 | 
data) > 0.95 and at least 3 evaluable patients have been treated at dose level 𝑗𝑗, where 𝑝𝑝𝑗𝑗 is the 
true DLT rate of dose level 𝑗𝑗, 𝑗𝑗= 1,⋯, 3. This posterior probability is evaluated based on the 
beta-binomial model 𝑦𝑦𝑗𝑗∣𝑝𝑝𝑗𝑗∼binomial(𝑝𝑝𝑗𝑗) with 𝑝𝑝𝑗𝑗∼uniform(0,1), where 𝑦𝑦𝑗𝑗 is the number of 
patients experienced DLT at dose level 𝑗𝑗. When the lowest dose is eliminated, stop the trial for 
safety. The probability cutoff 0.95 is chosen to be consistent with the common practice that when 
the target DLT rate <=1/6, a dose with 2/3 patients experienced DLT is eliminated. The above 
dose escalation/de-escalation and elimination rule can be equivalently presented in Table 18, 
which will be used to conduct the trial. 
The steps to implement the BOIN design are described as follows: 
1. 
Patients in the first cohort are treated at dose level 1. 
2. 
To assign a dose to the next cohort of patients, conduct dose escalation/de-escalation 
according to the rule displayed in Table 18. When using Table 18, please note the 
following: 
a. 
“Eliminate” means eliminate the current and higher doses from the trial to prevent 
treating any future patients at these doses because they are overly toxic. 
b. 
When we eliminate a dose, automatically de-escalate the dose to the next lower 
level. When the lowest dose is eliminated, stop the trial for safety. In this case, no 
dose should be selected as the MTD. 
c. 
If none of the actions (i.e., escalation, de-escalation or elimination) is triggered, treat 
the new patients at the current dose. 
d. 
If the current dose is the lowest dose and the rule indicates dose de-escalation, treat 
the new patients at the lowest dose unless the number of DLTs reaches the 
elimination boundary, at which point terminate the trial for safety. 


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e. 
If the current dose is the highest dose and the rule indicates dose escalation, treat the 
new patients at the highest dose. 
3. 
Repeat step 2 until the maximum sample size of 18 is reached, or stop the trial if the number 
of evaluable patients treated at the current dose reaches 9. 
Table 18. Dose Escalation/Deescalation Rule for the BOIN Design 
             
 
Number of evaluable patients treated at current dose 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Escalate if # of 
DLT <= 
0 
0 
0 
0 
0 
1 
1 
1 
1 
1 
2 
2 
Deescalate if # of 
DLT >= 
1 
1 
2* 
2 
2 
2 
3 
3 
3 
3 
4 
4 
Eliminate if # of 
DLT >= 
NA 
NA 
3 
3 
3 
4 
4 
4 
5 
5 
6 
6 
Note. “# of DLT” is the number of patients with at least 1 DLT. When none of the actions (i.e., 
escalate, de-escalate or eliminate) is triggered, stay at the current dose for treating the next cohort 
of patients. “NA” means that a dose cannot be eliminated before treating 3 evaluable patients. 
“*" indicates the 3+3 design run-in. 


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Figure 2. Flowchart for trial conduct using the BOIN design 
 
After the trial is completed, select the MTD based on isotonic regression as specified in Liu and 
Yuan (2015) (24). This computation is implemented by the shiny app “BOIN” (Zhou et al., 2020) 
(27) available at http://www.trialdesign.org. Specifically, select as the MTD the dose for which 
the isotonic estimate of the toxicity rate is closest to the target toxicity rate. If there are ties, 
select the higher dose level when the isotonic estimate is lower than the target toxicity rate and 
select the lower dose level when the isotonic estimate is greater than or equal to the target 
toxicity rate. 
Operating Characteristics 


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Table 19 shows the operating characteristics of the trial design based on 1000 simulations of the 
trial using shiny app “BOIN” (BOIN V2.6.3.0) available at http://www.trialdesign.org. The 
operating characteristics show that the design selects the true MTD, if any, with high probability 
and allocates more patients to the dose levels with the DLT rate closest to the target of 0.25. 
Table 19. Operating Characteristics of the BOIN Design 
 
Dose 
Level  
-2 
Dose 
Level  
-1 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Number 
of Patients 
% Early 
Stopping 
Scenario 1 
 
 
 
 
 
 
 
True DLT Rate 
0.25 
0.41 
0.45 
0.49 
0.53 
     
    
Selection % 
50.1 
29   
13.2 
2.4  
0.7  
     
4.6 
% Pts Treated 
24.7 
32.2 
34   
7.6  
1.4  
17.2 
    
Scenario 2 
  
  
  
  
  
  
  
True DLT Rate 
0.12 
0.25 
0.42 
0.49 
0.55 
     
    
Selection % 
19   
52.1 
24.1 
4    
0.6  
     
0.2 
% Pts Treated 
12.2 
35.7 
41.4 
9.2  
1.5  
17.1 
    
Scenario 3 
  
  
  
  
  
  
  
True DLT Rate 
0.04 
0.12 
0.25 
0.43 
0.63 
     
    
Selection % 
0.7  
18.4 
62.8 
17.4 
0.7  
     
0   
% Pts Treated 
1.7  
19   
50.6 
24.6 
4    
16.6 
    
Scenario 4 
  
  
  
  
  
  
  
True DLT Rate 
0.02 
0.06 
0.1  
0.25 
0.4  
     
    
Selection % 
0    
0.5  
25.3 
54.2 
20   
     
0   
% Pts Treated 
0    
2.6  
35.9 
39.2 
22.2 
17.1 
    
Note: “% Early Stopping”" refers to early stopping due to excessive DLT. 
 
13.2 Phase II Single-Arm Toxicity Monitoring and Efficacy Trial 
Phase II single-arm trial will be conducted to assess the overall response rate (ORR) for patients 
treated at the MTD.  Only patients with abnormal HER-family and c-Met signaling activity 
based on CELsignia MP Test results will be included in the efficacy analysis. The target ORR 
will be 25%, with unacceptable ORR as 5%. 
We will monitor the ORR using the Bayesian optimal phase 2 (BOP2) design (Zhou, Lee and 
Yuan, 2017)28. The assessment window for ORR monitoring is 4 cycles. Specifically, let 𝑛𝑛 


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67 | P a g e  
 
denote the interim sample size and 𝑁𝑁 denote the maximum sample size. Let 𝑝𝑝𝑒𝑒𝑒𝑒𝑒𝑒 denote the 
ORR and define the null hypothesis 𝐻𝐻0: 𝑝𝑝𝑒𝑒𝑒𝑒𝑒𝑒≤0.05, under which the treatment is deemed as 
unacceptable. We will stop enrolling patients and claim that the treatment is unacceptable if 
𝑃𝑃𝑃𝑃(𝑝𝑝𝑒𝑒𝑒𝑒𝑒𝑒> 0.05|𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑) < 𝜆𝜆ቀ𝑛𝑛
𝑁𝑁ቁ
𝛼𝛼
, 
where 𝜆𝜆=0.84 and 𝛼𝛼=0.86 are design parameters optimized to maximize power under the 
alternative hypothesis 𝐻𝐻1: 𝑝𝑝𝑒𝑒𝑒𝑒𝑒𝑒= 0.25, (i.e., the probability of correctly claiming that the 
treatment is acceptable under 𝐻𝐻1), while controlling the type I error rate (i.e., the probability of 
incorrectly claiming that the treatment is acceptable under 𝐻𝐻0) at 0.05. This optimization is 
performed assuming a vague prior Beta(0.05,0.95) for 𝑝𝑝𝑒𝑒𝑒𝑒𝑒𝑒. The above decision rule leads to the 
following stopping boundaries and yields a statistical power of 0.95 under 𝐻𝐻1: 
Table 20. Optimized Stopping Boundaries 
# patients treated Stop if # responses <= 
15 
0 
29 
3 
 
Based on Table 20, we perform the interim analysis when the number of enrolled patients 
reaches 15. When the total number of patients reaches the maximum sample size of 29, we reject 
the null hypothesis and conclude that the treatment is acceptable if the number of responses is 
greater than 3; otherwise we conclude that the treatment is unacceptable. The go/no-go criteria in 
Table 20 are non-binding and final decision will be based on the total evidence of efficacy. 
Below are the operating characteristics of the design based on 10000 simulations using the BOP2 
web application, which is available at http://www.trialdesign.org. 
Table 21. Operating Characteristics 
Response rate Early stopping (%) Claim promising (%) Sample size 
0.05 
46.3 
5.3 
22.5 
0.15 
8.7 
63.9 
27.8 
0.25 
1.3 
94.8 
28.8 
0.35 
0.2 
99.6 
29.0 
 
Toxicity monitoring 
We will monitor the Grade 3+ toxicity rate over 2 treatment cycles (28 days/cycle). Patients 
treated on Phase 1b at the MTD will be included for Phase II toxicity monitoring. Assuming 9 


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patients from phase 1b, the total sample size for toxicity monitoring will be 29+9=38. Formally, 
we will stop accrual if at any time: Pr (Grade 3+ toxicity > 0.20 | Data) > 0.90, with a prior 
beta(0.1, 0.4).  Stopping boundaries given an initial cohort of 6 followed by cohorts of 6 patients 
and with a total of up to 38 patients are: 
Table 22.  Safety Stopping Boundaries for Phase II 
Number of Total Patients (Cohorts of 6) 
Discontinuation of arm if Grade 3+ toxicity 
>= 
6 
3 
12 
5 
18 
7 
24 
8 
30 
10 
38 
12 
 
Below shows the operating characteristics of toxicity monitoring rule: 
Table 23. Operating Characteristics of Toxicity Monitoring 
True Toxicity 
Probability of Early Stop 
Avg. N Patients* 
.1 
.02 
37.4 
.2 
.19 
33.0 
.3 
.57 
23.9 
.4 
.89 
14.7 
.5 
.99 
9.7 
*include assumed 9 patients  in phase I 
 
Considering that patients with ER+ breast cancer will receive additional treatment with an 
aromatase inhibitor, in addition to the above overall toxicity monitoring rule, we will perform 
additional safety monitoring for the first 3 and 6 patients of ER+ breast cancer patients using the 
BOIN de-escalation boundaries provided in Table 18. That is,   ≥ 2 out of 3 or 6 ER+ breast 
cancer patients experience a DLT after receiving additional treatment with an aromatase 
inhibitor, the enrollment of ER+ breast cancer will be paused and dose reduction may be 
performed for ER+ breast cancer patients based on the totality of the data.  
Analyses of secondary outcomes will occur after all subjects have completed the study or 
completed at least 3 treatment cycles, each spanning 28 days, for a total of 84 days. A 95% level 
of confidence will be assumed. 
Incidence of adverse events will be summarized by CTCAE level as counts with percentages. 
Clinical benefit rate (CBR) is defined as the rate of patients who achieved complete response, 
partial response and stable disease for ≥ 24 weeks.  The CBR proportion will be reported 
together with 95% confidence interval. 


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Duration of response (DOR) is defined as the period from the date of the first occurrence of a CR 
or PR until the first date that progressive disease or death is documented.  Progression-Free 
survival (PFS) is defined as the time from treatment onset to either disease progression or death 
from any cause. 2 year overall survival (OS) is defined as the time from treatment onset to death 
over 2 years. For events that have not occurred by the time of data analysis, times will be 
censored at the last contact at which the patient was known to be progression-free for DOR and 
PFS, or the last time the patient was known to be alive for OS. DOR, PFS and OS will be 
summarized by the Kaplan-Meier method, including estimates of median and mean survival 
along with 95% CI.  
IND Office Safety and Efficacy Stopping Rule Monitoring: 
The Investigator is responsible for completing toxicity summary reports and submitting them to 
the IND office Medical Monitor for review.  These should be submitted as follows: 
• 
Phase 1b Dose-Finding: 
• A toxicity summary will be submitted after the first 3 evaluable patients complete 
2 cycles (56 days) of study treatment, and every 3 evaluable patients thereafter, 
prior to changing dose levels or moving to the study Phase II portion. IND 
Sponsor approval will be obtained after each submission, prior to enrolling 
additional subjects.  
• 
Phase II – Toxicity Monitoring: 
A toxicity summary will be submitted after every 6 evaluable subjects complete 2 
cycles (56 days) of study treatment until enrollment is complete. Patients treated 
at the MTD in the phase I portion will be included for phase II toxicity monitoring 
evaluation.  
• An additional toxicity summary will be submitted for the subjects with ER+ 
breast cancer treated at the MTD with AI therapy, after the first 3, and first 6 
evaluable patients with ER+ breast cancer treated at the MTD with AI therapy 
complete 2 cycles (56 days) of study treatment. This toxicity summary may 
include patients with ER+/HER2- breast cancer treated at the MTD in phase 1b 
and phase 2. If ≥ 2 out of 3 or 6 patients with ER+ breast cancer experience a 
DLT at the MTD, the MTD may be decreased to a lower dose level and used for 
patients with ER+ HER2 negative breast cancer in phase 2. 
 
 
• 
Phase II – Efficacy Monitoring: 
An efficacy summary will be submitted after 15 evaluable subjects complete 4 
cycles of study treatment. Final efficacy summary will be submitted when 
enrollment is complete. Only patients with abnormal HER-family and c-Met 


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signaling activity based on CELsignia MP Test results will be included in the 
efficacy analysis.  
A copy of each  safety summary report should be placed in the Investigator’s Regulatory Binder 
under “Protocol Summary”. 
14.0 Data Management  
The Principal Investigator is responsible for assuring that the data entered into the database is 
complete and accurate and that data entry is performed in a timely manner. RedCap will be used 
as the electronic case report form for this protocol and protocol specific data will be entered into 
RedCap.  
CORe (Clinical Oncology Research system) will be utilized for subject enrollment/registration.  
14.1 Data collection  
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  
All AEs will be collected. See details at 12.1.4. 
Concomitant medication will be recorded per standard of care in clinic database and will not be 
recorded in the study database.  
14.2 Data confidentiality plan 
Participant confidentiality and privacy is strictly held in trust by the participating investigator, 
their staff, the safety and oversight monitor(s), and the sponsor(s) and funding agency. This 
confidentiality is extended to the data being collected as part of this study. Data that could be 
used to identify a specific study participant will be held in strict confidence within the research 
team. No personally identifiable information from the study will be released to any unauthorized 
third party without prior written approval of the sponsor/funding agency, as applicable. 
 
All research activities will be conducted in as private a setting as possible. 
 
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. 
Access to Study Records 


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Study records may be accessed by IRB approved study personnel, or authorized inspectors. The 
study monitor, other authorized representatives of the sponsor or funding agency, representatives 
of the Institutional Review Board (IRB), regulatory agencies or representatives from companies 
or organizations supplying the product, may inspect all documents and records required to be 
maintained by the investigator, including but not limited to, medical records (office, clinic, or 
hospital) and pharmacy records for the participants in this study. The clinical study site will 
permit access to such records. 
 
Methods of Storage of Study Records 
All data collected from MD Anderson Cancer Center (MDACC) sources will be maintained on a 
password protected server compliant with HIPAA. Study staff will have role based restricted 
access to directories and files on the server, according to project responsibilities. Only those with 
data entry permissions can add records. The PI or a delegate will review the conditions under 
which data will be released to recipient- investigators. Each application for use will need IRB 
approval and consents, if appropriate. The level of identifiability will determine the process for 
review and approval as well as the way information is shared. 
 
Any study data or records maintained in paper documents will be stored in the offices of the PI 
or other delegated study staff, in a locked cabinet or other comparable controlled environment, 
and will be accessible only to authorized study team members or authorized inspectors.   
Information gathered for this study will be banked for future research with IRB approval. 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. 
Sharing of Study Records 
There are no plans to share study data with entities external to MD Anderson Cancer Center, 
aside from authorized inspectors as applicable (i.e. authorized representatives of the sponsor or 
funding agency, representatives of the Institutional Review Board (IRB), regulatory agencies or 
representatives from companies or organizations supplying the product).  If data will be shared, 
IRB approval will be sought, and applicable inter-institutional agreements executed, prior to data 
sharing.   
 
14.3 Data and Safety Monitoring  
Data and Safety Monitoring is the process for reviewing data collected as research progresses to 
ensure the continued safety of current and future participants as well as the scientific validity and 
integrity of the research.  Studies conducted at MD Anderson will follow the DSMP that has 
been approved by the NCI.   
 
The Principal Investigator is ultimately responsible for the conduct and monitoring of all aspects 
of the study on an ongoing basis. The Principal Investigator will provide an annual review and 
report of the study, including all adverse events, accrual information, efficacy and response data, 
along with overall study progress and continuation plans to MD Anderson’s Data and Safety 
Monitoring Committees (DSMC) responsible for study oversight.  


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14.4 Clinical Trial Monitoring 
Regular monitoring of trial conduct will be conducted to ensure that the rights and well-being of 
trial participants are protected, that the reported trial data are accurate, complete, and verifiable, 
and that the conduct of the trial is in compliance with the currently approved 
protocol/amendment(s), with ICH GCP, and with applicable regulatory requirement(s).  
 
15. Consent Process and Documentation  
This protocol will follow the SOP 04_Informed Consent Process. SOP 04 has been read 
by the research staff and investigators. Informed consent may be obtained using in-person 
consent and/or remote consent. 
 
 
16.0 References 
1. 
Loibl S, Gianni L: HER2-positive breast cancer. Lancet 389:2415-2429, 2017. 
2. 
Cameron D, Casey M, Oliva C, et al: Lapatinib plus capecitabine in women with HER-2-
positive advanced breast cancer: Final survival analysis of a phase III randomized trial. 
Oncologist 15:924-934, 2010. 
3. 
Piccart-Gebhart M, Holmes E, Baselga J, et al: Adjuvant lapatinib and trastuzumab for 
early human epidermal growth factor receptor 2-positive breast cancer: Results from the 
randomized phase III adjuvant lapatinib and/or trastuzumab treatment optimization trial. J Clin 
Oncol 34:1034-1042, 2016 
4. 
Paik S, et al. HER2 status and benefit from adjuvant trastuzumab in breast cancer. N Engl 
J Med. 2008;358(13):1409-1411. 
5. 
Perez EA, et al. HER2 and chromosome 17 effect on patient outcome in the N9831 
adjuvant trastuzumab trial. J Clin Oncol. 2010;28(28):4307-4315. 
6. 
Petrelli F,  Tomasello G, Barni S et al. Clinical and pathological characterization of 
HER2 mutations in human breast cancer: a systematic review of the literature Breast Cancer Res 
Treat. 2017 Nov;166(2):339-349. 
7. 
Bose R , Kavuri SM , Searleman AC , Shen W , Shen D , Koboldt DC , et al. Activating 
HER2 mutations in HER2 gene amplifi cation negative breast cancer . Cancer Discov 2013 ;3: 
224–37 
8. 
Ko B, et al. MET/HGF pathway activation as a paradigm of resistance to targeted 
therapies. Ann Transl Med. 2017;5(1):4. 


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9. 
Engelman JA, et al. MET amplification leads to gefitinib resistance in lung cancer by 
activating ERBB3 signaling. Science. 2007;316(5827):1039-1043. 
10. 
Minuti G, Cappuzzo F, Duchnowska R et al. Increased MET and HGF gene copy 
numbers are associated with trastuzumab failure in HER2-positive metastatic breast cancer. Br J 
Cancer. 2012 Aug 21;107(5):793-9.  
11. 
Lindemann K, Resau J, Nährig J et al. Differential expression of c-Met, its ligand 
HGF/SF and HER2/neu in DCIS and adjacent normal breast tissue. Histopathology. 2007 
Jul;51(1):54-62. 
12. 
Shattuck DL, Miller JK, Carraway KL, et al. Met receptor contributes to trastuzumab 
resistance of Her2-overexpressing breast cancer cells. Cancer Res. 2008;68:1471–7. 
13. 
Breindel J, et al. EGF receptor activates MET through MAPK to enhance non-small cell 
lung carcinoma invasion and brain metastasis. Cancer Res. 2013;73(16):5053. 
14. 
Mo HN, et al. Targeting MET in cancer therapy. Chronic Diseases and Translational 
Medicine 2017;3:148-153 
15. 
Laing et al. A functional signal profiling test for identifying a subset of HER2-negative 
breast cancers with abnormally amplified HER2 signaling activity. Oncotarget. 2016 Oct 5; 
7(48) 78577-590. 
16. 
Laing et al. Development of a test that measures real-time HER2 signaling activity in live 
breast cancer cell lines and primary cells. BMC Cancer. 2017 March 17:199. 
17. 
NCT03812393 Phase II Trial Evaluating the Efficacy and Safety of Neoadjuvant 
Neratinib and Chemotherapy in Early Stage Triple-Negative Breast Cancer Patients Who Exhibit 
Enhanced HER2 Signaling by Live Cell HER2 Signaling Transduction Analysis (FACT-2) 
18. 
NCT03812393 Phase II Trial to Evaluate the Efficacy and Safety of Neoadjuvant 
Neratinib Followed by Weekly Paclitaxel and Carboplatin Plus Neratinib in Early Stage Triple-
Negative Breast Cancer Patients Who Exhibit Enhanced HER2 Signaling by Live Cell HER2 
Signaling Transduction Analysis. 
19. 
Laing et al., Sub-group of HER2- breast cancer patients with hyperactive and co-involved 
c-Met and ErbB pathways identified: functional signal profiling test identifies patient group that 
may benefit from c-Met and pan-HER combination therapy, Cancer Research;79 (4 Supplement) 
P3-10-20 
20.       Lipton, et al. Serum HER-2/neu conversion to positive at the time of disease progression 
in patients with breast carcinoma on hormone therapy. Cancer. 2005;104(2). 
21.       Andre et al., Everolimus for women with trastuzumab-resistant, HER2-positive, 
advanced breast cancer (BOLERO-3): a randomised, double-blind, placebo-controlled phase 3 
trial. The Lancet Oncol. 2014; 15 (6) 


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22.       Gutierrez et al., Everolimus for women with trastuzumab-resistant, HER2-positive, 
advanced breast cancer (BOLERO-3): a randomised, double-blind, placebo-controlled phase 3 
trial. J Clin Oncol. 2005; 23 (11)  
23. 
Laing et al., Evaluation of pan-HER and c-MET inhibitors tested in primary HER2- 
breast cancer cells with hyperactive c-MET and ErbB family signaling, SABCS, 2018, Abstract 
# P2-05-05. 
24.      Liu S. and Yuan, Y. (2015). Bayesian optimal interval designs for phase I clinical trials. 
Journal of the Royal Statistical Society: Series C , 64, 507-523. 
25.      Yuan Y., Hess K.R., Hilsenbeck S.G. and Gilbert M.R. (2016) Bayesian optimal interval 
design: a simple and well-performing design for phase I oncology trials, Clinical Cancer 
Research, 22(17), 4291-4301.  
26.       Zhou, H., Yuan, Y., & Nie, L. (2018). Accuracy, safety, and reliability of novel phase I 
trial designs. Clinical Cancer Research, 24(18), 4357-4364.  
27.       Yanhong Zhou, Ruobing Li, Fangrong Yan, J. Jack Lee & Ying Yuan (2021) A 
Comparative Study of Bayesian Optimal Interval (BOIN) Design With Interval 3+3 (i3+3) 
Design for Phase I Oncology Dose-Finding Trials, Statistics in Biopharmaceutical Research, 
13:2, 147-155, DOI: 10.1080/19466315.2020.1811147          
28.       Heng Zhou,J. Jack Lee,Ying Yuan. (2017) BOP2: Bayesian optimal design for phase II 
clinical trials with simple and complex endpoints. Statistics in MedicineVolume 36, Issue 21 p. 
3302-3314 
29.       Barcenas, CH, et al. Improved tolerability of neratinib in patients with HER2-positive 
early-stage breast cancer: the CONTROL trial. Annals of Oncology 13 (9), 2020. 
30.      Dawood S, Merajver SD, Viens P, Vermeulen PB, Swain SM, Buchholz TA, Dirix LY, 
Levine PH, Lucci A, Krishnamurthy S, Robertson FM, Woodward WA, Yang WT, Ueno NT, 
Cristofanilli M. International expert panel on inflammatory breast cancer: consensus statement 
for standardized diagnosis and treatment. Ann Oncol. 2011 Mar;22(3):515-23. doi: 
10.1093/annonc/mdq345. Epub 2010 Jul 5. PMID: 20603440 
 
 


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Appendix 1: Phase Ib Trial and Design Specifications 
Parameter 
Value 
Number of doses 
5 
Starting dose 
3 
Max sample size 
18 
Cohort size 
3 
Stop trial if # patients assigned to single dose reaches 
9 
Apply the 3+3 design run-in 
TRUE 
Use accelerated titration 
FALSE 
Target toxicity probability 
0.25 
Use the default alternatives to minimize decision errors 
TRUE 
Alternative (unacceptable high toxicity) for optimization 
Default 
Alternative (unacceptable low toxicity) for optimization 
Default 
Eliminate dose threshold 
0.95 
Impose a more stringent safety stopping rule 
FALSE 
Require the isotonic estimate of the DLT probability for the dose selected as the 
MTD less than the de-escalation boundary 
FALSE 
Number of repetitions per scenario 
1000 
Random number generator seed 
6 
 
 
 


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Appendix 2: CELsignia Collection Kit User Instructions Card
 


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Appendix 3: CELsignia Specimen Collection Requisition 
 

ICF_000.pdf: 
Protocol 2020-0198 
February 1, 2024 
Page 1 of 15 
 
 
Informed Consent 
 
 
 
INFORMED CONSENT FORM/AUTHORIZATION FOR  
PARTICIPATION IN RESEARCH 
 
Neratinib and Capmatinib combination (phase Ib/II) in metastatic breast 
cancer and inflammatory breast cancer patients with abnormal HER-family 
and c-Met pathway activity as measured by the CELsignia Signaling 
Analysis Test  
2020-0198 
 
Subtitle:      Main Consent       
 
Study Chair:   Rachel Layman  
 
 
 
_________________________ 
 
_____________________________ 
Participant’s Name 
 
 
 
Medical Record Number  
 
This is an informed consent and authorization form for a research study. It includes a 
summary about the study. A more detailed description of procedures and risks is 
provided after the summary. 
 
This research has been reviewed and approved by an Institutional Review Board (IRB - 
a committee that reviews research studies). 
 
STUDY SUMMARY 
 
There are 2 parts to this study: Part 1b (dose escalation) and Part 2 (dose expansion).  
 
The goal of Part 1b in this clinical research study is to find the highest tolerable dose of 
2 study drugs, capmatinib and neratinib, that can safely be given to patients with breast 
cancer that is metastatic (has spread) or locally advanced. For patients with estrogen 
receptor positive breast cancer, the study will also find the highest tolerable dose of the 
2 study drugs, capmatinib and neratinib in combination with a type of standard of care 
endocrine therapy medication known as an aromatase inhibitor.  
 
The goal of Part 2 of this study is to learn if the dose of capmatinib and neratinib found 
in Part 1b can help to control the disease.  
 


Protocol 2020-0198 
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Page 2 of 15 
 
This is an investigational study. Neratinib is FDA approved and commercially 
available for the treatment of HER2-positive breast cancer. Capmatinib is FDA approved 
and commercially available for the treatment of metastatic lung cancer but is not 
approved to treat breast cancer. Aromatase inhibitors are FDA approved and 
commercially available for the treatment of estrogen receptor positive breast cancer. 
This drug combination is considered investigational and is currently being used for 
research purposes only.   
 
The study doctor can explain how the study drugs are designed to work. 
 
The study drugs may help to control the disease. Future patients may benefit from what 
is learned. There may be no benefits for you in this study.  
 
Your participation is completely voluntary. Before choosing to take part in this study, you 
should discuss with the study team any concerns you may have, including side effects, 
potential expenses, and time commitment. If you take part in this study, you may 
experience side effects, some of which may be severe or fatal. You may choose not to 
take part in this study because of hospitalization, a prolonged stay out of town, and/or 
because there are other standard options available. By participating in this study, you 
may be declining treatments that have been shown to improve survival. You should ask 
the study staff member obtaining your informed consent to describe any such 
treatments to you before you sign this consent form. 
 
You can read a full list of potential side effects below in the Possible Risks section of 
this consent. 
 
You may receive the study drugs for up to 3 years, as long as the study doctor thinks 
you are benefitting from the therapy. You will no longer be able to take the study drugs if 
the disease gets worse, if intolerable side effects occur, or if you are unable to follow 
study directions. 
 
PUMA Biotechnology, Novartis and Celcuity are study supporters. Neratinib (PUMA 
Biotechnology) and capmatinib (Novartis) will be provided at no cost to you while you 
are on study. The cost of endocrine therapy agents will be the responsibility of you 
and/or your insurance provider. The CELsignia test for patients in Part 2 of this study will 
be performed and the cost covered by Celcuity. 
 
You may choose not to take part in this study. Instead of taking part in this study, you 
may choose to receive standard of care therapy including chemotherapy, hormonal 
therapy, targeted therapy, or combination of these drugs, if appropriate. The study 
doctor will discuss with you which treatment options may be available outside of this 
study, including the possible risks and benefits of these treatments. You may choose to 
receive other investigational therapy, if available. You may choose not to have treatment 
for cancer at all. In all cases, you will receive appropriate medical care, including 
treatment for pain and other symptoms of cancer. 
 
 


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1. STUDY DETAILS 
 
Screening Tests 
Signing this consent form does not mean that you will be able to take part in this study. 
The following screening tests will help the doctor decide if you are eligible: 
• You will have a physical exam. 
• You will have an EKG and either a MUGA scan or echocardiogram (ECHO) to 
check your heart function.  
• Blood (about 3 tablespoons) will be drawn for routine and research testing, which 
may include genetic testing. Blood for research testing in this study will be stored 
in a research bank at MD Anderson for use in future research related to breast 
cancer and how characteristics of the tumor (such as certain genetic features or 
proteins) may affect your reaction to the study drug. 
• Urine sample will be obtained for routine tests.  
• You will have imaging scans (such as a chest x-ray, bone scan, ultrasound, 
PET/CT scans or chest, pelvis, and abdominal CT scans, and/or MRIs) to check 
the status of the disease. The study doctor will tell you which scans you will have. 
• If you are being screened for Part 2 of the study, you will have a core tumor 
biopsy for biomarker testing. Biomarkers are found in the blood/tissue and may 
be related to your reaction to the study drug. A biopsy may be taken of the tumor 
in the breast and/or metastatic sites (parts of the body other than the breast 
where the disease has spread). To perform a core biopsy, a sample of tissue is 
removed using a hollow core needle that has a cutting edge. A numbing drug will 
be given through a needle under the skin before the core biopsy. 
• If you can become pregnant, urine or part of the above blood sample will be 
collected for a pregnancy test. To take part in this study, you must not be 
pregnant. 
 
The study doctor will discuss the screening test results with you. If the screening tests 
show that you are not eligible to take part in the study, you will not be enrolled. Other 
treatment options will be discussed with you. 
 
Study Groups 
If you are found to be eligible to take part in this study, you will be assigned to a study 
group based on when you join this study. Up to 56 participants total (up to 27 in Part 
1b and up to 29 in Part 2) will be enrolled in this study. All will take part at MD 
Anderson. 
 
If you are enrolled in Part 1b, the dose of capmatinib and neratinib you receive will 
depend on when you join this study. Up to 4 dose levels of the study drugs will be 
tested. The first group of participants will receive the starting dose of capmatinib and 
neratinib. Each new group will receive a different dose level (which may be higher or 
lower) of capmatinib and neratinib from the group before it, depending on the side 
effects seen in previous groups. This will continue until the highest tolerable dose of 
capmatinib and neratinib is found. 
 


Protocol 2020-0198 
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If you are enrolled in Part 2, you will receive capmatinib and neratinib at the 
recommended dose that was found in Part 1b. 
 
In both Part 1b and Part 2, if you have estrogen receptor positive breast cancer, you will 
also take or continue to take an aromatase inhibitor (a type of endocrine therapy drug).   
The study doctor will choose the aromatase inhibitor that you will receive. The study 
doctor will give you instructions for taking the aromatase inhibitor. In addition, if you 
currently have menstrual cycles, a medication to suppress the hormones produced by 
your ovaries will be administered to you.  
 
The study doctor will tell you which part of the study you are in and which dose of study 
drugs you are receiving. 
 
Study Drug Administration 
You will receive the study drugs in 28-day cycles.   
 
You will take neratinib tablets by mouth 1 time in the morning with food at about the 
same time.  
 
You will take capmatinib tablets by mouth 2 times every day, with or without food, at the 
same time each day. Each dose should be taken about 12 hours apart (1 dose in the 
morning, 1 dose in the evening). You may take your morning dose of capmatinib at the 
same time as your dose of neratinib. 
 
The study doctor will tell you how many tablets you need to take every day. Tablets 
should be swallowed whole; do not crush, chew, or break the tablets.  
 
You be given a medication diary to write down when you take capmatinib and neratinib 
and if you miss any doses. If you miss or vomit a dose, do not take a “make up” dose or 
double dose; wait and take your next dose as scheduled. 
 
Bring this diary and the medication bottles with the leftover drug (if any) to the clinic at 
the beginning of each cycle.  
 
Study Visits 
 
You will come to the clinic on Day 1 of each cycle for up to 3 years. At each visit: 
• You will have a physical exam.  
• Blood (about 1-3 tablespoons) will be drawn for routine tests.  
• Urine sample will be obtained for routine tests.  
• Every 2 cycles (Cycles 1, 3, 5, and so on), an additional blood sample (about 2-4 
tablespoons) will be drawn for research testing, which may include genetic 
testing. This research blood sample will be stored in a lab at MD Anderson for 
use in future research and may help doctors understand your response to the 
study drugs. 
• Every 2 cycles, you will have imaging scans as part of your standard care to 
check the status of the disease.  


Protocol 2020-0198 
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• Every 3 cycles, if the doctor thinks it is needed as part of your standard care, you 
will have an EKG and either an ECHO or MUGA scan to check your heart 
function.  
• If you can become pregnant, urine or part of the above blood sample will be used 
for a pregnancy test. 
 
End-of-Dosing Visit 
As soon as possible after your last dose of study drugs: 
• You will have a physical exam. 
• Blood (about 1-2 tablespoons) will be drawn for routine tests. 
• Depending on when your last scans were done, you may have imaging scans to 
check the status of the disease as part of your routine care. 
• If you can become pregnant, urine or part of the above blood sample will be used 
for a pregnancy test. 
 
Follow-Up 
About 1 month after your last dose of study drugs and then every 6 months after that for 
up to 2 years, the study team will call you and ask how you are doing and if you have 
started any new anti-cancer medications. This may also be asked during a routine clinic 
visit, if you are planning to come to the clinic. If you are called, each call should last 
about 2-5 minutes.   
 
Your participation in this study will be over after 2 years of follow-up. 
 
2. POSSIBLE RISKS 
 
 While on this study, you are at risk for side effects. You should discuss these with the 
study doctor. The more commonly occurring side effects are listed in this form, as are 
rare but serious side effects. You may also want to ask about uncommon side effects 
that have been observed in small numbers of patients but are not listed in this form. 
Many side effects go away shortly after treatment is stopped, but in some cases side 
effects may be serious, long-lasting or permanent, and may even result in hospitalization 
and/or death.  
 
Side effects will vary from person to person, and some may occur after you have 
stopped receiving treatment. Tell the study staff about any side effects you may have, 
even if you do not think they are related to the study drugs/procedures. 
 
Capmatinib Side Effects  
 
Common (occurring in more than 20% of patients) 
 
• swelling (arm/leg) 
• fatigue 
• abnormal salts, 
minerals, and/or acids 
in the blood (possible 
weakness, swelling, 
fatigue, low blood 
• loss of appetite 
• nausea/vomiting 
• low red blood cell 
count 


Protocol 2020-0198 
February 1, 2024 
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• abnormal blood test 
(possible pancreas 
damage) 
• difficulty breathing 
pressure, organ failure, 
heart problems, 
changes in mental 
status, and/or seizure) 
• abnormal liver test 
(possible liver damage) 
• abnormal kidney test 
(possible kidney 
damage) 
 
Capmatinib may cause low blood cell counts (red blood cells). A low red blood cell count 
(anemia) may cause difficulty breathing and/or fatigue. You may need a blood 
transfusion.  
 
Occasional (occurring in 3-20% of patients)  
 
• skin rash 
• dry skin 
• fever 
• itching 
• constipation 
• diarrhea 
• abnormal protein in 
the blood 
• inflammation of the 
pancreas (possible 
abdominal pain) 
• chest/back pain 
• kidney failure  
• weight loss 
• build-up of fluid around 
the lungs  
• lung inflammation 
(possible difficulty 
breathing) 
• cough 
 
 
The drug may cause an increased risk of infection, such as a skin infection (cellulitis). 
An infection may occur anywhere. It may become life-threatening. Symptoms of infection 
may include fever, pain, redness, and difficulty breathing.  
 
Rare but serious (occurring in fewer than 3% of patients)  
 
• hives 
• severe skin rash 
• inflammation of the pancreas 
(possible abdominal pain) 
 
Capmatinib may cause birth defects. 
 
Capmatinib may cross the blood-brain barrier, but it is not known what side effects this 
may cause. It is important that you tell your doctor if you have a headache, are dizzy, 
have balance problems, tremors, difficulties when you speak, mental confusion, and/or 
changes in your personality or vision (like blurred vision, double vision, or blind spots). 
 
Capmatinib may cause you to get sunburned more easily. You should wear sunscreen, 
sun-protective clothing, a large rim hat, and sunglasses that protect you from the sun. 
You should also avoid direct sunlight, sunlamps, and tanning beds as much as possible. 
 
One case of worsened cough and notable shortness of breath leading to death has been 
reported in one patient with lung cancer, possibly related to capmatinib.  
 
Neratinib Side Effects 
 


Protocol 2020-0198 
February 1, 2024 
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Common (occurring in more than 20% of patients)       
 
• fatigue 
 
• diarrhea 
• vomiting 
• nausea 
• abdominal pain 
 
Occasional (occurring in 3-20% of patients)       
 
• skin rash 
• dry skin 
• nail changes 
• mouth blisters/sores 
(possible difficulty 
swallowing) 
• loss of appetite 
• dry mouth 
• dehydration 
• upset stomach 
• indigestion 
• weight loss 
• abdominal swelling 
• urinary tract infection 
• abnormal liver tests 
(possible liver damage) 
• muscle spasms 
• nosebleed 
 
Rare but serious (occurring in fewer than 3% of patients)  
 
• liver damage 
 
• kidney failure 
       abnormal kidney test 
(possible kidney damage) 
• lung inflammation 
(possible difficulty 
breathing) 
 
If you have severe diarrhea, abdominal pain, nausea, fatigue, and/or vomiting, even for 
a short period of time, it is important that you tell the study doctor right away. 
 
In this study, abnormal protein in the blood was reported as a serious event in 1 patient 
and reported by the investigator as unexpected and possibly related to Neratinib. 
Abnormal protein in blood has not been identified as a risk of Neratinib in other studies 
to date.  
 
 
Endocrine Therapy Side Effects 
 
Common side effects of aromatase inhibitors (such as anastrozole, letrozole, and 
exemestane) include: 
 
• fatigue 
• weakness 
• hot flashes 
• flushing 
• digestive issues 
• joint pain 
 
Common side effects of ovarian suppressors (such as goserelin and leuprolide) include:  
 
• swelling (arm/leg) 
• headache 
• depression 
• mood swings 
• sweating 
• hot flashes 
• flushing  
• acne-like rash  
• oily skin  
• decreased sex drive  
• sexual disorder  
• decrease in size of the 
breast 
• vaginal inflammation 
 


Protocol 2020-0198 
February 1, 2024 
Page 8 of 15 
 
Potential side effects will vary depending on which drug you receive. The study doctor 
can tell you more about specific information. 
 
Using the study drugs together and in combination with endocrine therapy agent(s) 
may cause side effects that are not seen when each is given alone and may also 
increase the frequency and/or severity of the side effects listed above. 
 
Other Risks 
 
Blood draws may cause pain, bleeding, and/or bruising. You may faint and/or develop 
an infection with redness and irritation of the vein at the site where blood is drawn. 
Frequent blood collection may cause anemia (low red blood cell count), which may 
create a need for blood transfusions. 
 
Having biopsies performed may cause pain, bruising, bleeding, redness, low blood 
pressure, swelling, and/or infection at the site of the biopsies. An allergic reaction to the 
anesthetic may occur. A scar may form at the biopsy site. 
 
Diagnostic procedures, such as EKGs, bones scans, X-rays, and CT, PET/CT, and 
MRI scans, are part of your standard of care. You may discuss the risks of these scans 
with the study staff/study doctor if you have questions about them. 
 
Although every effort will be made to keep study data safe, there is a chance that your 
personal health information could be lost or stolen, which may result in a loss of 
confidentiality. All study data will be stored in password-protected computers and/or 
locked file cabinets and will continue to be stored securely after the study. 
 
This study may involve unpredictable risks to the participants. 
 
Pregnancy Related Risks 
Taking part in this study can result in risks to an unborn or breastfeeding baby, so you 
should not become pregnant, breastfeed a baby, or father a child while on this study.  
 
If you can become pregnant or father a child and you are sexually active, you must use 
birth control during the study and for at least 7 days after your last dose of study drugs. 
Acceptable forms of birth control include: 
• Hormonal birth control methods (shots/injections, implants, or patches) 
• Intrauterine device (IUD) or intrauterine system (IUS) 
• Use of two (2) barrier methods (each partner must use 1 method) plus 
spermicide. Barrier methods include condoms, diaphragm, cervical cap, or 
sponge.  
 
Males: Tell the doctor right away if your partner becomes pregnant or suspects 
pregnancy. 
 
Females: If you are pregnant, you will not be enrolled on this study. If you become 
pregnant or suspect that you are pregnant, you must tell your doctor right away. 


Protocol 2020-0198 
February 1, 2024 
Page 9 of 15 
 
 
Getting pregnant will result in your removal from this study.   
 
3. COSTS AND PAYMENTS  
 
The cost of endocrine therapy agents will be the responsibility of you and/or your 
insurance provider. Certain tests, procedures, and/or drugs that you may receive as part 
of this study may be without cost to you because they are for research purposes only. 
However, your insurance provider and/or you may be financially responsible for the cost 
of care and treatment of any complications resulting from the research tests, 
procedures, and/or drugs. Standard medical care that you receive under this research 
study will be billed to your insurance provider and/or you in the ordinary manner. Before 
taking part in this study, you may ask about which parts of the research-related care 
may be provided without charge, which costs your insurance provider may pay for, and 
which costs may be your responsibility. You may ask that a financial counselor be made 
available to you to talk about the costs of this study. 
 
Samples that are collected from you in this study may be used for the development of 
treatments, devices, new drugs, or patentable procedures that may result in commercial 
profit. 
 
There are no plans to compensate you for any patents or discoveries that may result 
from your participation in this research.  
 
You will receive no compensation for taking part in this study. 
 
If you get sick or hurt and it is related to your participation in this study call your personal 
doctor right away (or in an emergency, call 911) or call the study chair Dr. Rachel 
Layman, at 713-745-8401. Tell your doctor or staff that you are in this study (try to give 
them a copy of this consent form or show them your participant card) 
 
If you suffer injury as a direct result of taking part in this study, MD Anderson health 
providers will provide medical care. However, this medical care will be billed to your 
insurance provider or you in the ordinary manner. You will not be reimbursed for 
expenses or compensated financially by MD Anderson or Novartis, Puma 
Biotechnology, or Celcuity for this injury.  
 
You may also contact the Chair of MD Anderson’s IRB at 713-792-6477 with questions 
about study-related injuries. 
 
By signing this consent form, you are not giving up any of your legal rights. 
 
Additional Information  
 


Protocol 2020-0198 
February 1, 2024 
Page 10 of 15 
 
4. You may ask the study chair (Dr. Rachel Layman, at 713-745-8401) any questions you 
have about this study. You may also contact the Chair of MD Anderson's Institutional 
Review Board (IRB - a committee that reviews research studies) at 713-792-6477 with 
any questions that have to do with this study or your rights as a study participant. 
 
5. You may choose not to take part in this study without any penalty or loss of benefits to 
which you are otherwise entitled. You may also withdraw from participation in this study 
at any time without any penalty or loss of benefits. If you decide you want to stop taking 
part in the study, please inform the study chair in writing. It is recommended for your 
safety that you first talk to your doctor. If you withdraw from this study, you can still 
choose to be treated at MD Anderson. The study staff may ask if they can continue 
collecting the results of routine care from your medical record. 
 
6. This study or your participation in it may be changed or stopped without your consent at 
any time by the study chair, Novartis, Puma Biotechnology, Celcuity, the U.S. Food and 
Drug Administration (FDA), the Office for Human Research Protections (OHRP), or the 
IRB of MD Anderson. 
 
7. You will be informed of any new findings or information that might affect your willingness 
to continue taking part in the study, including the results of all of your standard tests 
performed as part of this research, and you may be asked to sign another informed 
consent and authorization form stating your continued willingness to participate in this 
study. 
 
8. MD Anderson, Celcuity, Novartis, and/or Puma may benefit from your participation 
and/or what is learned in this study. 
 
9. This study is sponsored and/or supported by: Novartis; Puma Biotechnology; Celcuity. 
 
10. In a medical emergency, you may be cared for by someone who has a financial interest 
with the study sponsor(s)/supporter. If you have any questions about this, you may call 
the IRB at 713-792-6477. 
 
Future Research 
 
Data 
Your personal information (name, full date of birth, age, gender, biological samples, 
etc.), is being collected as part of this study. These data may be used by researchers at 
MD Anderson, and Novartis and its authorized agents, Puma Biotechnology, and 
Celcuity, and/or shared with other researchers and/or institutions for use in future 
research. 
 
Samples  
Samples (such as blood and/or tissue) are being collected from you as part of this 
study. Researchers at MD Anderson may use any leftover samples that are stored at 
MD Anderson in future research. Leftover samples stored by Celcuity, may be used in 


Protocol 2020-0198 
February 1, 2024 
Page 11 of 15 
 
future research. This is a required part of this study. Samples will not be sent to Novartis 
or Puma (other study supporters). 
 
Before being used or shared for future research, every effort will be made to remove 
your identifying information from any data and/or research samples. If all identifying 
information is removed, you will not be asked for additional permission before future 
research is performed. 
 
In some cases, all of your identifying information may not be removed before your data 
or research samples are used for future research. If future research is performed at MD 
Anderson, the researchers must get approval from the Institutional Review Board (IRB) 
of MD Anderson before your data and/or research samples can be used. At that time, 
the IRB will decide whether or not further permission from you is required. The IRB is a 
committee of doctors, researchers, and community members that is responsible for 
protecting study participants and making sure all research is safe and ethical. 
 
If this research is not performed at MD Anderson, MD Anderson will not have oversight 
of any data and/or samples. 
 
Genetic Research 
Samples collected from you as part of this study may be used for genetic research, 
which may include whole genome sequencing. Whole genome sequencing is a type of 
testing in which researchers study your entire genetic makeup (DNA). This may help 
researchers learn how changes in the ordering of genes may affect a disease or 
response to treatment. If genetic research is done with your samples, those who have 
access to those samples may be able to identify you. The results of this research may 
also be able to be linked to you. The same level of data protection that covers your 
individual data does not apply to summary results (when data from the whole study is 
combined). 
 
A federal law, called the Genetic Information Nondiscrimination Act (GINA), generally 
makes it illegal for health insurance companies, group health plans, and most employers 
to discriminate against you based on your genetic information. This law generally will 
protect you in the following ways: 
• Health insurance companies and group health plans may not request your 
genetic information that we get from this research. 
• Health insurance companies and group health plans may not use your genetic 
information when making decisions regarding your eligibility or premiums. 
• Employers with 15 or more employees may not use your genetic information that 
we get from this research when deciding to hire, promote, or fire you or when 
setting the terms of your employment. 
 
Be aware that this federal law does not protect you against genetic discrimination by 
companies that sell life insurance, disability insurance, or long-term care insurance. Nor 
does this federal law prohibit discrimination based on an already known genetic disease 
or disorder. 
 


Protocol 2020-0198 
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Conflict of Interest 
 
Outside relationships are disclosed to and approved by the Conflict of Interest 
Committee, which reviews these relationships for compliance with institutional policy. 
This review helps the IRB to assure that financial relationships do not have an impact on 
the conduct of this study. The following members of the study staff have disclosed 
compensation from the funding source(s) of this study: 
• Dr. Rachel Layman (Study Chair)  
• Dr. Azadeh Nasrazadani (Co-Investigator)  
 
Outside Care 
 
Part of your care may be provided outside of MD Anderson by your home doctor(s). 
 
Authorization for Use and Disclosure of Protected Health Information (PHI): 
 
A. During the course of this study, MD Anderson will be collecting and using your PHI 
(name, full date of birth, age, gender, biological samples, etc.), including identifying 
information, information from your medical record, and study results. For legal, ethical, 
research, and safety-related reasons, your doctor and the research team may share 
your PHI with: 
• Federal agencies that require reporting of clinical study data (such as the FDA, 
National Cancer Institute [NCI], and OHRP) 
• The IRB and officials of MD Anderson 
• Novartis and their authorized agents; Puma Biotechnology; and Celcuity, who are all   
sponsors or supporters of this study 
• Any future sponsors/supporters and/or licensee(s) of the study technology 
• Study monitors and auditors who verify the accuracy of the information 
• Individuals who put all the study information together in report form. 
• Governmental agencies in other countries where the study drug may be considered 
for approval. 
 
Study sponsors and/or supporters receive limited amounts of PHI. They may also view 
additional PHI in study records during the monitoring process. MD Anderson’s contracts 
require sponsors/supporters to protect this information and limit how they may use it. 
 
The results of this research may be published in scientific journals or presented at 
medical meetings, but your identity will not be disclosed. 
 
B. Signing this consent and authorization form is optional but you cannot take part in this 
study or receive study-related treatment if you do not agree and sign. 
 
C. MD Anderson will keep your PHI confidential when possible (according to state and 
federal law). However, in some situations, the FDA could be required to reveal the 
names of participants. 
 


Protocol 2020-0198 
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Once disclosed outside of MD Anderson, federal privacy laws may no longer protect 
your PHI. 
 
D. The permission to use your PHI will continue indefinitely unless you withdraw your 
authorization in writing. Instructions on how to do this can be found in the MD Anderson 
Notice of Privacy Practices (NPP) or you may contact the Chief Privacy Officer at 713-
745-6636. If you withdraw your authorization, you will be removed from the study and 
the data collected about you up to that point can be used and included in data analysis. 
However, no further information about you will be collected. 
 
 E. A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This Web site will not include information that can identify you. At 
most, the Web site will include a summary of the results. You can search this Web site 
at any time. 
 
 
 


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CONSENT/AUTHORIZATION 
I understand the information in this consent form.  I have had a chance to read the consent 
form for this study, or have had it read to me. I have had a chance to think about it, ask 
questions, and talk about it with others as needed. I give the study chair permission to 
enroll me on this study.  By signing this consent form, I am not giving up any of my legal 
rights. I will be given a signed copy of this consent document. 
 
________________________________________ 
_______ 
SIGNATURE OF PARTICIPANT 
DATE 
 
________________________________________ 
PRINTED NAME OF PARTICIPANT                 
 
WITNESS TO CONSENT 
I was present during the explanation of the research to be performed under Protocol 2020-
0198. 
 
_____________________________________________________  
_________ 
SIGNATURE OF WITNESS TO THE VERBAL CONSENT  
  
DATE  
PRESENTATION (OTHER THAN PHYSICIAN OR STUDY CHAIR) 
A witness signature is only required for non-English speakers utilizing the  
short form consent process (VTPS) and patients who are illiterate. 
 
 
PRINTED NAME OF WITNESS TO THE VERBAL CONSENT 
 
PERSON OBTAINING CONSENT 
I have discussed this research study with the participant and/or his or her authorized 
representative, using language that is understandable and appropriate.  I believe that I 
have fully informed this participant of the nature of this study and its possible benefits and 
risks and that the participant understood this explanation. 
 
______________________________________________ 
  
_________ 
PERSON OBTAINING CONSENT  
 
 
 
 
 
DATE 
 
______________________________________________ 
PRINTED NAME OF PERSON OBTAINING CONSENT 
 


Protocol 2020-0198 
February 1, 2024 
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TRANSLATOR 
I have translated the above informed consent as written (without additions or subtractions) 
into 
and assisted the people 
(Name of Language) 
obtaining and providing consent by translating all questions and responses during the 
consent process for this participant. 
 
_____________________       _______________________________    
___________ 
NAME OF TRANSLATOR       SIGNATURE OF TRANSLATOR 
 DATE 
 
   Please check here if the translator was a member of the research team.  (If checked, a 
witness, other than the translator, must sign the witness line below.)