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| Official Title   | AN OPEN-LABEL, PHASE 2 BASKET STUDY OF NERATINIB IN  PATIENTS WITH SOLID TUMORS WITH SOMATIC ACTIVATING  HER MUTATIONS   |
|------------------|--------------------------------------------------------------------------------------------------------------------------|
| NCT Number       | NCT01953926                                                                                                              |
| Version Date     | 03-FEB-2021                                                                                                              |
an open-label phase 2 basket
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Solid Tumors With Somatic Activating Her **Mutations**  
Study Protocol Number: PUMA-NER-5201 Disease Condition: Solid tumors harboring somatic HER mutations Sponsor's Investigational Product Name/Formulation: Neratinib Tablets US IND Number 107931  
| Sponsor's Investigational Product  US IND Number   | 107931         |
|----------------------------------------------------|----------------|
| EudraCT Number                                     | 2013-002872-42 |
| Lead Investigators:                                |                |  
Lead Investigators:  
  
Sponsor: Puma Biotechnology, Inc.  
10880 Wilshire Blvd, Suite 2150 Los Angeles, CA 90024 Phone: +1 424.248.6500 Fax: +1 424.248.6501 Sponsor's Medical Contacts:  
  
Date of Protocol Original 08-JUL-2013  
Amendment 1 07-NOV-2013 Amendment 2 02-APR-2014 Amendment 3 17-MAR-2015 Amendment 4 20-MAY-2016 Amendment A4.1 (France) 27-FEB-2017 Amendment 5 04-OCT-2017  
Amendment A5.1 (France) 26-MAR-2018  
Amendment A5.2 (FLC, select sites) 20-APR-2018 Amendment 6 21-JAN-2020 Amendment A6.1 (France) 20-APR-2020 Amendment 7 03-FEB-2021  
This document contains confidential information of Puma Biotechnology, Inc. This document must not be disclosed to anyone other than the study staff and members of the Independent Ethics Committee/Institutional Review Board. The information in this document cannot be used for any purpose other than the evaluation or conduct of the clinical investigation without the prior written consent of Puma Biotechnology Inc.
an open-label phase 2 basket
disclosure statement

This document contains information that is confidential and proprietary to the Sponsor. This information is being provided to you solely for the purpose of evaluating and/or conducting a clinical study for the Sponsor. You may disclose the contents of this document only to study personnel under your supervision, institutional review boards (IRBs)/independent ethics committees (IECs), or duly authorized representatives of regulatory agencies for this purpose under the condition that they maintain confidentiality. The contents of this document should not be used in any other clinical study, disclosed to any other person or entity, or published without the prior written permission of the Sponsor. The foregoing shall not apply to disclosure required by any regulations; however, you will give prompt notice to the Sponsor of any such disclosure. All other nonpublic information provided by the Sponsor, as well as any information that may be added to this document, also is confidential and proprietary to the Sponsor and must be kept in confidence in the same manner as the contents of this document.
an open-label phase 2 basket
protocol synopsis

Title: An open-label, Phase 2 basket study of neratinib in patients with solid tumors with somatic activating HER
mutations Condition or Disease: Solid tumors harboring somatic activating HER mutations  
| Approximate Values   |     |                                   |            |
|----------------------|-----|-----------------------------------|------------|
| Number of Patients   | 650 | Duration of Patient Participation | 18 months  |
| Number of Centers    | 90  | Duration of study                 | 102 months |
| Objectives:          |     |                                   |            |  
Objectives: The objectives of this study, applicable to each cohort, are:
For the randomized hormone receptor positive (HR+), *HER2* **negative metastatic breast cancer:** Primary:
- To determine the confirmed objective response rate (ORR) by independent central review according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 Secondary:
- To determine the confirmed ORR by investigator - To determine the duration of response (DOR) by both independent central review and investigator
- To determine the clinical benefit rate (CBR) by both independent central review and investigator
- To determine the progression-free survival (PFS) by both independent central review and investigator For the metastatic cervical cancer cohort: Primary:
- To determine the confirmed ORR by independent central review according to RECIST v1.1 Secondary:
- To determine the confirmed ORR by investigator - To determine the DOR by both independent central review and investigator
- To determine the CBR by both independent central review and investigator
- To determine the PFS by both independent central review and investigator
- To determine overall survival (OS)
For all other cohorts:
an open-label phase 2 basket
primary

- To determine the first objective response rate (ORRfirst) by investigator at the first post-baseline tumor assessment Secondary:
- To determine the confirmed ORR by investigator - To determine the DOR by investigator - To determine the CBR by investigator - To determine the PFS by investigator - To determine OS
an open-label phase 2 basket
safety objectives

For all cohorts, including the randomized HR+, *HER2* negative metastatic breast cancer and metastatic cervical cancer cohorts:
- To assess the safety profile and tolerability of study treatments
- To assess Patient Reported Outcomes (PRO)
Exploratory: The exploratory objectives of this study are:
- To collect and retrospectively evaluate somatic mutations or gene aberrations using next-generation sequencing (NGS) in the most recent pretreatment tumor biopsy or fresh tumor tissue biopsies at a central laboratory.  
- To explore genetic modifiers of sensitivity and/or resistance to neratinib using molecular profiling techniques in pretreatment archival and/or fresh tumor specimens and paired normal whole blood.  
- To evaluate cell-free DNA (cfDNA) from plasma specimens collected at baseline/screening, during the course of treatment, and upon disease progression to identify *HER2* and *EGFR* mutations and other gene aberrations and to assess any potential associations with neratinib sensitivity and/or primary/acquired resistance to neratinib or neratinib-containing therapy.  
- To evaluate potential genes or protein biomarkers that may be reported to confer neratinib sensitivity and/or primary/acquired resistance to neratinib or neratinib-containing therapy from *optional* fresh core tumor biopsies during time of treatment and/or at the time of treatment discontinuation or disease progression.
an open-label phase 2 basket
study design

This is an open-label, multicenter, multinational, Phase 2 study exploring the efficacy and safety of neratinib as monotherapy or in combination with other therapies in patients with HER (EGFR, *HER2*) mutation-positive solid tumors. Patients with tumors harboring somatic mutations in HER will be identified through previously documented mutation testing performed prior to screening. The presence of human HER mutations (*EGFR*,
HER2) will be retrospectively confirmed by central testing via next generation sequencing (NGS). The study has a basket design and includes several cohorts, either defined by an actionable somatic mutation or by actionable mutation and tumor histology (for example *HER2* mutant cervical cancer). In the course of the study, enrollment in certain cohorts can be completed and enrollment in new cohorts initiated to test the anticancer effect of neratinib in other histologies, specific molecular abnormalities, and/or in combination with other drugs.  
Patients with *HER2* mutant, *HER2* negative breast cancer will be divided into different treatment cohorts on the basis of HR status: HR negative (Triple Negative Breast Cancer [TNBC]) and HR+.  
- Patients in the HR negative breast cancer cohort (TNBC) will receive neratinib in combination with trastuzumab.  
- Patients in the HR+, *HER2* negative, *HER2* mutant breast cancer cohort with RECIST measurable tumors and who have been previously been treated with CDK4/6 inhibitors (CDK4/6i) will be randomized to receive single agent fulvestrant, fulvestrant in combination with trastuzumab, or neratinib in combination with trastuzumab and fulvestrant with a randomization ratio of 1:1:1. Randomization will be stratified by the number of lines of prior therapy for metastatic disease (≤ 2 and >2 lines) and by prior fulvestrant therapy.  
The randomized HR-positive (HR +), *HER2* negative, *HER2* mutant metastatic breast cancer cohort is designed to investigate the individual contribution of neratinib and/or trastuzumab to fulvestrant via Simon's 2 stage optimal design. The decision to carry over on enrollment of each arm in the cohort will be based on stage I and II analysis of Simon's 2 stage in consultation with the Independent Data Monitoring Committee (IDMC).  
o Patients in the HR+ cohort who receive single agent fulvestrant or fulvestrant plus trastuzumab will be eligible for triplet therapy (neratinib, fulvestrant, trastuzumab) upon progression. Patients who have unequivocal evidence of disease progression as documented by imaging, clinical examination, or disease related symptoms before the first scan post-treatment are eligible for the triplet therapy. Efficacy will be determined based on response to initial regimen only.  
- Patients in the HR+ breast cancer cohort who have not received prior CDK4/6i therapy (eg. CDK4/6i naïve) will receive neratinib in combination with trastuzumab and fulvestrant as part of an open label cohort.  
The trial will consist of a screening period, a treatment period, and a follow-up period after the study therapy is discontinued for any reason. An end of treatment (EOT) assessment is performed 28 days (+14 days) after the last dose of investigational product(s) and adverse events are collected 28 days after the last dose of investigational product(s). Neratinib will be administered orally with food once daily (recommended to be taken in the morning), on a continuous basis. Dose delays and modifications will be handled as per instructions in the package insert. All patients taking neratinib will maintain a patient diary for the study to record each dose of neratinib taken and while receiving antidiarrheal prophylaxis with loperamide taken for the first two cycles of treatment. For cohorts receiving combination treatment that includes trastuzumab, post-treatment radiographic evaluation of their disease will be conducted every 3 cycles. For all other cohorts, post-treatment disease assessment will be conducted every 2 cycles. Treatment should be administered until there is unequivocal evidence of disease progression as documented by imaging, clinical examination, or disease-related symptoms. Tumor markers or circulating tumor cells should not be used as the sole criteria for determining progression. At the time of decision regarding disease progression, radiological exam should be performed. Patients will continue study treatment until disease progression, unacceptable toxicity, patient withdrawal of consent, or death. Patients who develop disease progression, but in the opinion of the Investigator would still benefit from continuing study, may continue per-protocol therapy if approved by the Sponsor. Survival follow-up will be every 12 weeks after treatment discontinuation. Enrollment will continue as dictated by the Simon's 2-stage design in all the histology and mutation specific cohorts and/or up to 30 patients per cohort in multi-cancer, mutation specific NOS cohorts. Enrollment in the randomized breast cancer, non-randomized breast cancer and cervical cancer cohorts will also continue as dictated by the Simon's 2-stage design up to 50 patients per cohort.  
| Randomized Breast Cancer Cohort Cohort Mutation   | Randomized Treatment                                                           | Sample Size (#                                                                 |
|---------------------------------------------------|--------------------------------------------------------------------------------|--------------------------------------------------------------------------------|
| Tumor                                             | subjects) Up to 18                                                             |                                                                                |
| -                                                 | Fulvestrant: 500 mg on Study Day 1, 15, and 29;  once every 28 days thereafter |                                                                                |
| Or                                                | -                                                                              | Fulvestrant: 500 mg on Study Day 1, 15, and 29;  once every 28 days thereafter |
| -                                                 | Trastuzumab: 8 mg/kg IV followed by 6 mg/kg IV  every 3 weeks                  |                                                                                |
| Or                                                | -                                                                              | Neratinib: 240 mg daily                                                        |
| -                                                 | Fulvestrant: 500 mg on Study Day 1, 15, and 29;  once every 28 days thereafter |                                                                                |
| -                                                 | Trastuzumab: 8 mg/kg IV followed by 6 mg/kg IV  every 3 weeks                  | Up to 18                                                                       |
| Breast                                            |                                                                                |                                                                                |
| HR Positive  (with prior  CDK4/6i)                | HER2  mutant                                                                   | Up to 50                                                                       |
an open-label phase 2 basket
tumor cohorts open to enrollment

| Cohort                        | Mutation                                                                      | Assigned Treatment   | Cohort Sample   |
|-------------------------------|-------------------------------------------------------------------------------|----------------------|-----------------|
| Tumor                         | Size (# subjects)                                                             |                      |                 |
| -                             | Neratinib: 240 mg daily                                                       |                      |                 |
| -                             | Fulvestrant: 500 mg on Study Day 1, 15, and 29; once every 28 days thereafter |                      |                 |
| -                             | Trastuzumab: 8 mg/kg IV followed by 6 mg/kg IV every 3 weeks                  |                      |                 |
| Breast                        |                                                                               |                      |                 |
| HR Positive  (CDK4/6i  naïve) | HER2  mutant                                                                  | Up to 50             |                 |
| Breast                        |                                                                               |                      |                 |
| TNBC (HR  Negative)           | - Neratinib: 240 mg daily - Trastuzumab: 8 mg/kg IV followed by 6 mg/kg IV    | Up to 50             |                 |
| every 3 weeks                 |                                                                               |                      |                 |
| HER2 mutant                   |                                                                               |                      |                 |  
Non-randomized Breast Cancer Cohorts Cervical Cancer Cohort  
| Cohort   | Mutation          | Assigned Treatment        | Cohort Sample   |
|----------|-------------------|---------------------------|-----------------|
| Tumor    | Size (# subjects) |                           |                 |
| Cervical | HER2 mutant       | - Neratinib: 240 mg daily | 50              |  
Cohorts Not Receiving Trastuzumab  
| Tumor Cohort                                      | Mutation                | Assigned Treatment        |
|---------------------------------------------------|-------------------------|---------------------------|
| Salivary Gland                                    | HER2 mutant             | - Neratinib: 240 mg daily |
| Non-small Cell Lung                               | EGFR exon 18  mutations | - Neratinib: 240 mg daily |
| Tumor Cohorts Closed to Enrollment in Amendment 7 |                         |                           |  
The following cohorts were closed to enrollment in Amendment 7: solid tumors (NOS) *HER2* mutant monotherapy and bladder/urinary *HER2* mutant combination therapy of neratinib + paclitaxel.
an open-label phase 2 basket
investigational product dose and administration

- Neratinib: Patients will receive six 40-mg tablets (total daily dose 240 mg) administered orally, once daily with food (recommended to be taken in the morning), continuously.  
- Fulvestrant: Patients will receive 500 mg total dose administered as two 5 mL injections, by intramuscular injection, one in each buttock on Days 1, 15, and 29; then once every 4 weeks thereafter; see fulvestrant package insert and Schedule of Procedures.  
- Trastuzumab: Patients will receive an initial dose of 8 mg/kg of trastuzumab intravenously (IV)
administered on Cycle 1 Day 1 (C1D1), followed by 6 mg/kg IV once every 3 weeks thereafter; see Herceptin (trastuzumab) package insert and Schedule of Procedures.
an open-label phase 2 basket
study population inclusion criteria for

Each patient will be entered into this study only if she/he meets all of these criteria:  
1. Men and women who are ≥18 years old at signing of informed consent.  
2. At the time of screening, histologically confirmed cancers in patients with previously documented activating *EGFR (exon 18)* or qualifying *HER2* mutation confirmed by a Clinical Laboratory Improvement Amendments (CLIA)-certified or equivalent laboratory, and who are refractory to standard therapy or for which standard or curative therapy does not exist or is not considered sufficient or appropriate 3. At least one measurable lesion, as defined by Response Evaluation Criteria in Solid Tumors version 1.1
(RECIST v1.1; Eisenhauer et al, 2009).  
4. Left ventricular ejection fraction (LVEF) ≥50% measured by multiple-gated acquisition scan (MUGA) or echocardiogram (ECHO).  
5. Eastern Cooperative Oncology Group (ECOG) status of 0 to 2.  
6. Female patients with cancers known to secrete β-human chorionic gonadotropin (hCG), ie germinomas, are eligible if the pattern of serum β-hCG is suggestive of the malignancy and the pelvic ultrasound is negative for pregnancy.  
7. Male patients must agree and commit to use a barrier method of contraception while on treatment and for 3 months after the last dose of trastuzumab, fulvestrant, or neratinib monotherapy. Patients of childbearing potential must agree and commit to the use of a highly effective double-barrier method of contraception (eg, a combination of male condom with an intravaginal device such as the cervical cap, diaphragm, or vaginal sponge with spermicide) or a non-hormonal method, from the signing of the informed consent until:
i. 28 days after the last dose of neratinib monotherapy, or ii. 7 months after last dose of trastuzumab or iii. 1 year after the last dose of fulvestrant.
8. Provide written, informed consent to participate in the study and follow the study procedures. 9. Agree to provide most recent metastatic tumor sample or fresh tumor biopsy, and plasma/blood specimens for gene sequencing and other biomarker analysis.  
Additional Inclusion Criteria for all Breast Cancer Patients that Harbor *HER2* Mutations and NCSLC Patients that Harbor *EGFR* exon 18 Mutations 10. Must provide a pretreatment fresh biopsy within 28 days prior to starting treatment unless the biopsy procedure presents a safety concern for the patient as determined by the Investigator, or other exceptional reason upon agreement with the Sponsor Additional Inclusion Criteria for HR+ Breast Cancer Patients with Tumors that Harbor *HER2* Mutations 11. HR+ disease defined as ≥1% estrogen receptor (ER) positive and/or progesterone receptor (PR) positive cells (performed on the most recent biopsy as assessed locally and consistent with current American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) or European Society of Medical Oncology (ESMO) guidelines):
12. Biopsy from a non-bony metastatic site: preferred, or a. Biopsy from bony metastasis or if the sample is considered inadequate or unavailable:
assessment of HR status will be at the Investigator's discretion.  
13. Postmenopausal, as defined by at least one of the following criteria:
a. Age ≥60 years; b. Age <60 years and cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; and serum estradiol and follicle stimulating hormone (FSH) level within the laboratory's reference range for postmenopausal females; c. Documented bilateral oophorectomy, 14. Medically confirmed ovarian failure OR
15. Pre/perimenopausal, ie, not meeting the criteria for being postmenopausal:
a. Pre/perimenopausal women can be enrolled if amenable to be treated with a luteinizing hormone receptor hormone (LHRH) agonist. Patients must have commenced treatment with an LHRH agonist at least 4 weeks prior to the first dose of neratinib.  
16. Prior treatment with chemotherapy or hormonal therapy (including fulvestrant).  
Exclusion Criteria for All Patients A patient will be excluded from this study if she/he meets any of these criteria:  
1. Patients harboring ineligible somatic *HER2* mutations, such as those that are subclonal in nature or those resulting in the expression of truncated proteins including alterations that result in premature stop codon or a change in reading frame (ie, frame shift mutations).  
2. Prior treatment with any pan-HER, HER2-, or *EGFR* tyrosine kinase inhibitor (TKI) (eg, lapatinib, afatinib, dacomitinib, neratinib, tucatinib, poziotinib, gefitinib, erlotinib, osimertinib) is excluded with the following exception: patients with *EGFR* exon 18 mutated non-small cell lung cancer (NSCLC) who may have received afatinib, osimertinib, or other pan-HER or *EGFR* TKIs remain eligible.  
3. Not recovered to at least Grade 1 at screening (Common Terminology Criteria for Adverse Events v4.0
[CTCAE v4.0]) from all clinically significant adverse events related to prior therapies (excluding alopecia).  
4. Received chemotherapy or biologic therapy ≤2 weeks or 5 half-lives (t½) of the agent used, whichever is shorter, prior to the initiation of investigational product.  
5. Received radiation therapy ≤14 days prior to initiation of investigational product. 6. Patients who are receiving any other anticancer agents with the exception of patients on 1) a stable dose of bisphosphonates or denosumab or 2) sex hormone therapy in the case of breast, or gynecological cancers.  
7. Received prior therapy resulting in a cumulative epirubicin dose >900 mg/m2 or cumulative doxorubicin dose >450 mg/m2. If another anthracycline or more than one anthracycline has been used, the cumulative dose must not exceed the equivalent of 450 mg/m2 doxorubicin.  
8. Symptomatic or unstable brain metastases. (Note: Asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for at least 14 days are eligible to participate in the study.)
9. Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of ≥2), unstable angina (symptomatic angina pectoris within the past 180 days that required the initiation of or increase in anti-anginal medication or other intervention), myocardial infarction within 12 months of enrollment, or ventricular arrhythmia (except for benign premature ventricular contractions).  
10. Demonstrates a QTc interval >450 ms for men or >470 ms for women or known history of congenital QT-prolongation or Torsade de pointes (TdP).  
11. Inadequate bone marrow, renal or hepatic function as defined on screening laboratory assessments outside the following limits:
Laboratory Assessments Endpoints  
| Laboratory endpoint                   | Required limit for exclusion                                                                             |
|---------------------------------------|----------------------------------------------------------------------------------------------------------|
| Absolute neutrophil count (ANC)       | <1,000/µL (1.0 x 109 /L)                                                                                 |
| Platelet count                        | <100,000/µL (<100 x 109 /L)                                                                              |
| Hemoglobin                            | <8 g/dL (transfusion allowed to treat low hemoglobin) Transfusion must be at least 7 days prior to C1D1. |
| Total bilirubin                       | >1.5 x institutional upper limit of normal (ULN) (in case of known  Gilbert's syndrome, >2x ULN)         |
| Aspartate aminotransferase (AST)      | >3 x institutional ULN                                                                                   |
| and/or alanine aminotransferase (ALT) | OR >5 x ULN if liver metastases are present                                                              |  
Creatinine >1.5 x institutional ULN  
OR Calculated Creatinine Clearance <30 mL/min (as measured directly  
with a 24-hour urine or calculated by Cockcroft-Gault formula a or Modification of Diet in Renal Disease [MDRD] formula b)  
a Cockcroft and Gault, 1976.  
b Levey et al, 1999.  
12. Active infection or unexplained fever >38.5°C (101.3°F).  
13. Women who are pregnant, are planning on becoming pregnant, or are breast-feeding. 14. Significant chronic gastrointestinal disorder with diarrhea as a major symptom (eg, Crohn's disease,  
malabsorption, or Grade ≥2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events Version 4.0 [CTCAE version 4.0] diarrhea of any etiology at baseline.  
15. Clinically active infection with a hepatitis virus.  
16. Evidence of significant medical illness, abnormal laboratory finding, or psychiatric illness/social  
situations that could, in the Investigator's judgment, make the patient inappropriate for this study.  
17. Known hypersensitivity to any component of the investigational product, required combination therapy,  
or loperamide.  
18. Unable or unwilling to swallow tablets.  
19. Patients with known activating *KRAS* mutations.  
Additional Exclusion Criteria for Patients with Breast Cancer With *HER2* Mutations  
20. Patients with known *HER2*+ tumors (protein overexpression or gene amplification as defined by  
ASCO/CAP guidelines or HER2 amplifications as determined by copy number alterations by NGS) are excluded.  
Additional Exclusion Criteria for Patients With *HER2* Mutations Treated With Trastuzumab Combination Therapy or Being Randomized into HR+ Breast Cancer Cohorts  
21. Hypersensitivity to trastuzumab, murine proteins or any of the excipients listed in the Herceptin label. 22. Severe dyspnea at rest due to complications of advanced malignancy or requiring supplementary oxygen  
therapy
an open-label phase 2 basket
efficacy assessments

For cohorts receiving combination treatment that includes trastuzumab, post-treatment disease assessment by CT
or magnetic resonance imaging (MRI) will be conducted at the beginning of Week 10 (ORRfirst), and every 3 cycles (± 7 days) thereafter (see Schedule of Procedures, Appendix 1 Table A1.1). For all other cohorts not receiving trastuzumab, post-treatment disease assessment will be conducted at the beginning of Week 9 (ORRfirst),
and every 2 cycles (± 7 days) thereafter (see Schedule of Procedures, Appendix 1 Table A1.2). Complete or partial response (CR or PR) must be confirmed with a repeat scan performed no sooner than 4 weeks after the criteria for response are first met. In cases where the subject discontinues treatment for reasons other than progressive disease (eg., adverse event, patient choice, noncompliance, etc.) and the response is either CR or PR,
then a confirmation scan is required no sooner than 4 weeks after the criteria of response is met. Radiological response is assessed by RECIST v1.1. Following one year on therapy, scans may move to every 4 cycles for trastuzumab-containing regimens and every 3 cycles for non-trastuzumab containing regimens. Following two years on therapy, scans may move to every 5 cycles for trastuzumab-containing regimens and every 4 cycles for non-trastuzumab-containing regimens.
an open-label phase 2 basket
safety assessments

Patients receiving at least one dose of the investigational products will be evaluable for safety. Safety will be assessed based on medical history, vital sign measurements, physical examination findings, electrocardiogram (ECG) results, cohort specific MUGA or ECHO, laboratory assessments, and adverse events.  
Adverse events will be graded according to the National Cancer Institute Common Terminology Criteria (NCI CTC) version 4.0. Adverse events and serious adverse events will be reported until 28 days after the last dose of investigational product(s) and will be followed until resolution or until condition stabilizes.  
Should an Investigator be made aware of any serious adverse events occurring any time after the reporting period that may be causally related to the administration of neratinib, it should be promptly reported. In addition to cardiac evaluations conducted during the study, patients who are receiving trastuzumab are required to be followed-up for potential cardiac toxicity (as assessed by MUGA or ECHO scans, see Schedule of Procedures, Appendix 1 Table A1.1 and Table A1.2) every 6 months and up to 24 months after the last dose of trastuzumab.
an open-label phase 2 basket
other assessments

The most recent metastatic tumor tissue will be obtained for all patients and banked by the sponsor for retrospective centralized confirmation of somatic mutations in the ERBB gene family (EGFR, *HER2*). This tumor sample should preferably be from the specimens used to detect the initial mutation prior to study enrollment. For patients that do not have an archived tumor tissue, a fresh biopsy will be obtained if medically feasible. For all breast cancer cohorts and NSCLC exon 18 mutations cohort, a fresh pretreatment tumor biopsy collection is mandated unless the biopsy procedure presents a safety concern for the patient. Whole blood for germline DNA analysis will be collected once at screening. Cell-free DNA will be obtained from plasma samples collected at screening, on-treatment in accordance with the Schedule of Procedures (Schedule of Procedures, Appendix 1 Table A1.1 and Table A1.2), and at the time of treatment discontinuation; cfDNA will be subject to molecular profiling to identify *HER2* and *EGFR* mutations and other gene aberrations related to treatment response and resistance.  
Health-related Quality of Life Assessment The following patient-reported outcomes will be assessed for all patients: the FACT-G questionnaire. Patient-reported outcome assessments will be collected at screening, and at the beginning of each cycle for up to 6 months or EOT, whichever comes first.
an open-label phase 2 basket
statistical methods sample size justification

A Simon's 2-stage optimal design (Simon, 1989) will be used to determine whether there is sufficient activity to warrant further development of the therapy and to minimize the number of patients exposed to therapy if ineffective. For each treatment arm, using Simon's 2-stage optimal design (with significance level 10% and power of 80%), an ORR (confirmed) of 10% or less per RECIST by independent assessment will be considered unacceptable (null hypothesis) whereas an ORR (confirmed) of 30% per RECIST by independent assessment will merit further study (alternative hypothesis). In the first stage, 7 patients are enrolled in each treatment arm. If at least 1 response is observed in the first stage, the second stage will be opened. In the second stage, 11 additional response evaluable patients will be accrued and randomized for a total of 18 patients in the treatment arm. The null hypothesis will be rejected (for each arm separately) if at least 4 responses are observed in Stage 2 for each arm. Once the Simon's 2-stage criteria are met, enrollment of the neratinib arm may continue until up to 50 patients have been enrolled.
an open-label phase 2 basket
sample size justification for all

A Simon's 2-stage optimal design (Simon, 1989) will be used to determine whether neratinib monotherapy has sufficient activity to warrant further development in the following cohorts: cervical, salivary gland, and *EGFR*
exon 18 non-small cell lung cancers. A similar Simon's 2-stage design will be used to determine whether neratinib combination therapy has sufficient activity to warrant further development in the following cohorts:
HR+ and CDK4/6i naïve and TNBC. Early study termination will be permitted if data at the first stage indicate that the treatment is ineffective. For each cohort, using Simon's optimal 2-stage design (with significance level 10% and power of 80%), an ORRfirst of 10% or less will be considered unacceptable (null hypothesis) whereas an ORRfirst of 30% will merit further study (alternative hypothesis). In the first stage, enrollment will continue until 7 patients received at least one dose of study treatment and completed the first tumor assessment by the investigator (response evaluable). If no responses are observed, the second stage for the cohort must be discontinued. Otherwise 11 additional response evaluable patients will be accrued for a total of 18 patients in the cohort. The null hypothesis will be rejected (for each cohort separately) if at least 4 responses are observed in Stage 2 for each cohort. Once the Simon's 2-stage criteria are met, enrollment into the salivary gland and *EGFR* exon 18 mutant NSCLC cohorts may continue until up to 30 patients; and the enrollment into the cervical, HR+ CDK4/6i naïve, and TNBC cohorts may continue up to 50 patients. A new cohort may also be opened separately at any time per Sponsor discretion and follow the Simon's 2-stage criteria. Cohorts may close prior to planned enrollment.
an open-label phase 2 basket
statistical analysis

In general, efficacy and safety analyses in this study are cohort-specific and will be summarized by monotherapy and combination therapy separately. Safety analyses will also be summarized across some cohorts where appropriate. Integrated analysis of HR+ metastatic breast cancer patients receiving neratinib, fulvestrant, and trastuzumab from either the randomized cohort or the original cohort will be performed. Categorical variables will be summarized using counts and percentages. Percentages will be displayed to 1 place after the decimal point (xx.x), with the exception of 100%, which will be displayed without additional decimal places. Continuous variables will be summarized using number of patients, mean, standard deviation, median, Q1, Q3, minimum, and maximum.  
The binary endpoints (eg, ORRfirst, ORR, CBR) will be estimated and its associated two-sided 95% ClopperPearson confidence intervals will be determined.  
Time to event endpoint (eg, PFS, OS, DOR) will be estimated via Kaplan-Meier with its associated two-sided 95% confidence intervals. Patient-reported outcomes will be summarized and plotted over time. Changes from baseline will be provided with both point estimates and confidence intervals.
an open-label phase 2 basket
safety

All patients who receive at least one dose of the investigational product will be analyzed for safety by cohort and across some cohorts where appropriate. Safety endpoints will be summarized descriptively for vital signs, adverse events, laboratory tests, and ECG. Serious adverse events, deaths, and patients discontinued from study treatment will be listed. The IDMC will oversee the safety of patients during the study.
an open-label phase 2 basket
interim analysis

Interim analyses may be performed at the completion of each stage for cohorts with a Simon's 2-stage design and for other cohorts as necessary. An IDMC will be established to regularly review accumulating safety data and efficacy data throughout the study.
an open-label phase 2 basket
primary analysis

The primary analysis will be performed when all enrolled patients have been followed for at least 6 months or when all responses have had a chance to be confirmed.
table of contents
primary analysis

| STUDY CONTACTS 2 PROTOCOL SYNOPSIS 3 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 18 1. INTRODUCTION 21 1.1. The Epidermal Growth Factor Receptor (ERBB) Family 21 1.1.1. Somatic Mutations in ERBB2 21 1.1.2. Somatic EGFR Exon 18 Mutations in Lung Cancer 23 1.2. Neratinib as a Cancer Therapy That Targets ERBB Receptors 25 1.2.1. Neratinib, An Irreversible Inhibitor of EGFR, ERBB2, and ERBB4 Receptor  Tyrosine Kinases 25 1.2.2. Neratinib Treatment for ERBB2 Mutant Solid Tumors 25 1.2.3. Neratinib Treatment for EGFR Exon 18 Mutations in Lung Cancer 26 1.3. Neratinib Phase 1 and Pharmacokinetic Data 26 1.4. Adverse Event Profile of Neratinib Monotherapy 28 1.5. Rationale for Proposed Combination Therapies with Neratinib in Select  Cohorts 29 1.5.1. Rationale for Treatment With Neratinib Combined With Fulvestrant in  HER2 Mutant Breast Cancer 29 1.5.1.1. Adverse Event Profile of Combination Therapy of Neratinib and Fulvestrant 31 1.5.2. Rationale for Treatment With Neratinib Combined With Trastuzumab in  ERBB2 Mutant Breast Cancer 32 1.5.3. Adverse Event Profile of Combination Therapy of Neratinib and  Trastuzumab 33 1.6. Rationale for Treatment with Neratinib Monotherapy in EGFR Exon 18  Mutant Lung Cancer 34 2. STUDY OBJECTIVES 36 2.1. Primary Objectives 36 2.2. Secondary Objectives 36 2.3. Exploratory Objectives 37 3. OVERALL DESIGN AND PLAN OF THE STUDY 38 3.1. Study Design 38 3.2. Randomization and Blinding 41   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| Neratinib Tablets (PB-272)   | 03-FEB-2021                                             |              |
|------------------------------|---------------------------------------------------------|--------------|
| PUMA-NER-5201                | AMENDMENT 7                                             |              |
| 4.                           | STUDY POPULATION 42                                     |              |
| 4.1.                         | Inclusion Criteria 42                                   |              |
| 4.2.                         | Exclusion Criteria 43                                   |              |
| 4.3.                         | Patient Enrollment 45                                   |              |
| 4.4.                         | Cohort Assignment 46                                    |              |
| 5.                           | INVESTIGATIONAL PRODUCT AND ADMINISTRATION 47           |              |
| 5.1.                         | Investigational Product Administration 47               |              |
| 5.1.1.                       | Neratinib 47                                            |              |
| 5.1.2.                       | Fulvestrant 47                                          |              |
| 5.1.3.                       | Trastuzumab 48                                          |              |
| 5.2.                         | Investigational Product Dose Adjustment for Toxicity 48 |              |
| 5.3.                         | Packaging, Labeling and Storage 53                      |              |
| 5.3.1.                       | Neratinib 53                                            |              |
| 5.3.2.                       | Fulvestrant 53                                          |              |
| 5.3.3.                       | Trastuzumab 54                                          |              |
| 5.4.                         | Drug Accountability 54                                  |              |
| 6.                           | CONCOMITANT TREATMENT 55                                |              |
| 6.1.                         | Required Concomitant Treatment 55                       |              |
| 6.1.1.                       | Loperamide 55                                           |              |
| 6.1.2.                       | Loperamide Dose Adjustment 56                           |              |
| 6.1.2.1.                     | Loperamide Antidiarrheal Therapy 56                     |              |
| 6.2.                         | Permitted Concomitant Treatment 59                      |              |
| 6.3.                         | Prohibited Concomitant Treatment 59                     |              |
| 6.4.                         | Potential for Drug-Drug Interactions 60                 |              |
| 7.                           | STUDY ASSESSMENTS 61                                    |              |
| 7.1.                         | Efficacy Assessments 61                                 |              |
| 7.1.1.                       | Tumor Assessments 61                                    |              |
| 7.1.1.1.                     | General Information 61                                  |              |
| 7.1.1.2.                     | Radiographic/Imaging Evaluations 62                     |              |
| 7.1.2.                       | Tumor Assessments - Clinical 62                         |              |
| 7.1.3.                       | Quality of Life Assessments 63                          |              |
| 7.1.4.                       | ECOG Performance Status 63                              |              |
| 7.2.                         | Safety Assessments 63                                   |              |
| Puma Biotechnology           | Page 13 of 120                                          | CONFIDENTIAL |  
| Neratinib Tablets (PB-272)   | 03-FEB-2021                                                                                             |
|------------------------------|---------------------------------------------------------------------------------------------------------|
| PUMA-NER-5201                | AMENDMENT 7                                                                                             |
| 7.2.1.                       | Laboratory Assessments 63                                                                               |
| 7.2.2.                       | Vital Signs 64                                                                                          |
| 7.2.3.                       | Physical Examinations 65                                                                                |
| 7.2.4.                       | Electrocardiograms 65                                                                                   |
| 7.2.5.                       | Left Ventricular Ejection Fraction (LVEF) 65                                                            |
| 7.2.6.                       | Archival and Fresh Tumor Tissue, Whole Blood (for Germline DNA), and  Plasma Collection 65              |
| 7.3.                         | Protocol Deviations 66                                                                                  |
| 7.4.                         | Patient Diary 66                                                                                        |
| 8.                           | STUDY CONDUCT 67                                                                                        |
| 8.1.                         | Informed Consent 67                                                                                     |
| 8.2.                         | Screening All Cohorts 67                                                                                |
| 8.2.1.                       | Active Treatment Stage 68                                                                               |
| 8.2.2.                       | End of Treatment Visit for All Cohorts 69                                                               |
| 8.3.                         | Long-term Follow-up for All Cohorts 69                                                                  |
| 8.4.                         | End of Study 70                                                                                         |
| 9.                           | PATIENT WITHDRAWAL AND REPLACEMENT 71                                                                   |
| 9.1.                         | Investigational Product Discontinuation 71                                                              |
| 9.2.                         | Withdrawal from the Study 71                                                                            |
| 9.3.                         | Procedures for Investigational Product Discontinuation/Study Withdrawal 72                              |
| 10.                          | PREMATURE TERMINATION OF THE STUDY 73                                                                   |
| 11.                          | STATISTICAL METHODS 74                                                                                  |
| 11.1.                        | Sample Size Justification 74                                                                            |
| 11.1.1.                      | Sample Size Justification for the Randomized HR+ and with Prior CDK4/6i  Breast Cancer Study Cohort: 74 |
| 11.1.2.                      | Sample Size Justification for All Other Cohorts: 74                                                     |
| 11.2.                        | Statistical Analyses 75                                                                                 |
| 11.2.1.                      | Populations for Analysis 75                                                                             |
| 11.2.2.                      | Primary Endpoint 75                                                                                     |
| 11.2.3.                      | Secondary Endpoints 75                                                                                  |
| 11.2.4.                      | Exploratory Endpoints 76                                                                                |
| 11.2.5.                      | Adverse Events, Serious Adverse Events, and Deaths 76                                                   |
| 11.2.6.                      | Laboratory Results 77                                                                                   |  
| Neratinib Tablets (PB-272)                                                                                                                              | 03-FEB-2021                                                                                                                                                      |              |
|---------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------|
| PUMA-NER-5201                                                                                                                                           | AMENDMENT 7                                                                                                                                                      |              |
|                                                                                                                                                         |                                                                                                                                                                  |              |
| 12.                                                                                                                                                     | SAFETY DATA COLLECTION, RECORDING, AND REPORTING.....................78                                                                                          |              |
| 12.1.                                                                                                                                                   | Definitions .................................................................................................................................................78  |              |
| 12.1.1.                                                                                                                                                 | A Adverse Events .............................................................................................................................................78 |              |
| 12.1.2.                                                                                                                                                 | Abnormal Laboratory Results                                                                                                                                      |              |
| Serious Adverse Events ...........................................................................................................................79    |                                                                                                                                                                  |              |
| 12.1.3.                                                                                                                                                 | Hospitalization                                                                                                                                                  |              |
| 12.1.4.                                                                                                                                                 |                                                                                                                                                                  |              |
| 12.1.5.                                                                                                                                                 | Suspected Unexpected Serious Adverse Reaction ...........................................................80                                                      |              |
| 12.1.6.                                                                                                                                                 | Severity Assessment .......................................................................................................................80                    |              |
| Causality Assessment .....................................................................................................................81            |                                                                                                                                                                  |              |
| 12.1.7.                                                                                                                                                 |                                                                                                                                                                  |              |
| 12.1.8.                                                                                                                                                 | Special Reporting Situations                                                                                                                                     |              |
| 12.2.                                                                                                                                                   | Reporting Adverse Events .............................................................................................................82                         |              |
| 12.3.                                                                                                                                                   | Reporting Serious Adverse Events ..........................................................................................82                                    |              |
| Pregnancy ...........................................................................................................................................83 |                                                                                                                                                                  |              |
| 12.4.                                                                                                                                                   |                                                                                                                                                                  |              |
| 12.5.                                                                                                                                                   | Sponsor Reporting Requirements to Health Authorities and IRB/IEC ......................84                                                                        |              |
| ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS ........................................85                                                                   |                                                                                                                                                                  |              |
| 13.                                                                                                                                                     |                                                                                                                                                                  |              |
| 13.1.                                                                                                                                                   | Data Collection, Processing, and Monitoring                                                                                                                      |              |
| 13.1.1.                                                                                                                                                 | Case Report Forms and Source Documentation ..................................................................85                                                  |              |
| 13.1.2.                                                                                                                                                 | Study Monitoring and Access to Source Documentation ....................................................85                                                       |              |
| 13.1.3.                                                                                                                                                 | DATA QUALITY Assurance ................................................................................................................86                        |              |
| 13.1.4.                                                                                                                                                 | DATA Processing ..............................................................................................................................86                 |              |
| 13.1.5.                                                                                                                                                 | Retention of Data and Study Records                                                                                                                              |              |
| 13.2.                                                                                                                                                   | Ethical Aspects ...............................................................................................................................87                |              |
| Good Clinical Practice and Ethical Conduct of the Study.                                                                                                |                                                                                                                                                                  |              |
| 13.2.1.                                                                                                                                                 | Informed Consent Responsibilities                                                                                                                                |              |
| 13.2.2.                                                                                                                                                 |                                                                                                                                                                  |              |
| 13.3.                                                                                                                                                   | Other Study Administration Aspects .........................................................................................88                                   |              |
| 13.3.1.                                                                                                                                                 | Protocol Approval and Protocol Amendment..........................................................................88                                             |              |
| Investigator Responsibilities                                                                                                                           |                                                                                                                                                                  |              |
| 13.3.2.                                                                                                                                                 |                                                                                                                                                                  |              |
| 13.3.3.                                                                                                                                                 | Patient Confidentiality ....................................................................................................................89                   |              |
| 13.3.4.                                                                                                                                                 | Financial Disclosure ..............................................................................................................90                            |              |
| Publication Policy................................................................................................................90                    |                                                                                                                                                                  |              |
| 13.3.5.                                                                                                                                                 | REFERENCE LIST ..........................................................................................................................91                      |              |
| 14.                                                                                                                                                     |                                                                                                                                                                  |              |
| 15.                                                                                                                                                     | SIGNATURE PAGES ...............................................................................................................96                                |              |
| 16.                                                                                                                                                     | APPENDICES ..................................................................................................................................99                  |              |
|                                                                                                                                                         |                                                                                                                                                                  |              |
| Puma Biotechnology                                                                                                                                      | Page 15 of 120                                                                                                                                                   | CONFIDENTIAL |  
| APPENDIX 1                        | SCHEDULE OF PROCEDURES 100                             |
|-----------------------------------|--------------------------------------------------------|
| APPENDIX 2                        | EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG)              |
| PERFORMANCE STATUS 106            |                                                        |
| APPENDIX 3                        | INHIBITORS AND INDUCERS OF THE CYTOCHROME P450         |
| ISOENZYMES 107                    |                                                        |
| APPENDIX 4                        | SUBSTRATES AND INHIBITORS OF P-GLYCOPROTEIN (P-GP) 109 |
| APPENDIX 5                        | DRUGS ASSOCIATED WITH RISK OF QT/QTC PROLONGATION      |
| LEADING TO TORSADE DE POINTES 110 |                                                        |
| APPENDIX 6                        | RECIST V1.1 CRITERIA 112                               |
| APPENDIX 7                        | SPECIFIC GUIDANCE ON EGFR AND ERBB2 MUTATIONS 117      |
| APPENDIX 8                        | PATIENT-REPORTED HEALTH OUTCOMES ASSESSMENT            |
| (FACT-G): 119                     |                                                        |
table of contents
list of tables

| LIST OF TABLES   |                                                                                                                                                         |
|------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------|
| Table 1:         | Overall Response Rate (ORR), Disease Control (DC), Progression-free  Survival (PFS, Weeks), and Overall Survival (OS, Weeks) According to  Drug Type 33 |
| Table 2:         | Randomized Breast Cancer Cohort 39                                                                                                                      |
| Table 3:         | Non-randomized Breast Cancer Cohorts 40                                                                                                                 |
| Table 4:         | Cervical Cancer Cohort 40                                                                                                                               |
| Table 5:         | Cohorts Not Receiving Trastuzumab 40                                                                                                                    |
| Table 6:         | Investigational Product Administration Schedule 47                                                                                                      |
| Table 7:         | Dose Reduction Levels for Investigational Product-Related Toxicity 48                                                                                   |
| Table 8:         | General Toxicity Related to Neratinib and Requiring Dose Adjustmenta 49                                                                                 |
| Table 9:         | Diarrhea Related to Neratinib and Requiring Dose Adjustment 50                                                                                          |
| Table 10:        | Pulmonary Toxicity Related to Neratinib or Trastuzumab Requiring Dose  Adjustment 51                                                                    |
| Table 11:        | Dose Adjustment for Neratinib or Fulvestrant for Patients With Hepatic  Impairment 51                                                                   |
| Table 12:        | Liver Toxicity Requiring Dose Adjustment 52                                                                                                             |
| Table 13:        | Left Ventricular Ejection Fraction Toxicity Related to Trastuzumab  Requiring Dose Adjustment 53                                                        |
| Table 14:        | Symptomatic Cardiac Failure Toxicity Related to Neratinib or Trastuzumab  Requiring Dose Adjustment 53                                                  |
| Table 15:        | Infusion Reactions Related to Trastuzumab Requiring Dose Adjustment 53                                                                                  |  
Table 16: Loperamide Dosing for Neratinib Treatment .............................................................55  
| Table 17:   | Loperamide Dose Reduction Levels for Constipation 56   |
|-------------|--------------------------------------------------------|
| Table 18:   | Laboratory Parameters 64                               |
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list of figures

Figure 1: Frequency and Location of *ERBB2* Mutations in Cancer Biopsy Samples
(*ERBB2* Amplification and Mutations across Cancer Types) ....................................22 Figure 2: Frequency and Location of *ERBB2* Mutations in Cancer Biopsy Samples
(*ERBB2* Mutation Hotspots across Cancer Types).....................................................23  
| Figure 3:   | Distribution of EGFR Mutations in Lung Cancers (Aichi Cancer Center) 24                                                                                |
|-------------|--------------------------------------------------------------------------------------------------------------------------------------------------------|
| Figure 4:   | Distribution of EGFR Exon 18 Mutations (COSMIC Database) 24                                                                                            |
| Figure 5:   | Distribution of Mutations at Codons 709 and 719 in EGFR Exon 18  (COSMIC Database) 25                                                                  |
| Figure 6:   | Neratinib Monotherapy or Neratinib Plus Fulvestrant Displays Enhanced  Tumor Growth Inhibition in HER2+/ER+ Breast Patient-Derived Xenograft  Model 30 |
| Figure 7:   | Neratinib Monotherapy or Neratinib Plus Fulvestrant Displays Enhanced  Tumor Growth Inhibition in Breast Cell-Derived Xenograft Model 31               |  
Figure 8: Combined Treatment With Neratinib and Trastuzumab Has an Additive Effect in Reducing BT474 and SKBR3 Cell Numbers ..............................................33 Figure 9: Sensitivity of Ba/F3 Cells Expressing Exon 18 Mutations to Various EGFR
Tyrosine Kinase Inhibitors .........................................................................................34  
| Figure 10:   | Percent Change in Measurable Tumor for EGFR Mutation-Positive NSCLC  Patients Treated with Neratinib 35   |
|--------------|-----------------------------------------------------------------------------------------------------------|
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list of appendix tables

Table A1.1.Schedule of Study Procedures for Cohorts Receiving Trastuzumab Combination Therapy ...............................................................................................101 Table A1.2.Schedule of Study Procedures for Cohorts Not Receiving Trastuzumab.................104  
| Table A6.1.Evaluation Criteria 115 Table A7.1.Eligible ERBB2 Mutations 117 Table A7.2.Eligible EGFR exon 18 Mutations 118   |
|-----------------------------------------------------------------------------------------------------------------------------|
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list of abbreviations and definition

| LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ADL activities of daily living  ADR adverse drug reaction  AE adverse event ALT alanine aminotransferase ANC absolute neutrophil count ASCO American Society of Clinical Oncology  AST aspartate aminotransferase AUC area under the plasma drug concentration-versus-time curve; exposure BID twice a day BUN blood urea nitrogen C1D1 Cycle 1 Day 1 CBR clinical benefit rate cfDNA cell-free DNA CFR Code of Federal Regulations Cmax maximum plasma drug concentration CR complete response  CRF case report form CS clinically significant CT computerized tomography CTCAE Common Terminology Criteria for Adverse Events CYP cytochrome P450 enzyme DLT dose limiting toxicity DOR duration of response ECG electrocardiogram ECHO echocardiogram ECOG Eastern Cooperative Oncology Group EGFR epidermal growth factor receptor (also known as HER1) EIU exposure-in-utero EORTC European Organization for Research and Treatment of Cancer EOS end of study EOT end of treatment 18F-FDG 18F-fluorodeoxyglucose ER estrogen receptor ERBB human protein product of the ERBB gene (also known as HER) ERBB2 v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 EU European Union FLC fibrolamellar carcinoma GCP Good Clinical Practice Hb hemoglobin hCG human chorionic gonadotropin Hct hematocrit HER human epidermal growth factor receptor HR hormone receptor   |
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| PUMA-NER-5201      | AMENDMENT 7                                                                                |              |
|--------------------|--------------------------------------------------------------------------------------------|--------------|
| IB                 | Investigator's Brochure                                                                    |              |
| IC50               | concentration at which there is 50% inhibition                                             |              |
| ICF                | informed consent form                                                                      |              |
| ICH                | International Conference on Harmonisation or International Council for  Harmonisation      |              |
| IDMC               | Independent Data Monitoring Committee                                                      |              |
| IEC                | Independent Ethics Committee                                                               |              |
| IM                 | intramuscular(ly)                                                                          |              |
| IP                 | investigational product                                                                    |              |
| IRB                | Institutional Review Board                                                                 |              |
| ITT                | intent-to-treat; intention-to-treat                                                        |              |
| IV                 | intravenous(ly)                                                                            |              |
| LD                 | longest diameter                                                                           |              |
| LDH                | lactate dehydrogenase                                                                      |              |
| LLN                | lower limit of normal                                                                      |              |
| LV                 | left ventricle                                                                             |              |
| LVEF               | left ventricular ejection fraction                                                         |              |
| MDRD               | Modification of Diet in Renal Disease                                                      |              |
| MedDRA             | Medical Dictionary for Regulatory Activities                                               |              |
| mmHg               | millimeters mercury                                                                        |              |
| MRI                | magnetic resonance imaging                                                                 |              |
| MTD                | maximum tolerated dose                                                                     |              |
| MUGA               | multi-gated acquisition scan                                                               |              |
| NCI                | National Cancer Institute                                                                  |              |
| NCS                | not clinically significant                                                                 |              |
| NGS                | next-generation sequencing                                                                 |              |
| NOS                | not otherwise specified                                                                    |              |
| NSCLC              | non-small cell lung cancer                                                                 |              |
| ORR                | objective response rate                                                                    |              |
| ORRfirst           | objective response rate at the first post-baseline tumor assessment timepoint              |              |
| OS                 | overall survival                                                                           |              |
| PAC                | Picture Archival Communication                                                             |              |
| PB-272             | neratinib                                                                                  |              |
| PD                 | progressive disease                                                                        |              |
| PET                | positron emission tomography                                                               |              |
| PET/CT             | 18F-fluorodeoxyglucose positron emission tomography combined with  computerized tomography |              |
| PFS                | progression-free survival                                                                  |              |
| P-gp               | P-glycoprotein                                                                             |              |
| PI3K               | phosphoinositide-3 kinase                                                                  |              |
| PK                 | pharmacokinetic                                                                            |              |
| PLC                | phospholipase C                                                                            |              |
| PPI                | proton pump inhibitor                                                                      |              |
| PR                 | partial response                                                                           |              |
| QID                | four times a day                                                                           |              |
| Puma Biotechnology | Page 19 of 120                                                                             | CONFIDENTIAL |  
| PUMA-NER-5201   | AMENDMENT 7                                        |
|-----------------|----------------------------------------------------|
| QTc             | corrected QT interval                              |
| RANK            | receptor activator of nuclear factor kappa-B       |
| RAS             | rat sarcoma (family of ras genes)                  |
| RBC             | red blood cell                                     |
| RECIST          | Response Evaluation Criteria in Solid Tumors       |
| ROI             | region of interest                                 |
| RTK             | receptor tyrosine kinase                           |
| SAE             | serious adverse event                              |
| SAP             | statistical analysis plan                          |
| SC              | subcutaneous                                       |
| SD              | stable disease                                     |
| SOC             | system organ class                                 |
| SUL             | standard uptake value normalized by lean body mass |
| SUSAR           | suspected unexpected serious adverse reaction      |
| t1/2            | half-life                                          |
| TdP             | Torsade de Pointes                                 |
| TEAE            | treatment-emergent adverse event                   |
| TID             | three times a day                                  |
| TKI             | tyrosine kinase inhibitor                          |
| Tmax            | time to peak concentration                         |
| ULN             | upper limit of normal                              |
| US              | United States (of America)                         |
| WBC             | white blood cell                                   |
| WHO Drug        | World Health Organization Drug Reference List      |
| WT              | wild type                                          |
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1. introduction 1.1. the epidermal

The epidermal growth factor receptor (EGFR) class of receptor tyrosine kinases (RTKs)
comprises four receptor proteins encoded by four genes (in parentheses): EGFR (EGFR), *HER2* (ERBB2[Neu]), HER3 (*ERBB3*) and HER4 (*ERBB4*), together known as the HER protein family. Canonically, HER family proteins exist as inactive monomers until bound to ligand. Ligand binding prompts a conformational change and enables homodimerization or heterodimerization with another HER protein, leading to transphosphorylation and downstream signaling (reviewed by Yarden and Sliwkowski, 2001). EGFR binds to and is activated by a number of ligands, including EGF, TGFα, HB-EGF, amphiregulin, betacellulin, epiregulin, and epigen (Yarden and Sliwkowski, 2001; Jones et al, 1999). *HER3* and *HER4* bind to ligands in the neuregulin family, including heregulin (reviewed in Stove and Bracke, 2004). A ligand for *HER2* has not been identified; however *HER2* can still homodimerize (Ghosh et al, 2011; Peckys et al, 2015) and has been characterized as the preferred dimerization partner for EGFR and HER3 (Graus-Porta et al, 1997; Zaczek et al, 2005). In contrast, *HER3* does bind ligand, but lacks intrinsic kinase activity (Pinkas-Kramarski et al, 1996). Despite the lack of ligand binding and kinase activity in *HER2* and *HER3*, respectively, *HER2-HER3* heterodimers possess the most potent mitogenic activity among the HER family hetero- and homodimer combinations (Okines et al, 2011). Alterations within the HER family of RTKs have been reported in a number of tumor types. Oncogenic HER kinase alterations include receptor overexpression, elevated ligand levels, and somatic activating mutations. Sustained activation of HER signaling due to such alterations can result in oncogene or pathway-addicted tumors, and selective HER kinase inhibitors are now a component of standard treatment for several malignancies.
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1.1.1. somatic mutations in erbb2

Mutations in the *ERBB2* gene have been identified in multiple tumor types (Figure 1), and cluster primarily in the kinase domain at exons 19 and 20 (between amino acids 737-831) and the extracellular domain at exon 8 (amino acids 301-340) (Figure 2). The latter induce kinase activation by elevating C-terminal tail phosphorylation or by covalent dimerization via intermolecular disulfide bond formation (Greulich et al, 2012). Activating point mutations in the *ERBB2* gene that have been associated with primary breast cancer include but are not limited to amino acid positions G309, S310, R678, L755, D769, V777, V842, and E930. Activating insertions/deletions associated with breast cancer include but are not limited to L755_T759del, and 774-755 and 776 in-frame insertions. Activating mutations in the ERBB2 gene associated with colorectal cancer may include S310F, L755S, V777L, V842I, and L866M (Kavuri et al, 2015).  
Figure 1: Frequency and Location of *ERBB2* **Mutations in Cancer Biopsy Samples**  
  
(*ERBB2* Amplification and Mutations across Cancer Types)
Figure 2: Frequency and Location of *ERBB2* **Mutations in Cancer Biopsy Samples**  
  
(*ERBB2* **Mutation Hotspots across Cancer Types)**
Reference: Figures duplicated with permission from Dr. Solit (www.iom.edu/Activities/Disease/NCPF/2013-FEB11/Day%201/Session%204/17-Solit.aspx [accessed 21OCT2013]).
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1.1.2. somatic egfr exon 18

Somatic mutations in the *EGFR* kinase domain have been identified in approximately 40% and 17% of patients with NSCLC in Asian and American patients, respectively (Yatabe et al, 2015; Kris et al, 2014). EGFR exon 18 mutations, which are much less common, occur in 3-5% of all *EGFR*-mutant lung cancers (Kris et al, 2014; Cheng et al, 2015; Kobayashi et al, 2015; Lai et al, 2017). At the Aichi Cancer Center, mutation analyses of tumor samples identified 1,402 *EGFR* mutation-positive lung cancers (Kobayashi et al, 2015, Figure 3). Most tumors harbored mutations such as deletion of exon 19 (40%) or L858R (47%). Exon 18 mutations, comprising of G719X (n=41), E709X+G719X (n=1), and deletion of exon 18 (n=3), were present in 3.2% (n=45) of tumor samples.  
Figure 3:
Distribution of EGFR Mutations in Lung Cancers (Aichi Cancer Center)  
  
EGFR exon 18 mutations accounted for 4.1% of all EGFR mutations spanning from exons 18 through 21 from analysis of the publicly available COSMIC database (Kobayashi et al, 2015).  
Furthermore, mutations at codon 709 and 719 accounted for 84% of mutations in exon 18
(Figure 4). At codon 709, the delE709_T710insD mutation was the most frequently reported deletion, and the E709K and G719A mutations were the most frequent point mutations at codon 709 and 719, respectively (Figure 5).  
  
Figure 5: Distribution of Mutations at Codons 709 and 719 in *EGFR* **Exon 18**
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(cosmic database) 1.2. neratinib as

Neratinib (PB-272) is an orally available, small molecule, irreversible tyrosine kinase inhibitor (TKI) of EGFR, *ERBB2*, and *ERBB4*. Preclinical characterization showed that neratinib inhibits EGFR and *ERBB2* phosphorylation, downstream signaling, and cell growth in *EGFR*- and HER2-dependent cell lines, and decreased tumor formation in HER2-dependent xenograft models (Rabindran et al, 2004). A summary of preclinical studies, human pharmacokinetic studies, and previous clinical studies of neratinib for treatment of *HER2*+ breast cancer is provided in the Investigator's Brochure (Neratinib IB). On 17-JUL-2017, the United States (US) Food and Drug Administration (FDA) approved neratinib (NERLYNX™) for the extended adjuvant treatment of adult patients with early stage HER2-overexpressed/amplified breast cancer, to follow adjuvant trastuzumab-based therapy. On 25-FEB-2020, the FDA approved neratinib for use in combination with capecitabine, for the treatment of adult patients with advanced or metastatic *HER2+* breast cancer who have received two or more prior anti-*HER2* based regimens in the metastatic setting.
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1.2.2. neratinib treatment for erbb2

Several preclinical studies have shown utility of neratinib in *ERBB2*-mutant, tumor models. Survival of Ba/F3 cells transformed by *ERBB2* wild type (WT) or G309E, S310F, S310Y, S312G, or A775_G776insYVMA mutant alleles was inhibited by neratinib (Greulich et al, 2012). A seminal publication by Ron Bose and colleagues (Bose et al, 2013) identified 25 cases of breast cancer patients with *ERBB2* mutations reported in American Society of Clinical Oncology (ASCO) Group Z1031 Clinical Trial or The Cancer Genome Atlas (TCGA) Breast Cancer Database. Seven of these mutations, including five in the kinase domain (V777L, D769H, V842I,
L755S, L755_T759del), one in the extracellular domain (G309A), and one in the intracellular juxtamembrane region (R687Q) were introduced into MCF10A, MCF7, and NIH 3T3 cell lines using retroviral vectors. The V777L, D769H, and V842I mutants strongly increased ERBB2 autophosphorylation and substrate protein (phospholipase C1, PLC) phosphorylation relative to WT ERBB2. Modest increases in ERBB2, PLC, and EGFR phosphorylation were reported with G309A, L755S, and R678Q. ERBB2 L755_T759del showed a marked decrease in ERBB2 and PLC phosphorylation, but an increase in EGFR phosphorylation, suggesting that L755_T759del may have the ability to activate other ERBB family members. Soft agar growth of cells expressing these mutants with the tyrosine kinase inhibitors lapatinib or neratinib revealed that all mutants were sensitive to neratinib, even the lapatinib-resistant L755S and L755_T759del mutations (Bose et al, 2013). Examination of HER2-targeted therapies on the growth of colorectal cancer patient-derived xenografts harboring *ERBB2* mutations (S310Y, L866M, and V777L) showed that single agent therapy (trastuzumab, neratinib, or lapatinib) delayed tumor growth while dual HER2-targeted therapy with trastuzumab plus tyrosine kinase inhibitors caused tumor regression
(Kavuri et al, 2015).  
In summation, the preclinical experience suggests that cancer patients with solid tumors harboring activating *ERBB2* mutations could potentially benefit from treatment with neratinib.
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1.2.3. neratinib treatment for egfr

Neratinib has potent irreversible EGFR binding properties. EGFR exon 18 mutations, including G719, E709, and Del18 mutations, are observed less frequently (3%) in lung cancers and have poor response to first generation tyrosine kinase inhibitors (Kobayashi et al, 2015; Greulich et al, 2005). Preclinical studies suggest that *EGFR* exon 18 mutations display enhanced sensitivity to irreversible pan-HER inhibitors, including neratinib, as compared to approved benchmark EGFR TKIs including gefitinib and erlotinib (Kobayashi et al, 2015). Clinical responses to neratinib treatment have been previously reported in NSCLC patients harboring EGFR exon 18 mutations (Sequist et al, 2010). Here, we propose targeting these rare mutations in non-small cell lung cancer patients that may not benefit from currently approved EGFR TKIs.
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1.3. neratinib phase 1 and

Clinical pharmacokinetic (PK) results from the first-in-human study with ascending single and multiple doses in subjects with cancer showed that absorption of neratinib was slow with time to peak concentration (Tmax) ranging from 3-6.5 hours post dose. After single or multiple daily oral doses of neratinib with food, the maximum plasma drug concentration (Cmax) and the area under the plasma concentration-versus-time curve (AUC) increased with increasing dose. Furthermore, no major accumulation was observed when comparing Day 14 exposure with Day 1 exposure following once-daily dosing of neratinib 240 mg and 360 mg with food. The mean half-life (t1/2) following a single dose on Day 1 ranged from 8 to 17 hours, which supports once-daily dosing of neratinib. Fecal excretion of radiolabeled neratinib accounted for approximately 97% of the total dose administered and is the major route of elimination. Data suggested no sex-related effect on the PK profile of neratinib (Neratinib IB). Data from a Phase 1 dose-escalation study in patients with advanced solid tumors demonstrated the safety and feasibility of once-daily oral treatment with neratinib. The maximum tolerated dose (MTD) was initially determined to be 320 mg. The higher frequency of high-grade diarrhea for subjects who received neratinib 320 mg in a subsequent Phase 2 study (46.2% at 320 mg daily vs 22.7% at 240 mg daily) led to the decision to reduce the recommended dose for neratinib to 240 mg (Neratinib IB).  
In healthy subjects, a high-fat meal increased neratinib peak and total exposure (Cmax and AUCinf) by approximately 2-fold, and a standard breakfast increased neratinib exposure by 13%-17%, compared with exposure under fasting conditions (Neratinib IB).  
Neratinib, a substrate of cytochrome P450 enzyme (CYP), is susceptible to interaction with potent CYP3A4 inducers or inhibitors such as rifampin and ketoconazole, respectively. In a clinical study in healthy subjects, exposures of neratinib were substantially reduced when neratinib was coadministered with rifampin. Ketoconazole was found to increase exposure to neratinib by ~481% in healthy subjects. Nonclinical in vitro experiments indicate that neratinib inhibits the transport of P-glycoprotein (P-gp) substrates, which may decrease the clearance of drugs that are P-gp substrates. This P-gp interaction of neratinib would only be clinically relevant for P-gp substrate drugs with a narrow therapeutic window, such as digoxin. In a study with healthy subjects, neratinib was not associated with prolongation of the QTc interval at either the 240 mg daily dose of neratinib with food or under conditions of supratherapeutic plasma concentrations (neratinib 240 mg with ketoconazole 400 mg) (Neratinib IB). The solubility of neratinib is pH dependent and treatments that alter gastrointestinal pH, such as proton pump inhibitors (PPIs), H2-receptor antagonists, and antacids may lower the solubility of neratinib. Once-daily doses of lansoprazole, a PPI, administered with a single dose of neratinib to healthy subjects resulted in decrease of neratinib Cmax by 71% and AUC by 65% compared with when neratinib was administered alone; there was a delay in tmax of 1.5 hours. The potential PK interaction of H2-receptor antagonists with neratinib has not been evaluated. It is unknown whether separating PPI or H2-receptor antagonist and neratinib doses reduce the interaction. If antacids are necessary, the antacid dose and the neratinib dose should be separated by 3 hours
(Neratinib IB). In clinical studies conducted in patients with advanced tumors who received neratinib 240 mg daily with weekly paclitaxel 80 mg/m2, the PK data analysis suggested no meaningful differences in neratinib or paclitaxel exposure when administered as monotherapy compared with exposure when neratinib and paclitaxel were administered in combination (Study 3144A21115-JA and 3144A1-203-WW; Neratinib IB). In a clinical study conducted in women with advanced ERBB2-positive breast cancer who received neratinib 240 mg daily in combination with trastuzumab (a loading dose of 4 mg/kg, followed by 2 mg/kg weekly thereafter), the PK data analysis suggested no interactions between neratinib and trastuzumab (Study 3144A1-202- WW; Neratinib IB).
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1.4. adverse event profile of

In neratinib monotherapy (240 mg/day) studies conducted in patients with early-stage HER2-positive, or locally advanced, or metastatic solid malignancies, the most frequently reported treatment-emergent adverse events (TEAEs) were associated with gastrointestinal disorders, and included diarrhea, nausea, abdominal pain, and vomiting (Neratinib IB). In the Phase 3 Study 3144A2-3004-WW, in the extended adjuvant breast cancer setting, the intent-to-treat (ITT) population consisted of a total of 2840 subjects (1420 subjects in each arm) who had early stage HER2-positive breast cancer and had received prior adjuvant trastuzumab. The safety sample consisted of subjects who received at least 1 dose of study drug (neratinib or placebo), 1408 subjects in each arm. Subjects had a median age of 52 years (range, 23 to 83 years). Prophylactic loperamide was not mandated.  
In the neratinib arm (N = 1408), Grade 3 TEAEs were reported for 684 (48.6%) patients and Grade 4 TEAEs for 15 (1.1%) patients. The most commonly reported Grade 3 TEAEs were diarrhea (561 subjects, 39.8%), vomiting (47 subjects, 3.3%), nausea (26 subjects, 1.8%), abdominal pain (24 subjects, 1.7%), and fatigue (23 subjects, 1.6%). The most common (>5%) adverse drug reactions (ADRs) occurring in patients receiving neratinib monotherapy are diarrhea, nausea, abdominal pain, abdominal pain upper, fatigue, vomiting, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased, nail disorder, dry skin, abdominal distension, and urinary tract infection (see Neratinib IB). In the placebo arm (N = 1408), Grade 3 TEAEs were reported for 169 (12.0%) patients and Grade 4 TEAEs for 14 (1.0%) patients. The most commonly reported Grade 3 TEAEs were diarrhea (23 subjects, 1.6%) and electrocardiogram QT prolonged (7 subjects, 0.5%). During Study 3144A2-3004-WW, cardiac associated adverse events (AEs) were reported in 10.5% of subjects in the neratinib arm and 12.9% of subjects in the placebo arm. In contrast to treatment with other HER2-targeted agents, such as trastuzumab, 4 patients treated with neratinib reported nonserious Grade 3 AEs pertaining to left ventricular ejection fraction (LVEF). Three out of the 4 neratinib-treated patients had LVEF ≤50% that resolved after treatment interruption, and 1 patient had an absolute decrease of 9% from baseline of 54% to 45% that resolved after treatment discontinuation. One patient who discontinued due to LVEF decreased had comorbidities of Grade 1 diarrhea and Grade 3 hyperglycemia prior to the event. Interstitial lung disease, which can sometimes be fatal, has been reported with other oral tyrosine kinase inhibitors that target EGFR and/or HER2, including lapatinib, gefitinib, and erlotinib. Rare cases of pneumonitis, which was considered to be drug related according to the Investigator's assessment, have been reported in clinical studies of neratinib. Patients receiving neratinib should be monitored for acute onset or worsening of pulmonary symptoms such as dyspnea, cough, and fever, and treated appropriately. Neratinib clinical safety data show no consistent pattern of hematologic toxicity and no biologic mechanism has been currently defined. In Study 3144A2-3004-WW neratinib monotherapy arm, treatment-emergent serious adverse events (SAEs) that occurred in more than 4 patients were diarrhea (22 patients, 1.6%); vomiting (12 patients, 0.9%); dehydration (9 patients, 0.6%); cellulitis (6 patients, 0.4%); and erysipelas (5 patients, 0.4). Grade 4 ALT increased, and AST increased was reported for 3 (0.2%) patients each. Refer to the most recent version of the IB for a summary of findings from nonclinical studies that potentially have clinical significance and from clinical studies that are relevant to the study (Neratinib IB). Also, refer to the IB for a summary of the known and potential risks and benefits to human patients.
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1.5. rationale for proposed combination

This open-label, multicenter, multinational, Phase 2 study has a basket design and as such it is predicated on the hypothesis that the presence of a molecular marker predicts response to the investigational products (Mandrekar et al, 2015). In addition to the typical "basket" cohorts, identified mainly by mutation, this study includes cohorts recognizing the role of tumor histology, especially in the case of combination therapies. These cohorts are defined by tumor type and actionable mutations. The tumor type, the mutation and the combination therapy are identified prospectively, with patients assigned in a nonrandomized way to a specific treatment arm. As a result, the study is composed of multiple parallel "small' Phase 2 trials, with the cohorts defined by histology and mutations enrolling patients following a Simon's design based on response. During the conduct of the study, cohorts may be closed and new ones may be opened in new histologies, new molecular abnormalities and/or different treatment strategies may be examined based on data emerging from the trial itself, from other neratinib trials, or from clinical or preclinical data generated by the Sponsor or reported in literature. The following sections will discuss the rationale of patient selection on the basis of mutations and the rationale for the use of diverse therapeutic approaches in the different cohorts. Recent clinical studies have shown that dual inhibition of HER2, such as the combination of lapatinib and trastuzumab or trastuzumab and pertuzumab, is more effective than trastuzumab treatment alone (Baselga et al, 2012; Swain et al, 2013; Gianni et al, 2012). The rationale underlying the combination therapies in the lung, colon, and breast cancer cohorts is essentially to overcome the resistance due to oncogenic switches (Erjala et al, 2006) with dual ERBB blockade (neratinib and trastuzumab in lung, breast and colon cancer) or a blockade of a second oncogenic pathway (neratinib and fulvestrant in hormone receptor positive breast cancer). Notably, trastuzumab is effective in patients with advanced ERBB2-mutated lung cancer (Mazieres et al, 2016) and the combination of trastuzumab and lapatinib, another anti-EGFR TKI, was recently reported as effective in colorectal cancer (Siena et al, 2015). In addition, taxanes are extensively used with the anti-HER2 trastuzumab in breast cancer; clinical data suggest that their anticancer activity may be enhanced by ERBB mutations (Park et al, 2012).
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1.5.1. rationale for treatment with

The 'cross-talk' between the estrogen and HER2 receptors has been previously reported, with HER2 amplification resulting in reduced estrogen-receptor signaling (De Laurentiis et al, 2005; Dowsett et al, 2001). HER2 overexpression increases the aggressiveness of breast cancer cells, lowering their response to endocrine therapies and resulting in a poorer prognosis. A review of patients with HER2 overexpression who were treated with fulvestrant suggested these patients may receive benefit from dual HER2-ER targeting (Charif et al, 2014). Endocrine responsiveness may also be limited by resistance potentially due to upregulation of HER2/*EGFR* signaling. Preclinical evidence suggests that combining fulvestrant and an *EGFR* blocker may be an effective anti-tumor strategy in HER2-overexpressing/positive cells
(Emde et al, 2011). Therapies aimed at inhibiting the 'cross-talk' between ER and HER2 using combinations of endocrine and HER2-directed therapies to overcome any potential ER signalling resistance mechanisms have been shown to improve anti-tumor efficacy compared to single agent treatments alone in preclinical studies. For example, in HER2+/ER+ breast cancer patientderived xenograft (Figure 6) and cell-derived xenograft models (Figure 7), the combination of neratinib plus fulvestrant resulted in significant inhibition of tumor growth compared to single agent treatments (internal Puma data). Figure 6: **Neratinib Monotherapy or Neratinib Plus Fulvestrant Displays Enhanced**  
  
Tumor Growth Inhibition in HER2+/ER+ Breast Patient-Derived Xenograft Model Figure 7: **Neratinib Monotherapy or Neratinib Plus Fulvestrant Displays Enhanced**  
  
Tumor Growth Inhibition in Breast Cell-Derived Xenograft Model A retrospective chart analysis of 85 patients with metastatic breast cancer treated with fulvestrant with and without the HER2 antibody treatment, trastuzumab, was recently conducted by Charif et al (2014); 13% of patients had documented HER2+ primary tumors that were treated with both fulvestrant and trastuzumab. The combination was associated with a longer clinical response (median duration of therapy 772 days [51-1911]) than HER2 negative patients who received fulvestrant alone (median duration of therapy 360 days [60-2739]), suggesting that trastuzumab may help overcome resistance to fulvestrant (Charif et al, 2014).
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1.5.1.1. adverse event profile of

Few clinical studies have explored the combination of fulvestrant with tyrosine kinase inhibitors in the clinical setting. Lapatinib was combined with fulvestrant in a randomized Phase 3 trial in patients with metastatic estrogen receptor (ER) positive, HER2+ breast cancer resistant to aromatase inhibitors (Burstein et al, 2014). The combination of fulvestrant plus lapatinib exhibited an overall response rate of 20% compared to 9% in the fulvestrant plus placebo arm alone. The combination regimen did not appear to decrease the tolerability of either agent alone. In the Phase 3 ExteNET study (NCT00878709), in a pre-specified subgroup analysis in the hormone receptor positive cohort in which >93% received concurrent hormone therapy, an enhanced neratinib benefit in improving disease free survival was observed (Chan et al, 2015). Diarrhea was the most common AE in neratinib-treated patients with 40% of patients reporting Grade 3 diarrhea (1 patient reported Grade 4 diarrhea). Other individual AEs ≥Grade 3 occurred in <4% of neratinib-treated patients. LVEF decrease ≥Grade 2 was seen in 1.3% of neratinib-treated patients vs. 1.1% of placebo-treated patients. The mean relative dose intensity was 88% in neratinib-treated patients vs. 98% in placebo-treated patients. As of the data cutoff date of 01-MAY-2017 for the Neratinib IB, there were 27 patients with ERBB2 mutant breast cancer in the neratinib+fulvestrant combination therapy cohort of Study PUMA-NER-5201. At least 1 TEAE of Grade 1 to Grade 4 was reported for 25 (92.6%) patients. In this cohort, the most commonly reported (≥20% incidence) TEAEs of Grade 1 to 4 were: diarrhea (20 patients, 74.1%); nausea (10 patients, 37.0%); and constipation and decreased appetite (7 patients, 25.9%, each). Diarrhea was the only Grade 3 TEAE that occurred in more than 1 patient (3 patients, 11.1%). No TEAEs of Grade 4 or 5 were reported (Neratinib IB). No new safety signals from the neratinib+fulvestrant combination cohort have been observed. Preclinical studies have shown that neratinib did not alter the mRNA or activity levels of any cytochrome P450 enzyme (CYP) studies at concentrations 7 times that of the 240 mg dose used in clinical trials. Based on these in vitro findings, it is improbable that neratinib will be involved in induction mediated drug-drug interactions with concomitant medications that are metabolized by CYP1A2, CYP2B6, CYP3A4 or CYP2C9. Given that fulvestrant is metabolized by CYP3A4, neratinib is unlikely to be involved in any drug-drug interactions with fulvestrant.
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1.5.2. rationale for treatment with

For HER2-positive breast cancer, there has been a focus in recent years to develop therapeutic agents to potentiate the effect of trastuzumab on target cells that have become resistant to trastuzumab. Preclinical evidence suggest that co-inhibition of HER2, other members of the HER family and/or the downstream pathway by giving trastuzumab/lapatinib in combination with other targeted therapies might prevent or at least prolong time to resistance and treatment failure (Baselga, 2010; O'Donovan et al, 2011).  
There is clinical evidence that dual HER2 blockade with trastuzumab in combination in women with metastatic HER2-positive breast cancer resulted in significant clinical benefit in a heavily pre-treated population (prior exposure to trastuzumab, lapatinib, T-DM1, a taxane, and multiple lines of chemotherapy; Jankowitz et al, 2013). Additionally in the clinic, lapatinib in combination with trastuzumab significantly improved overall survival and progression-free survival compared to lapatinib alone despite disease progression on prior trastuzumab-based therapy (Blackwell et al, 2010; Blackwell et al, 2012). The combination of neratinib and trastuzumab had a greater growth inhibitory effect than either drug alone in both HER2 over-expressing cell lines and cell lines that had acquired resistance to trastuzumab (Canonici et al, 2013; Figure 8). This result also held true in the mouse BT474 xenograft model. The xenograft experiment showed that the combination treatment lead to the greatest decrease in pHER2 with decreased activation of pAkt and pERK, correlating with increased efficacy compared to the single agents (Mazieres et al, 2016). These examples support the notion that dual blockade using combination therapy is more effective than treatment with trastuzumab alone under conditions where HER2 is over-expressed/amplified; the same approach may also work in a setting where *ERBB2* is mutated. Figure 8: **Combined Treatment With Neratinib and Trastuzumab Has an Additive**  
  
Effect in Reducing BT474 and SKBR3 Cell Numbers Table 1: **Overall Response Rate (ORR), Disease Control (DC), Progression-free**
Survival (PFS, Weeks), and Overall Survival (OS, Weeks) According to Drug Type  
| Treatment                                                                                                             | n             | ORR   | DC    | PFS median     | OS median        |
|-----------------------------------------------------------------------------------------------------------------------|---------------|-------|-------|----------------|------------------|
| (95% CI)                                                                                                              | (95% CI)      |       |       |                |                  |
| First-line; without HER2-targeting treatment                                                                          | 93            | 43.5% | 70.7% | 6 (5; 7.1)     | 24 (19.1; 36.4)  |
| Second-line; without HER2-targeting  treatment                                                                        | 52            | 10%   | 36%   | 4.3 (3.1; 5)   | 19.4 (9.6; 24.7) |
| EGFR-TKIa                                                                                                             | 26            | 7.6%  | 26.8% | 2.99           | 20.14            |
| (1.87; 4.47)                                                                                                          | (7.14; 32.95) |       |       |                |                  |
| Trastuzumab combination, T-DMIa                                                                                       | 58            | 50.9% | 75.5% | 4.8 (3.4; 6.5) | 13.3 (8.1; 15)   |
| Neratinib, lapatinib, and afatiniba                                                                                   | 29            | 7.4%  | 55.5% | 3.4 (2.4; 4)   | 6.5 (4.7; 30.6)a |
| a If the same drug has been given more than one time, the results presented here are from their first administration. |               |       |       |                |                  |
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1.5.3. adverse event profile of

Dual blockade with trastuzumab and neratinib was assessed in a Phase 1/2 clinical trial to determine the MTD and safety of the combination in patients with advanced breast cancer (Study 3144A1-202-WW, Neratinib IB). In Part 1 of the study, 4 patients received neratinib 160 mg and 4 patients received neratinib 240 mg in combination with trastuzumab 4 mg/kg as a loading dose and trastuzumab 2 mg/kg weekly thereafter. No dose limiting toxicity (DLT) was reported. In Part 2, all 37 patients received neratinib 240 mg in combination with trastuzumab 4 mg/kg as a loading dose and trastuzumab 2 mg/kg weekly thereafter. No MTD was defined for this study because no DLT was reported. All 45 patients (100.0%) in the safety population reported at least 1 AE. The most commonly reported TEAEs of Grade 1 to 4 were diarrhea (42 patients, 93.3%), nausea (23 patients, 51.1%), decreased appetite (22 patients, 48.9%), vomiting (18 patients, 40.0%), and asthenia (13 patients, 28.9%). Grade 3 TEAEs that occurred in more than 1 patient were diarrhea (7 patients, 15.6%);
and nausea, vomiting, AST increased, and dyspnea (2 patients, 4.4% each). Grade 4 TEAEs of metastases to the central nervous system and hyperbilirubinemia were reported for 1 patient each. Grade 5 TEAE of disease progression was reported for 1 patient. Based on the above safety data and the low risk of drug-drug interactions with the combination of trastuzumab and neratinib, the risk of additional toxicities using a single 8 mg/kg loading dose followed by 6 mg/kg every 3 weeks is small.
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1.6. rationale for treatment with

In a preclinical study, NIH-3T3 cells transfected with EGFR exon 18 mutations (Del18, E709K, and G719A) were observed to form foci with marked pile-up (Kobayashi et al, 2015). This indicated that EGFR Del18, E709K, and G719A were oncogenic drivers. Furthermore, Ba/F3 cells transfected with EGFR exon 18 mutations (Del18, E709K, and G719A) exhibited higher sensitivity to neratinib (25-fold for G719A, 5-fold for E709K, and by comparable extent for Del18) compared to control cells (Kobayashi et al, 2015). Compared with various EGFR tyrosine kinase inhibitors, including irreversible pan-HER TKIs (eg, afatinib), neratinib demonstrated the most sensitivity for blocking cell proliferation in exon 18 mutant Ba/F3 cells in vitro (Figure 9; Kobayashi et al 2015).
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figure 9 sensitivity of ba/f3

Tyrosine Kinase Inhibitors  
In a Phase 2 trial of neratinib in patients with advanced NSCLC who previously benefited from first-generation TKI and developed acquired resistance, it was ascertained that a response to neratinib was observed in patients harboring the *EGFR* exon 18 G719X point mutation
(Sequist et al, 2010; Figure 10). Three of the 4 patients harboring G719X mutations had a partial response and the fourth had SD that lasted for 40 weeks (PFS: 52.7 weeks, 90% CI: 25.6 to 57 weeks). It was noted that one of the patients who demonstrated a partial response and the patient with SD had transitioned from receiving erlotinib (due to lack of treatment response) to neratinib.  
Figure 10: Percent Change in Measurable Tumor for *EGFR* **Mutation-Positive NSCLC**  
  
Patients Treated with Neratinib More recently, the incidence and natural epidemiology of lung cancer patients with tumors harboring *EGFR* exon 18 mutations were reviewed at Memorial Sloan Kettering Cancer Center to better understand the clinical-pathological characteristics and outcomes to TKI therapy (Lai et al, 2017). Patients with *EGFR* exon 18 mutations appeared to have a shorter median overall survival (OS; 22 months vs. 31 months) when compared to patients with more common sensitizing *EGFR* mutations (Lai et al, 2017). The above preclinical and clinical results suggest that NSCLC patients with tumors harboring EGFR exon 18 mutations may benefit with neratinib monotherapy. Part of the primary objective of this study will be to determine whether neratinib monotherapy induces tumor regression in NSCLC patients with tumors harboring *EGFR* exon 18 mutations.
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2. study objectives 2.1. primary

The primary objectives of this study, applicable to each cohort, are:
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for the randomized hormone receptor

- To determine the confirmed objective response rate (ORR) by independent central review according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
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for the metastatic cervical cancer

- To determine the confirmed ORR by independent central review according to RECIST v1.1
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for all other cohorts

- To determine the first objective response rate (ORRfirst) by investigator at the first post-baseline tumor assessment 2.2. **Secondary Objectives** The secondary objectives of this study, applicable to each cohort, are:
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for the randomized hormone receptor

- To determine the confirmed ORR by investigator  
- To determine the duration of response (DOR) by both independent central review and investigator
- To determine the clinical benefit rate (CBR) by both independent central review and investigator
- To determine the progression-free survival (PFS) by both independent central review and investigator
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for the metastatic cervical cancer

- To determine the confirmed ORR by investigator  
- To determine the DOR by both independent central review and investigator
- To determine the CBR by both independent central review and investigator
- To determine the PFS by both independent central review and investigator - To determine overall survival (OS)
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for all other cohorts

- To determine the confirmed ORR by investigator  
- To determine the DOR by investigator
- To determine the CBR by investigator  
- To determine the PFS by investigator
- To determine OS
For all cohorts including the randomized HR+, *HER2* negative metastatic breast cancer and metastatic cervical cancer cohorts, the safety objectives are:
- To assess the safety profile and tolerability of study treatments  
- To assess Patient Reported Outcomes (PRO)
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2.3. exploratory objectives

For all cohorts including the randomized HR+, *HER2* negative metastatic breast cancer and metastatic cervical cancer cohorts, the exploratory objectives are:  
- To collect and retrospectively evaluate somatic mutations or gene aberrations using next-generation sequencing (NGS) in the most recent pretreatment tumor biopsy or fresh tumor tissue biopsies at a central laboratory.  
- To explore genetic modifiers of sensitivity and/or resistance to neratinib using molecular profiling techniques in pretreatment archival and/or fresh tumor specimens and paired normal whole blood.  
- To evaluate cell-free DNA (cfDNA) from plasma specimens collected at baseline/screening, during the course of treatment, and upon disease progression to identify *HER2* and *EGFR* mutations and other gene aberrations and to assess any potential associations with neratinib sensitivity and/or primary/acquired resistance to neratinib or neratinib-containing therapy.  
- To evaluate potential genes or protein biomarkers that may be reported to confer neratinib sensitivity and/or primary/acquired resistance to neratinib or neratinibcontaining therapy from *optional* fresh core tumor biopsies during time of treatment and/or at the time of treatment discontinuation or disease progression.
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3. overall design and plan

This is an open-label, multicenter, multinational, Phase 2 study exploring the efficacy and safety of neratinib as monotherapy or in combination with other therapies in patients with HER (*EGFR*, HER2) mutation-positive solid tumors. Patients with tumors harboring somatic mutations in HER will be identified through previously documented mutation testing performed prior to screening. The presence of human HER mutations (EGFR, *HER2*) will be retrospectively confirmed by central testing NGS sequencing. The study has a basket design and includes several cohorts, either defined by an actionable somatic mutation or by actionable mutation and tumor histology (for example *HER2* mutant cervical cancer). In the course of the study, enrollment in certain cohorts can be completed and enrollment in new cohorts initiated to test the anticancer effect of neratinib in other histologies, specific molecular abnormalities and/or in combination with other drugs. Patients with *HER2* mutant, *HER2* negative breast cancer will be divided into different treatment cohorts on the basis of HR status: HR negative (Triple Negative Breast Cancer [TNBC]) and HR+.  
- Patients in the HR negative cohort (TNBC) will receive neratinib in combination with trastuzumab (Table 3).  
- Patients in the HR+, *HER2* negative, *HER2* mutant breast cancer cohort with RECIST
measurable tumors and who have been previously treated with CDK4/6 inhibitors (CDK4/6i) will be randomized to receive single agent fulvestrant, fulvestrant in combination with trastuzumab, or neratinib in combination with trastuzumab and fulvestrant with a randomization ratio of 1:1:1. Randomization will be stratified by the number of lines of prior therapy for metastatic disease (≤ 2 and >2 lines) and prior fulvestrant therapy (Table 2).  
- The randomized HR-positive (HR +), *HER2* negative, *HER2* mutant metastatic breast cancer cohort is designed to investigate the individual contribution of neratinib and/or trastuzumab to fulvestrant via Simon's 2 stage optimal design. The decision to carry over on enrollment of each arm in the cohort will be based on stage I and II analysis of Simon's 2 stage in consultation with the Independent Data Monitoring Committee
(IDMC).  
− Patients in the HR+ cohort who receive single agent fulvestrant or fulvestrant plus trastuzumab will be eligible for triplet therapy (neratinib, fulvestrant, trastuzumab) upon progression. Patients who have unequivocal evidence of disease progression as documented by imaging, clinical examination, or disease related symptoms before the first scan post-treatment are eligible for the triplet therapy. Efficacy will be determined based on response to initial regimen only.  
- Patients in the HR+ cohort who have not received prior CDK4/6i therapy (eg.  
CDK4/6i naïve) will receive neratinib in combination with trastuzumab and fulvestrant as part of an open label cohort (Table 3).
The cervical cancer cohort and cohorts not receiving trastuzumab are summarized in Table 4 and Table 5, respectively. The trial will consist of a screening period, a treatment period, and a follow-up period after the study therapy is discontinued for any reason. An end of treatment (EOT) assessment is performed 28 days (+14 days) after the last dose of investigational product(s) and adverse events are collected 28 days after the last dose of investigational product(s). Neratinib will be administered orally with food once daily (recommended to be taken in the morning), on a continuous basis. Dose delays and modifications will be handled as per instructions in the package insert. All patients taking neratinib will maintain a patient diary for the study to record each dose of neratinib taken and while receiving antidiarrheal prophylaxis with loperamide taken for the first two cycles of treatment. For cohorts receiving combination treatment that includes trastuzumab, post-treatment radiographic evaluation of their disease will be conducted every 3 cycles. For all other cohorts, post-treatment disease assessment will be conducted every 2 cycles. Treatment should be administered until there is unequivocal evidence of disease progression as documented by imaging, clinical examination, or disease-related symptoms. Tumor markers or circulating tumor cells should not be used as the sole criteria for determining progression. At the time of decision regarding disease progression, radiological exam should be performed. Patients will continue on study treatment until disease progression, unacceptable toxicity, patient withdrawal of consent, or death. Patients who develop disease progression, but in the opinion of the Investigator would still benefit from continuing study, may continue on per-protocol therapy if approved by the Sponsor. Survival follow-up will be every 12 weeks after treatment discontinuation. Enrollment will continue as dictated by the Simon's 2-stage design in all the histology and mutation specific cohorts and/or up to 30 patients per cohort in multi-cancer, mutation specific NOS cohorts. Enrollment in the randomized breast cancer, non-randomized breast cancer and cervical cancer cohorts will also continue as dictated by the Simon's 2-stage design up to 50 patients per cohort.  
Table 2: Randomized Breast Cancer Cohort  
| Cohort                                     | Mutation                                                                          | Randomized Treatment                                                              | Sample Size (#   |
|--------------------------------------------|-----------------------------------------------------------------------------------|-----------------------------------------------------------------------------------|------------------|
| Tumor                                      | subjects)                                                                         |                                                                                   |                  |
| -                                          | Fulvestrant: 500 mg IM on Study Day 1, 15, and  29; once every 28 days thereafter |                                                                                   |                  |
| Or                                         | -                                                                                 | Fulvestrant: 500 mg IM on Study Day 1, 15, and  29; once every 28 days thereafter |                  |
| -                                          | Trastuzumab: 8 mg/kg IV followed by 6 mg/kg  IV every 3 weeks                     |                                                                                   |                  |
| Or                                         | -                                                                                 | Neratinib: 240 mg PO daily                                                        |                  |
| -                                          | Fulvestrant: 500 mg IM on Study Day 1, 15, and  29; once every 28 days thereafter |                                                                                   |                  |
| -                                          | Trastuzumab: 8 mg/kg IV followed by 6 mg/kg  IV every 3 weeks                     | Up to 18                                                                          |                  |
| Breast HR  Positive  (with prior  CDK4/6i) | Up to 18                                                                          |                                                                                   |                  |
| HER2  mutant                               | Up to 50                                                                          |                                                                                   |                  |
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table 3 non-randomized breast cancer

| Tumor                                 | Mutation                                                      | Assigned Treatment                                                                | Cohort                     |
|---------------------------------------|---------------------------------------------------------------|-----------------------------------------------------------------------------------|----------------------------|
| Cohort                                | Sample Size (#  subjects)                                     |                                                                                   |                            |
| Breast HR  Positive  (CDK4/6i  naïve) | HER2                                                          | -                                                                                 | Neratinib: 240 mg PO daily |
| mutant                                | -                                                             | Fulvestrant: 500 mg IM on Study Day 1, 15, and  29; once every 28 days thereafter |                            |
| -                                     | Trastuzumab: 8 mg/kg IV followed by 6 mg/kg  IV every 3 weeks | Up to 50                                                                          |                            |
| Breast TNBC  (HR                      |                                                               |                                                                                   |                            |
| Negative)                             | HER2                                                          | -                                                                                 | Neratinib: 240 mg PO daily |
| mutant                                | -                                                             | Trastuzumab: 8 mg/kg IV followed by 6 mg/kg  IV every 3 weeks                     | Up to 50                   |
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table 4 cervical cancer cohort

| Tumor    | Mutation                  | Assigned Treatment   | Cohort                     |    |
|----------|---------------------------|----------------------|----------------------------|----|
| Cohort   | Sample Size (#  subjects) |                      |                            |    |
| Cervical | HER2                      | -                    | Neratinib: 240 mg PO daily | 50 |
| mutant   |                           |                      |                            |    |
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table 5 cohorts not receiving

| Tumor Cohort   | Mutation                | Assigned Treatment   |                            |
|----------------|-------------------------|----------------------|----------------------------|
| Salivary Gland | HER2 mutant             | -                    | Neratinib: 240 mg PO daily |
| Non-small Cell | EGFR exon 18  mutations | -                    | Neratinib: 240 mg PO daily |
| Lung           |                         |                      |                            |
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tumor cohorts closed to enrollment

The following cohorts were closed to enrollment in Amendment 7: solid tumors (NOS) *HER2* mutant treated with neratinib monotherapy and *HER2* mutant bladder/urinary tract cancer treated with neratinib + paclitaxel.  
The approximate duration of the study is 90 months and approximate duration for patient's participation is 18 months. The end-of-study (EOS) is defined as the last visit of the last patient or the completion of any/all follow-up monitoring and data collection described in the protocol (ie, survival). The EOS will occur when all patients have been followed for OS or death, withdrawal of consent, or are lost to follow-up. The Sponsor reserves the right to terminate the study early for any reason and offer patients receiving treatment benefit the option to continue to receive neratinib via a separate treatment extension study or an expanded access protocol.
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3.2. randomization and blinding

Patients in the HER2-negative, *HER2* mutant, HR positive breast cancer cohort with RECIST measurable tumors who have previously been treated with CDK4/6 inhibitors (CDK4/6i) will be randomized to receive single agent fulvestrant, fulvestrant in combination with trastuzumab, or neratinib in combination with trastuzumab and fulvestrant with a randomization ratio of 1:1:1. Randomization will be stratified by the number of lines of prior therapy for metastatic disease (≤ 2 and >2 lines) and by prior exposure to fulvestrant.  
Randomization will be suspended after the 21st patient unless the decision has been made previously to drop any cohort earlier for futility/safety, and further patients will be enrolled into the T+N+F arm until the 'final' decision on expansion into the second stage has been made, randomization has been reintroduced (if 2 or 3 cohorts remain) or sufficient data are present to reconvene with the Independent Data Monitoring Committee (IDMC). For all other cohorts, this is an open-label, single arm study.
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4. study population 4.1. inclusion

Each patient will be entered into this study only if she/he meets all of these criteria:  
1. Men and women who are ≥18 years old at signing of informed consent. 2. At the time of screening, histologically confirmed cancers in patients with previously documented activating *EGFR (exon 18)* or qualifying *HER2* mutation confirmed by a Clinical Laboratory Improvement Amendments (CLIA)-certified or equivalent laboratory, and who are refractory to standard therapy or for which standard or curative therapy does not exist or is not considered sufficient or appropriate.  
3. At least one measurable lesion, as defined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1; Eisenhauer et al, 2009).  
4. Left ventricular ejection fraction (LVEF) ≥50% measured by multiple-gated acquisition scan (MUGA) or echocardiogram (ECHO).  
5. Eastern Cooperative Oncology Group (ECOG) status of 0 to 2. 6. Female patients with cancers known to secrete β-human chorionic gonadotropin (hCG),
ie germinomas, are eligible if the pattern of serum β-hCG is suggestive of the malignancy and the pelvic ultrasound is negative for pregnancy.  
7. Male patients must agree and commit to use a barrier method of contraception while on treatment and for 3 months after the last dose of trastuzumab, fulvestrant, or neratinib monotherapy. Patients of child-bearing potential must agree and commit to the use of a highly effective double-barrier method of contraception (eg, a combination of male condom with an intravaginal device such as the cervical cap, diaphragm, or vaginal sponge with spermicide) or a non-hormonal method, from the signing of the informed consent until:
i. 28 days after the last dose of neratinib monotherapy, or ii. 7 months after last dose of trastuzumab or iii. 1 year after the last dose of fulvestrant.  
8. Provide written, informed consent to participate in the study and follow the study procedures.  
9. Agree to provide most recent metastatic tumor sample or fresh tumor biopsy, and plasma/blood specimens for gene sequencing and other biomarker analysis.
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additional inclusion criteria for all

10. Must provide a pretreatment fresh biopsy within 28 days prior to starting treatment unless the biopsy procedure presents a safety concern for the patient as determined by the Investigator, or other exceptional reason upon agreement with the Sponsor
Additional Inclusion Criteria for HR+ Breast Cancer Patients with Tumors that Harbor *HER2* Mutations 11. HR+ disease defined as ≥1% estrogen receptor (ER) positive and/or progesterone receptor (PR) positive cells (performed on the most recent biopsy as assessed locally and consistent with current American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) or European Society of Medical Oncology (ESMO) guidelines):  
12. Biopsy from a non-bony metastatic site: preferred, or a. Biopsy from bony metastasis or if the sample is considered inadequate or unavailable:
assessment of HR status will be at the Investigator's discretion.  
13. Postmenopausal, as defined by at least one of the following criteria:
a. Age ≥60 years; b. Age <60 years and cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; and serum estradiol and follicle stimulating hormone (FSH) level within the laboratory's reference range for postmenopausal females; c. Documented bilateral oophorectomy, 14. Medically confirmed ovarian failure
OR
15. Pre/perimenopausal, ie, not meeting the criteria for being postmenopausal:  
a. Pre/perimenopausal women can be enrolled if amenable to be treated with a luteinizing hormone receptor hormone (LHRH) agonist. Patients must have commenced treatment with an LHRH agonist at least 4 weeks prior to the first dose of neratinib.
16. Prior treatment with chemotherapy or hormonal therapy (including fulvestrant).
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4.2. exclusion criteria

A patient will be excluded from this study if she/he meets any of these criteria:  
1. Patients harboring ineligible somatic *HER2* mutations, such as those that are subclonal in nature or those resulting in the expression of truncated proteins including alterations that result in premature stop codon or a change in reading frame (ie, frame shift mutations).  
2. Prior treatment with any pan-HER-, HER2-, or *EGFR* tyrosine kinase inhibitor (TKI)
(eg, lapatinib, afatinib, dacomitinib, neratinib, tucatinib, poziotinib, gefitinib, erlotinib, osimertinib) is excluded with the following exception: patients with *EGFR* exon 18 mutated NSCLC who may have received afatinib, osimertinib, or other pan-HER or EGFR TKIs remain eligible.  
3. Not recovered to at least Grade 1 at screening (Common Terminology Criteria for Adverse Events v4.0 [CTCAE v4.0]) from all clinically significant adverse events related to prior therapies (excluding alopecia).  
4. Received chemotherapy or biologic therapy ≤2 weeks or 5 half-lives (t½) of the agent used, whichever is shorter, prior to the initiation of investigational product.  
5. Received radiation therapy ≤14 days prior to initiation of investigational product. 6. Patients who are receiving any other anticancer agents with the exception of patients on 1) a stable dose of bisphosphonates or denosumab or 2) sex hormone therapy in the case of breast, or gynecological cancers.  
7. Received prior therapy resulting in a cumulative epirubicin dose >900 mg/m2or cumulative doxorubicin dose >450 mg/m2. If another anthracycline or more than one anthracycline has been used, the cumulative dose must not exceed the equivalent of 450 mg/m2doxorubicin.  
8. Symptomatic or unstable brain metastases. (Note: Asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for at least 14 days are eligible to participate in the study.)
9. Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure
(New York Heart Association functional classification of ≥2), unstable angina (symptomatic angina pectoris within the past 180 days that required the initiation of or increase in anti-anginal medication or other intervention), myocardial infarction within 12 months of enrollment, or ventricular arrhythmia (except for benign premature ventricular contractions).  
10. Demonstrates a QTc interval >450 ms for men or >470 ms for women or known history of congenital QT-prolongation or Torsade de pointes (TdP).  
11. Inadequate bone marrow, renal or hepatic function as defined on screening laboratory assessments outside the following limits:  
| Laboratory endpoint                                                      | Required limit for exclusion                                                                             |
|--------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------|
| Absolute neutrophil count                                                | <1,000/µL (1.0 x 109 /L)                                                                                 |
| (ANC)  Platelet count                                                    | <100,000/µL (<100 x 109 /L)                                                                              |
| Hemoglobin                                                               | <8 g/dL (transfusion allowed to treat low hemoglobin) Transfusion must be at least 7 days prior to C1D1. |
| Total bilirubin                                                          | >1.5 x institutional upper limit of normal (ULN) (in case of  known Gilbert's syndrome, >2x ULN)         |
| Aspartate aminotransferase  (AST) and/or alanine  aminotransferase (ALT) | >3 x institutional ULN  OR >5 x ULN if liver metastases are present                                      |
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laboratory assessments endpoints

| PUMA-NER-5201       | AMENDMENT 7                  |
|---------------------|------------------------------|
| Laboratory endpoint | Required limit for exclusion |
| Creatinine          | >1.5 x institutional ULN OR Calculated Creatinine Clearance <30 mL/min (as measured  directly with a 24-hour urine or calculated by CockcroftGault formula a or Modification of Diet in Renal Disease  [MDRD] formula b )                              |  
a Cockcroft and Gault, 1976. b Levey et al, 1999.  
12. Active infection or unexplained fever >38.5°C (101.3°F). 13. Women who are pregnant, are planning on becoming pregnant, or are breast-feeding.  
14. Significant chronic gastrointestinal disorder with diarrhea as a major symptom (eg, Crohn's disease, malabsorption, or Grade ≥2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events Version 4.0 [CTCAE version 4.0] diarrhea of any etiology at baseline).  
15. Clinically active infection with a hepatitis virus. 16. Evidence of significant medical illness, abnormal laboratory finding, or psychiatric illness/social situations that could, in the Investigator's judgment, make the patient inappropriate for this study.  
17. Known hypersensitivity to any component of the investigational product, required combination therapy, or loperamide.  
18. Unable or unwilling to swallow tablets.
19. Patients with known activating *KRAS* mutations.  
Additional Exclusion Criteria for Patients with Breast Cancer With *HER2* Mutations  
20. Patients with known *HER2*+ tumors (protein overexpression or gene amplification as defined by ASCO/CAP guidelines or HER2 amplifications as determined by copy number alterations by NGS) are excluded.
Additional Exclusion Criteria for Patients With *HER2* Mutations Treated With Trastuzumab Combination Therapy or Being Randomized into HR+ Breast Cancer Cohorts 21. Hypersensitivity to trastuzumab, murine proteins or any of the excipients listed in the Herceptin label.  
22. Severe dyspnea at rest due to complications of advanced malignancy or requiring supplementary oxygen therapy.
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4.3. patient enrollment

Enrollment will occur only after the patient has given written informed consent, all screening assessments have been completed, and the patient meets all eligibility criteria.
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4.4. cohort assignment

Patients will be assigned to cohorts based on tumors harboring somatic mutations in *EGFR* or HER2 identified through previously documented mutation testing performed prior to screening and by the tumor type and approved by the Sponsor (Appendix 7). Mutation status of a tumor should be documented using molecular assays available at study sites (Appendix 7).
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5. investigational product and administration

The investigational product administration schedule is outlined in Table 6, and is described in the subsections below. For patients enrolled to a *HER2*-mutant bladder cohort treated with neratinib in combination with paclitaxel reference Protocol Amendment 6/6.1 for paclitaxel investigational product administration details.  
| Study Drug                                                                                                      | Total Initial Dose                                                                   | Administration           | Dosing Schedule                                                                                                              |
|-----------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------|--------------------------|------------------------------------------------------------------------------------------------------------------------------|
| Neratinib                                                                                                       | 240 mg                                                                               | Oral (PO) 6 x 40 mg      | Daily, continuously                                                                                                          |
| tablets                                                                                                         |                                                                                      |                          |                                                                                                                              |
| Fulvestranta                                                                                                    | 500 mg                                                                               | IM 2 x 250 mg injections | Days 1, 15, and 29; then once  every 4 weeks thereafter; see  Schedule of Procedures,  Appendix 1 Table A1.1 and Table A1.2. |
| Trastuzumabb                                                                                                    | 8 mg/kg on C1D1,                                                                     | IV                       | C1D1 then                                                                                                                    |
| then 6 mg/kg                                                                                                    | once every 3 weeks  thereafter; see Schedule of  Procedures, Appendix 1 Table  A1.1. |                          |                                                                                                                              |
| a Dosing schedule will include a window of ±2 days. For dosing outside the window, the Medical Monitor needs to |                                                                                      |                          |                                                                                                                              |  
Trastuzumabb 8 mg/kg on C1D1, then 6 mg/kg IV C1D1 then once every 3 weeks thereafter; see Schedule of Procedures, Appendix 1 Table A1.1.  
a Dosing schedule will include a window of ±2 days. For dosing outside the window, the Medical Monitor needs to be informed. For rate of administration, premedication, treatment of infusion reactions, and for dose adjustments, consult the label of fulvestrant . For patients with hepatic impairment defined by the Childs-Turcott-Pugh Class B criteria, the dose of fulvestrant should be reduced to 250 mg as one 5 mL injection on the same schedule.  
b Dosing schedule will include a window of ±7 days. For dosing outside the window, the Medical Monitor needs to be informed. If rounding is necessary, trastuzumab should be rounded to the nearest 20 mg. Infusion of trastuzumab should be performed in accordance with local guidelines and/or prescribing information, consult the label of trastuzumab.
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5.1.1. neratinib

Neratinib is self-administered as six 40-mg tablets (total daily dose 240 mg) orally, once daily with food (recommended to be taken in the morning), continuously. Daily dosing should continue until a criterion for treatment withdrawal is met (see Section 9.1).
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5.1.2. fulvestrant

Patients receiving fulvestrant (see Table 2) will receive 500 mg total dose of fulvestrant administered as two 5 mL intramuscular (IM) injections, one in each buttock, on Day 1, 15, and 29; then once every 4 weeks thereafter (Appendix 1 Table A1.1 and Table A1.2). For patients with hepatic impairment defined by the Childs-Turcott-Pugh Class B criteria, the dose of fulvestrant should be reduced to 250 mg as one 5 mL injection on the same schedule. Dosing should continue until a criterion for treatment withdrawal is met (see Section 9.1).
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5.1.3. trastuzumab

Patients receiving trastuzumab combination therapy (see Table 2) will receive an initial dose of 8 mg/kg of trastuzumab IV administered on C1D1, followed by 6 mg/kg IV once every 3 weeks thereafter (Appendix 1 Table A1.1 and Table A1.2). Trastuzumab infusion should be interrupted in all patients experiencing significant signs/symptoms, and intervention of medical therapy should be administered, which may include epinephrine, corticosteroids, diphenhydramine, bronchodilators, and oxygen. Patients should be evaluated and carefully monitored until complete resolution of signs and symptoms. Permanent discontinuation should be strongly considered in all patients with severe infusion reactions (follow Herceptin [trastuzumab] package insert). Dosing should continue until a criterion for treatment withdrawal is met (see Section 9.1).
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5.2. investigational product dose adjustment

Dose adjustment and/or discontinuation for fulvestrantand trastuzumab should follow dosing guidelines provided in Section 5.3.1 through Section 5.3.3 and the respective country-approved label. If, in the opinion of the investigator, the patient will be discontinued from combination therapy with fulvestrant or trastuzumab but may benefit from neratinib single agent, patient may remain on study after consulting the medical monitor. Recommended dose reductions for the -1 and -2 dose levels are listed in Table 7.  
If doses of the IPs are held, study procedures for that cycle will proceed on schedule as planned, without any delay. This also applies to tumor assessments, which should continue as per cohort schedule regardless of any changes in dose or occurrence of AEs. Missed dose(s) of IPs (ie, any dose that is not administered within the protocol-defined administration window; Table 6) will not be made up. Note: **Patients should take one dose of neratinib per calendar day.**  
| Study Drug               | Initial Dose   | Dose Level -1   | Dose Level -2   |
|--------------------------|----------------|-----------------|-----------------|
| Neratinib                | 240 mg         | 160 mg          | 120 mg          |
| Fulvestrant              | 500 mg         | 250 mg          | NA              |
| NA                       | NA             |                 |                 |
| for the remaining cycles |                |                 |                 |  
The dose adjustment guidelines represent the minimum set of measures the Investigator must follow. However, additional measures may be taken, as necessary, for certain patients per the Investigator's medical judgment. All dose modifications/adjustments should be documented in the patient's source file. If other toxicities are observed, consult the approved country label and the medical monitor. Once a dose has been reduced for a patient, all subsequent cycles must be administered at that dose, unless further dose reduction is required. Dose re-escalation will only be permitted if explicitly approved in advance by the Sponsor. Evidence of this approval must be contained within the patient's source file. Patients should discontinue IP if a criterion for withdrawal is met (see Section 9.1). Detailed rules for dose adjustments of IP in case of toxicity, including the dose levels to which IP should be adjusted, are provided in Table 8 to Table 15. For infusion reactions requiring dose adjustment, follow the country-approved label for trastuzumab as appropriate.
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table 8 general toxicity related

| NCI CTCAE v.4.0b                                                      | Action with Neratinib                                                                               |                                                                                                                                                                                               |                                                                                    |
|-----------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------|
| Grade 2 adverse reaction  - 1st appearance -                          | Hold neratinib until event resolves to Grade ≤1; then resume neratinib at the  starting dose level. |                                                                                                                                                                                               |                                                                                    |
| -                                                                     | 2nd appearance                                                                                      | -                                                                                                                                                                                             | Hold neratinib until event resolves to Grade ≤1; then resume neratinib at  160 mg. |
| -                                                                     | 3rd appearance                                                                                      | -                                                                                                                                                                                             | Hold neratinib until event resolves to Grade ≤1; then resume neratinib at 120  mg. |
| -                                                                     | 4th appearance                                                                                      | -                                                                                                                                                                                             | Discontinue neratinib permanently.                                                 |
| Grade 3 adverse reaction - 1st appearance                             | -                                                                                                   | Hold neratinib until event resolves to Grade ≤1; then resume neratinib at  160 mg.                                                                                                            |                                                                                    |
| -                                                                     | 2nd appearance                                                                                      | -                                                                                                                                                                                             | Hold neratinib until event resolves to Grade ≤1; then resume neratinib at  120 mg. |
| -                                                                     | 3rd appearance                                                                                      | -                                                                                                                                                                                             | Discontinue neratinib permanently.                                                 |
| Grade 4 adverse reaction - 1st appearance                             | -                                                                                                   | Discontinue neratinib permanently OR if Investigator deems it to be in the  patient's best interest to continue, hold neratinib until resolved to Grade ≤1;  then resume neratinib at 160 mg. |                                                                                    |
| -                                                                     | If the event occurs again despite one dose reduction, permanently discontinued  neratinib.          |                                                                                                                                                                                               |                                                                                    |
| a For fulvestrant and trastuzumab, follow the country-approved label. |                                                                                                     |                                                                                                                                                                                               |                                                                                    |
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table 9 diarrhea related to

| Table 9:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Diarrhea Related to Neratinib and Requiring Dose Adjustment  NCI CTCAE V4.0 Action with Neratinib                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |                                                                                                                                                                              |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade 1 Diarrhea [Increase of <4 stools per day  over baseline; mild increase in ostomy output  compared to baseline.]  OR  Grade 2 Diarrhea [Increase of 4-6 stools per day  over baseline; moderate increase in ostomy output  compared to baseline;] lasting <5 days  OR  Grade 3 Diarrhea [Increase of ≥7 stools per day  over baseline; incontinence; hospitalization  indicated; severe increase in ostomy output  compared to baseline limiting self-care activities of  daily living (ADL)] lasting <2 days | -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | Adjust anti-diarrheal treatment, as per the guidelines  for management of diarrhea at the first onset of  diarrhea. Continue neratinib at full dose. (see  Section 6.1.2.1 ) |
| -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Instruct patient to follow dietetic recommendations in  the guidelines for management of diarrhea (see  Section 6.1.2.1 for dietetic measures)                                                                                                                                                                                                                                                                                                                                                                                                                           |                                                                                                                                                                              |
| -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Fluid intake of ~2L should be maintained to avoid  dehydration.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |                                                                                                                                                                              |
| -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Once the event resolved to ≤ Grade 1 or baseline,  continue loperamide as per the guidelines for  management of diarrhea at the first onset of diarrhea.  Continue neratinib at full dose. (see Section 6.1.1)                                                                                                                                                                                                                                                                                                                                                           |                                                                                                                                                                              |
| Persisting and intolerable Grade 2 Diarrhea lasting >5 days despite being treated with optimal  medical therapy, or associated with fever,  dehydration, or Grade 3-4 neutropenia OR  Grade 3 Diarrhea lasting > 2 days despite being  treated with optimal medical therapy, or associated  with fever, dehydration, or Grade 3-4 neutropenia                                                                                                                                                                       | -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | Adjust anti-diarrheal treatment, as per the guidelines  for management of diarrhea at the first onset of  diarrhea. (see Section 6.1.2.1 pharmacological  treatment)         |
| -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Hold neratinib until recovery to ≤ Grade 1 or baseline.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                                                                                                                                                              |
| -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Instruct patient to follow dietetic recommendations of  the guidelines for management of diarrhea (see  Section 6.1.2.1 for dietetic measures)                                                                                                                                                                                                                                                                                                                                                                                                                           |                                                                                                                                                                              |
| -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Fluid intake of ~2L should be maintained,  intravenously if needed.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |                                                                                                                                                                              |
| -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | If diarrhea resolves to Grade 0-1:  - ≤1 week after withholding treatment, resume  same dose of neratinib.  - Within 1-4 weeks after withholding treatment,  reduce neratinib dose to the next lower dose level.  - If event occurs a 2nd time and the neratinib dose  has not already been decreased, reduce neratinib dose to the next lower dose level. - If subsequent events occur, reduce neratinib dose  to the next lower dose level.  - Once the event resolved to ≤Grade 1 or baseline,  start loperamide 4 mg with each subsequent  neratinib administration. |                                                                                                                                                                              |
| Any Grade 4 diarrhea [Life-threatening                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | Permanently discontinue neratinib                                                                                                                                            |
| consequences; urgent intervention indicated]                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |                                                                                                                                                                              |  
Table 10: **Pulmonary Toxicity Related to Neratinib or Trastuzumab Requiring Dose**
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adjustment

| NCI CTCAE V4.0                                                                                                            | Action with Neratinib                                                                            | Action with Trastuzumab                                 |                                                                               |                                      |
|---------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------|---------------------------------------------------------|-------------------------------------------------------------------------------|--------------------------------------|
| Grade 2 Pneumonitis/Interstitial  Lung Disease [Symptomatic;  medical intervention indicated;  limiting instrumental ADL] | -                                                                                                | Hold neratinib until recovery to ≤ Grade 1 or baseline. |                                                                               |                                      |
| -                                                                                                                         | Reduce neratinib to 160 mg or discontinue neratinib as per Investigator's best medical judgment. | -                                                       | Hold trastuzumab until recovery to ≤ Grade 1 or baseline; then resume dosing. |                                      |
| Grade 3 Pneumonitis/Interstitial  Lung Disease [Severe symptoms;  limiting self-care ADL; oxygen  indicated]             | -                                                                                                | Discontinue neratinib permanently                       | -                                                                             | Discontinue trastuzumab permanently. |  
Table 11: Dose Adjustment for Neratinib or Fulvestrant for Patients With Hepatic
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impairment

| LIVER FUNCTION              | Action with Neratinib   | Action with Fulvestrant                                                  |    |                                                                  |
|-----------------------------|-------------------------|--------------------------------------------------------------------------|----|------------------------------------------------------------------|
| TOXICITY                    |                         |                                                                          |    |                                                                  |
| Childs-Turcott-Pugh Class A | -                       | No dose adjustment required.                                             | -  | Continue 500 mg                                                  |
| Childs-Turcott-Pugh Class B | -                       | No dose adjustment required.                                             | -  | Reduce dose to 250 mg on same schedule of administration         |
| Childs-Turcott-Pugh Class C | -                       | Reduce starting dose to 80 mg in patients with severe hepatic impairment | -  | No data in this patient population; consult with medical monitor |  
| Table 12:                                                                                                                                              | Liver Toxicity Requiring Dose Adjustment                                                                                                                                                                                                                                                                                                                                                            |                                                                                                                                                        |                         |                             |                             |
|--------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------|-----------------------------|-----------------------------|
| NCI CTCAE                                                                                                                                              | Action with                                                                                                                                                                                                                                                                                                                                                                                         | Action with                                                                                                                                            | Action with Trastuzumab |                             |                             |
| V4.0                                                                                                                                                   | Neratinib                                                                                                                                                                                                                                                                                                                                                                                           | Fulvestrant                                                                                                                                            |                         |                             |                             |
| Grade 3  ALT/AST (>5-20x  ULN) OR  Grade 3  bilirubin  (>3-10x  ULN)                                                                                   | -                                                                                                                                                                                                                                                                                                                                                                                                   | Hold neratinib until recovery to ≤ Grade 1 for patients with ALT/AST ≤ Grade 1 at baseline OR ≤ Grade 2 for patients with Grade 2 ALT/AST at baseline. |                         |                             |                             |
| -                                                                                                                                                      | Evaluate alternative causes.                                                                                                                                                                                                                                                                                                                                                                        |                                                                                                                                                        |                         |                             |                             |
| -                                                                                                                                                      | For patients with ALT/AST ≤ Grade 1 at baseline: resume neratinib at the next lower dose level if recovery to ≤Grade 1 occurs within 4 weeks. If Grade 3 ALT, AST or bilirubin occurs again despite one dose reduction, permanently discontinue neratinib. For patients with Grade 2 ALT/AST at baseline due to liver metastases: contact the Sponsor for guidance on appropriate dose adjustments. | Refer to Table 11.                                                                                                                                     | -                       | No dose adjustment required |                             |
| Grade 4  ALT/AST (>20x ULN) OR Grade 4  Bilirubin (>10x ULN)                                                                                           | -                                                                                                                                                                                                                                                                                                                                                                                                   | Permanently discontinue neratinib.                                                                                                                     |                         |                             |                             |
| -                                                                                                                                                      | Evaluate alternative causes.                                                                                                                                                                                                                                                                                                                                                                        | -                                                                                                                                                      | Permanently discontinue |                             |                             |
| -                                                                                                                                                      | Evaluate alternative causes                                                                                                                                                                                                                                                                                                                                                                         | -                                                                                                                                                      | Permanently discontinue |                             |                             |
| -                                                                                                                                                      | Evaluate alternative causes                                                                                                                                                                                                                                                                                                                                                                         |                                                                                                                                                        |                         |                             |                             |
| ALT/AST >3x ULN AND Total bilirubin >2x ULN AND Alkaline phospatase <2x ULN (potential  Hy's Law  indicators of  drug-induced  liver damage)           | -                                                                                                                                                                                                                                                                                                                                                                                                   | Hold neratinib.                                                                                                                                        |                         |                             |                             |
| -                                                                                                                                                      | The patient should return to the investigational site and be evaluated by clinical laboratory tests as soon as possible, preferably within 48 hours from awareness of the abnormal results.                                                                                                                                                                                                         | -                                                                                                                                                      | No dose adjustment required unless ChildsTurcott-Pugh Class B criteria met                         | -                           | No dose adjustment required |
| -                                                                                                                                                      | Contact the Sponsor immediately to discuss next steps, including evaluation of alternative causes, and management of IP.                                                                                                                                                                                                                                                                            |                                                                                                                                                        |                         |                             |                             |
| -                                                                                                                                                      | These events must be reported as SAEs.                                                                                                                                                                                                                                                                                                                                                              |                                                                                                                                                        |                         |                             |                             |
| NOTE: During evaluation of hepatotoxicity, bilirubin must be fractionated, prothrombin time must be measured,  and liver imaging should be considered. |                                                                                                                                                                                                                                                                                                                                                                                                     |                                                                                                                                                        |                         |                             |                             |  
| Absolute Decrease from Baseline                                                                               |          |          |       |
|---------------------------------------------------------------------------------------------------------------|----------|----------|-------|
| Relationship of LVEF to LLN                                                                                   | <10%     | 10%-15%  | >16%  |
| Within normal limits                                                                                          | Continue | Continue | Holda |
| 1% - 5% below LLN                                                                                             | Continue | Holda    | Holda |
| >6% below LLN                                                                                                 | Continue | Holda    | Holda |
| a Repeat LVEF assessment after 4 weeks. If criteria for continuation were met, trastuzumab is resumed. If not |          |          |       |
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table 13 left ventricular ejection

| NCI CTCAE V4.0              | Action with Neratinib             | Action with Trastuzumab            |
|-----------------------------|-----------------------------------|------------------------------------|
| Symptomatic cardiac failure | Neratinib should be discontinued. | Trastuzumab should be discontinued |
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table 15 infusion reactions related

| NCI CTCAE V4.0             | Action with Trastuzumab                                                                                                                                                                                                                                       |                                                                       |
|----------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------|
| Grade 1 / 2                | -                                                                                                                                                                                                                                                             | Decrease the rate of infusion for mild to moderate infusion reaction. |
| Hypersensitivity reactions | -                                                                                                                                                                                                                                                             | Interrupt the infusion if necessary.                                  |
| -                          | Treat as per institutional policy. Patients should be evaluated and carefully  monitored. When symptoms resolve to ≤ Grade 1, infusion may be resumed  (maintain dose) later that day at a slower rate or on the next day at slower  rate with premedication. |                                                                       |
| -                          | Premedication should be used for all subsequent treatments.                                                                                                                                                                                                   |                                                                       |
| Grade 3 Severe infusion    | -                                                                                                                                                                                                                                                             | Discontinue trastuzumab infusion permanently.                         |
| reactions                  |                                                                                                                                                                                                                                                               |                                                                       |
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5.3. packaging labeling and storage

Detailed packaging information is available in the study manual. The IPs will be labeled according to local regulations.
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5.3.1. neratinib

Neratinib will be supplied as 40-mg film-coated tablets packaged in opaque, plastic bottles with desiccant and a child-proof lid. Neratinib will be stored at 25°C (77°F) or below with desiccant; do not freeze. Excursions are permitted to 30°C (86°F). Neratinib should be stored in a secure location with limited access. Patients should be instructed to store neratinib in a safe place at room temperature.
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5.3.2. fulvestrant

The Sponsor may provide commercial supply of fulvestrant, labeled for clinical trial use. Clinical sites that are not allowed to accept commercially available product may utilize their own commercial supply. The pharmaceutical form of fulvestrant is clear, colorless to yellow, viscous solution. Pre-filled syringe of fulvestrant should be stored in the original packaged container to protect from light in refrigerator at (2C-8C).  
The commercially available fulvestrant is supplied in two clear Type 1 glass pre-filled syringe presentation.
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5.3.3. trastuzumab

The Sponsor may provide commercial supply of trastuzumab vials labeled for clinical trial use. Clinical sites that are not allowed to accept commercially available product may utilize their own commercial supply. Trastuzumab is supplied as a lyophilized sterile powder to be reconstituted for IV infusion. Trastuzumab should be stored in a refrigerator at (2C-8C).
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5.4. drug accountability

The study site must maintain accurate records documenting dates and quantities of IP received from the Sponsor. Records must be maintained on a per-patient basis documenting dates and quantities of IP dispensed and returned at the beginning and end of each visit. Any IP accidentally or deliberately destroyed must be documented. Records also must be maintained of all IPs received and dispensed such that the amount of IP present within the pharmacy is accurate at any point in time against this record. Reconciliation will be made throughout the study between the amounts of IP supplied, dispensed, returned, and subsequently destroyed or returned to Sponsor. All IPs will be returned to Sponsor or its representative or destroyed at the site in accordance with local standard operating procedures, as specified in writing by the Sponsor. Individual patient dosing compliance should be reviewed at each study visit by study site staff. If patient noncompliance is noted, the patient should be re-instructed regarding proper dosing procedures in order to continue in the study. If repeated noncompliance is noted, additional steps may be taken, including withdrawal of the patient from the study (see Section 9.2).
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6. concomitant treatment

All combination therapies, concomitant treatments, non-drug interventions, and medications will be captured from the signing of the informed consent form (ICF) until the end of the treatment (EOT). This will include the start date, stop date, generic name, route of administration, dose, frequency and indication for treatment. At screening, patients will be asked which medications are ongoing at the time of screening, any medical conditions that require medication, and all prior cancer therapies. At each subsequent study visit, patients will be asked what concomitant medications they are currently taking or have taken since their last visit.
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6.1. required concomitant treatment

Diarrhea is the major dose-limiting toxicity of neratinib with onset typically occurring during the first few weeks of treatment. In particular, after the implementation of diarrhea prophylaxis with loperamide, most episodes of Grade 3 diarrhea occur during the first cycle of therapy (Neratinib IB; Ustaris et al, 2015). Primary prophylactic use of antidiarrheal medication is mandatory for all enrolled patients taking neratinib. Loperamide is the recommended standard therapy to prevent and treat diarrhea in this study. If alternative antidiarrheal medication is proposed, this should be discussed with the Medical Monitor and the reason documented in the source documents. Second-line antidiarrheal treatments and adjunctive therapies (ie, diphenoxylate hydrochloride and atropine sulfate [Lomotil], or octreotide [SANDOSTATIN
®]) (or equivalent, as approved by the Sponsor) are also recommended for use when appropriate.
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6.1.1. loperamide

All patients receiving neratinib will take loperamide for the first 2 cycles of neratinib treatment. Patients will take 4 mg three times a day (TID) on Days 1-14 of Cycle 1 with the first dose of loperamide given concomitantly with the first dose of neratinib. After two weeks on study, patients will take loperamide 4 mg twice a day (BID) until the completion of Cycle 2 (42 days for trastuzumab containing regimens and 56 days for non-trastuzumab-containing regimens). Thereafter, loperamide will be administered as needed throughout neratinib treatment. Recommended loperamide dosing is listed below in Table 16. Patients randomized to fulvestrant or fulvestrant and trastuzumab will not be required to take loperamide.  
| Loperamide Dose                                    | Day                                                                                           |
|----------------------------------------------------|-----------------------------------------------------------------------------------------------|
| 4 mg TID with a total daily dose of 12 mg          | Days 1-14                                                                                     |
| 4 mg BID with a total daily dose of 8 mg           | Days 15-end of Cycle 2                                                                        |
| Daily dose as needed (not to exceed 16 mg per day) | Day 42+ for trastuzumab-containing  regimens Day 56+ for non-trastuzumab-containing  regimens |  
Patients must use a diary to record intake of loperamide during the first 2 cycles. Loperamide pill counts will be conducted only during the first 28 days of therapy.